Practical Pulmonary Pathology 3rd ed. Kevin O. Leslie, MD

Chapter 15. Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

Mark R. Wick, MD, Kevin O. Leslie, MD, and Mark H. Stoler, MD

Primary malignant pleuropulmonary tumors showing sarcomatoid features are exceedingly uncommon. Overwhelmingly, such lesions are typically epithelial in nature; neoplasms with a mesenchymal lineage in the lung and pleura are most often proven to be secondary, emanating from deep soft tissue sites or the female genital tract. In fact, because of the rarity of this category of pleuropulmonary malignancies, relatively few data exist in the literature regarding the morphologic or clinical details of such lesions. Hence, one can correctly anticipate that most pulmonologists, oncologists, radiologists, and pathologists are unfamiliar with intrathoracic tumors composed of spindled and pleomorphic cells.

This chapter summarizes the clinicopathologic information pertaining to such lesions. It devotes exclusive attention to malignant lesions; benign mesenchymal neoplasms of the lung and pleura are discussed in Chapter 19. “Pseudotumors” are likewise considered in another portion of this book. Nevertheless, those pathologic categories and other lesions will indeed be mentioned here in the context of differential diagnosis. The entities that are discussed are arranged in order of frequency, to give the reader a sense of their relative incidences.

Part I. Sarcomatoid Carcinoma of the Lung

Recent changes in the classification of lung tumors have included sarcoma-like tumors. Five subtypes of those lesions are now codified— including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma (PB)—and are predicated on the particulars of their microscopic appearances.^1,2 We consider all of these neoplasms to be part of the same tumor family, that of sarcomatoid carcinomas (SCs), as discussed in more detail subsequently. Although they are rare in an absolute sense, SCs represent the most common mesenchymal-like malignancies of the airways.³ True sarcomas are very infrequently seen in the tracheobronchial tree.^4-12 There fore one usually considers a cytologically atypical spindle cell tumor of the lung to be an SC unless thorough immunohistologic and ultrastructural studies indicate otherwise.³ This review will discuss neoplasms in this general category, using information taken from the pertinent literature and the personal experience of the authors.

Historical and Terminologie Considerations

Controversy has existed for some time concerning the mechanisms through which obvious foci of carcinoma of the lung are admixed with malignant but nondescript spindle cell elements or tissues with a “committed” sarcomatous differentiation pattern. Also, purely spindle cell and pleomorphic pulmonary carcinomas are recognized nosologically but are incompletely characterized at a molecular level.

Figure 15.1 (A) Computed-tomographic image 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.

Over time, morphologically similar tumors have been given a variety of designations in the upper and lower respiratory tracts. These diagnostic terms have included blastoma, sarcomatoid carcinoma, spindle cell carcinoma, squamous cell carcinoma with pseudosarcomatous stroma, pseudosarcoma, and carcinosarcoma, based largely on the specific microscopic attributes of the lesions in question and the conceptual leanings of the authors describing them.^13-47

Over 60 years ago, Saphir and Vass⁴⁸ assessed the literature then extant on carcinosarcomas, and concluded that they represented primary epithelial malignancies that had undergone divergent differentiation (“tumor metaplasia”). ’tteir paper cited several lesions of the lung. There after, opposing publications on histogenesis espoused the opinion that biphasic neoplasms of the airways were “collision” tumors, or that they reflected the proliferation of nonneoplastic mesenchymal tissue components that were induced by the carcinomatous elements.^49-51 At the turn of the last century, Krompecher⁵² and others⁵³ held to the same theories as those of Saphir and Vass. In the last three decades, results of studies using electron microscopy, immunohistology, and “molecular” assays of clonality have tended to support the latter foresighted views of those pioneers convincingly. Hence, it is believed currently that blastomas, carcinosarcomas, carcinomas with pseudosarcomatous stroma, and SCs comprise a single morphologic spectrum of basically epithelial tumors, regardless of their anatomic locations.^33-40 Biphasic sarcomatoid carcinoma and monophasic sarcomatoid carcinoma have been proposed as replacements for the former designations of carcinosarcoma and spindle cell carcinoma, respectively.^32,33 In the penultimate iteration of the World Health Organization nosological scheme, such lesions were included in the category designated “carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements.”³⁶

Clinicopathologic Features of Pulmonary Sarcomatoid Carcinomas

SCs much more often arise in the large bronchi and peripheral lung fields than in the trachea, although the authors have indeed seen some lesions that took origin above the carina. The majority of individuals with pulmonary SCs are men, and most have a history of heavy smoking.^13,22,23 the average patient age is 60 years.³² Clinical signs and symptoms produced by these tumors are directly associated with their specific locations. 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.^13-16,49-55 In contrast, SC in the peripheral lung often manifests no symptoms or, alternatively, presents with chest pain caused by invasion of the pleura and extrapulmonary soft tissue.²² As might be expected, central endobronchial tumors are smaller than peripheral SCs; their average sizes are 6 cm and greater than 10 cm, respectively (Fig. 15.1).⁵⁰,⁵⁶

In spite of their anaplastic nature, SCs of the lung are surgically resectable in roughly 90% of cases,^22,32 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.^22,32,56 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.^50,55 the metastases may exhibit either carcinomatous or sarcoma-like histologic configurations, or both.⁵⁰ Adjuvant radiation treatment and chemotherapy have been used in many cases of pulmonary SC, but these measures have provided little benefit in general.^8,32,42

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 (Fig. 15.2).^32,33 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 tissue⁵⁶; SCs in the peripheral lung parenchyma may have the gross appearance of conventional adenocarcinomas.³³

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.

Figure 15.2 (A) Peripheral sarcomatoid carcinoma of the right lung, as seen in a plain chest film, and (B) in a lobectomy specimen. (C) Reconstructed computed-tomographic image demonstrates the image of a Pancoast tumor.

Homologous Biphasic Sarcomatoid Carcinomas. 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, components. 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 moderately to well-differentiated squamous malignancy in most instances, whereas adenosquamous, adenocarcinomatous, large cell undifferentiated, or neuroendocrine carcinoma is seen in a minority of cases (Fig. 15.3).^13,57-60 Rare examples of this tumor type show mixtures of several carcinoma morphotypes.⁵⁸ Zones of transition between epithelial and sarcoma-like components are usually evident, at least focally.

The sarcomatoid elements of this subtype of SC lack specialized differentiation into identifiable myogenic, chondroosseous, 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 fibromatosislike 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 mitoses (Fig. 15.4).^{13-15,22,32,49 the} last of these descriptions is closely similar to that attending spindle cell-pleomorphic malignant fibrous histiocytoma (MFH) of the soft tissues.⁵⁸ 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.^32,33

Sarcoma-like elements in some biphasic spindle cell carcinomas may include cytologically bland, osteoclast-like giant cells (Fig. 15.5).^{56,61,62 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.³²

Heterologous Biphasic Sarcomatoid Carcinomas. Other biphasic sarcomatoid neoplasms differ from the descriptions just given, in regard to their content of focal myogenous, vasogenic, chondroosseous, or lipogenic differentiation.⁶³ ’Hius they are analogous to the heterologous form of malignant mixed müllerian tumors of the uterus, ovaries, and other female genital sites.^64,65 ttose neoplasms may exhibit microscopic foci that simulate embryonal or adult-type pleomorphic rhabdomyosarcoma, containing proliferations of closely apposed compact round with a slightly myxoid background, or large “strap” cells with cytoplasmic eosinophilia and cross-striations, respectively (Fig. 15.6).^{13-15,32,33,50,56} Other heterologous SCs contain components that closely imitate the histologic features of osteosarcoma or chondrosarcoma.^22,33,66 In light of this information, it is easy to understand why lesions with such microscopic features were felt 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.^13,58,59 Transitional zones between obvious epithelial foci, nondescript sarcomatoid areas, and myosarcoma-like components are often evident.

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 synonymy with sarcomatoid epithelial tumors in other body sites.^64,65

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.³²

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. 15.7), and areas imitating rhabdomyosarcoma, osteosarcoma, or other morphologic appearances that do not correspond to native tissues in the nonneoplastic 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 neoplasms⁶⁷ (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.³⁴

Indeed, one might well 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,^63,68 are, in reality, monophasic SCs. That statement pertains even if no immunohistochemical evidence of epithelial differentiation can be found, because the ultimate biologic evolution of such lesions is identical to that of conventional lung cancers.

Figure 15.3 (A to C) Homologous biphasic sarcomatoid carcinoma of the lung, showing overtly epithelial growth apposed to sarcoma-like pleomorphic elements. (D) Immunostain for keratin demonstrates reactivity in both neoplastic components.

Figure 15.4 (A and B) Storiform growth of neoplastic fusiform and pleomorphic cells in sarcomatoid carcinoma of the lung, simulating malignant fibrous histiocytoma. (C) Fine-needle aspiration biopsy of sarcomatoid carcinoma, showing dyshesive and pleomorphic malignant cells like those seen in true sarcomas.

Figure 15.5 Osteoclast-like giant cells are interspersed with the neoplastic spindle cells of this sarcomatoid pulmonary carcinoma.

Special Variants of Sarcomatoid Carcinoma of the Lung

There are three subtypes of SC of the lung that deserve additional discussion. These include the tumors known as pulmonary blastoma, pseudoangiosarcomatous (pseudovascular) carcinoma, and inflammatory SC.

Pulmonary Blastoma

Since its initial description by Barnett and Barnard⁶⁹ and a later discussion by Spencer,⁷⁰ PB has been regarded by some observers as the pulmonary counterpart of primitive childhood tumors of other organs.^37,71-76 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 children and adolescents.^77-83 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 (Fig. 15.8).^43,77,78 These resemble the elements of renal Wilms tumors.⁸⁴ On the other hand, PPB altogether lacks epithelial differentiation and may instead show divergent mesenchymal differentiation into myogenous or chondroosseous tissues.⁸⁰ Moreover, PB shows no particular disease associations, whereas PPB is linked in a familial fashion to a number of other malignant neoplasms and nonneoplastic disorders.⁸²

Figure 15.6 (A) Heterologous biphasic sarcomatoid carcinoma of the lung, showing obviously epithelial elements juxtaposed to sarcoma-like elements (arrows). (B) Cytoplasmic eosinophilia is present in the rhabdomyosarcoma (RMS)-like cells in this biphasic sarcomatoid carcinoma. (C) Immunoreactivity is seen for myogenin in the RMS-like foci.

Figure 15.7 (A) Monophasic spindle cell sarcomatoid carcinoma of the lung, simulating fibrosarcoma. (B) Fine-needle aspiration specimens from this case demonstrate loosely cohesive aggregates of the spindle cells.

Figure 15.8 Pulmonary blastoma showing an admixture of fetal glands and undifferentiated spindle cell elements. This tumor is a special morphologic form of sarcomatoid carcinoma, and it occurs preferentially in adults rather than children.

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 et al.,⁸⁵ Stackhouse et al.,¹³ and Millard,⁸⁶ among others. Those authors had the opinion that PB is merely a special, usually peripheral form of pulmonary SC (“carcinosarcoma”), rather than a blastemal neoplasm, which contains truly embryonal tissues. We also espouse that 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.^43,73,87 the epithelial elements in PB resemble fetal pulmonary pseudoglands (a misnomer), composed of stratified columnar cells with glycogen-rich clear cytoplasm and high nucleocytoplasmic ratios.^73,87-89 Luminal mucin may be present in those cellular arrays, and squamous morules are sometimes also evident.⁷³ Interestingly, “occult” neuroendocrine differentiation is a rather common finding in the epithelial components of PB, with potential histochemical argyrophilia and immunoreactivity for neuroendocrine markers.^90,91 ttere is a significant sharing of microscopic features between classical PB and the tumor described as “pulmonary endodermal tumor resembling fetal lung” or alternatively as “well-differentiated adenocarcinoma simulating fetal lung” (Fig. 15.9). It differs in its relative lack of a malignant stromal component and more frequent synthesis of a particular oncofetal polypeptide, a-fetoprotein.^43,88,90-93

The elements of PB showing mesenchymoid differentiation are, as stated earlier, usually nondescript morphologically and blastema- or fibroblast-like. However, examples of this tumor have been documented in which heterologous rhabdomyoblastoid, leiomyosarcomatoid, or apparent chondroosseous tissues were present.^73,87 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.^85,94-96

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.^71,73,87 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 (Fig. 15.10).⁹⁷ ’Hiese neoplasms are felt to represent the pulmonary counterparts of pseudovascular adenoid squamous cell carcinoma, as seen in the skin, breast, thyroid gland, and other organs.^33,97-102 This is a tumor type that is known to simulate true angiosarcoma but lacks actual endothelial differentiation. Thus “pseudoangiosarcomatous carcinoma” (PASC) is also an apt _synonym.^99,103

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.⁶ Mainly anecdotal reports of this tumor exist in the remaining literature, and not all of them satisfy rigorous diagnostic criteria. 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.

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 et al.,⁹⁹ 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 cigare The 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 coworkers,⁹⁷ the tumors were essentially identical microscopically to pseudovascular squamous carcinomas of the breast and skin. Important differences between PASC and true pleuropulmonary angiosarcoma 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.⁹⁷

The behavioral features of PASC are similar to those of other sarcomatoid pulmonary carcinomas. The patients studied by Nappi et al. developed distant metastases to the bones, liver, adrenal glands, and contralateral lung and 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).¹⁰⁴¹¹⁷ 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 clinicopathologic features. The nomenclature used for this group of lesions has been well summarized by Koss¹¹⁷ and Matsubara et al.¹⁰⁹ ttere is still some controversy over whether all such lesions are neoplastic or whether some also might be reactive in nature.¹¹⁸ Occasional cases have been linked causally to specific infectious organisms,^119,120 but the etiologic factors associated with most pulmonary IPs are uncertain.

In contrast, primary SC is generally regarded as a neoplasm, which 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.^108,111 However, we have observed several examples of pulmonary SC that exhibited surprisingly bland morphologic appearances, and that, 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).^121,122

Figure 15.9 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 Dr. Samuel A. Yousem, Pittsburgh, Pennsylvania.)

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. 15.11). 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.

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. 15.12). Cytoplasm is moderate in amount and amphophilic. Mitoses generally average less than 2 per 10 high-power (x400) fields, and pathologic division figures are absent. borough 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 (Fig. 15.12B).¹²¹

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.¹²³ This produces clinical symptoms and signs that are indistinguishable from those of malignant mesothelioma; hence, the names pleurotropic or pseudomesotheliomatous carcinoma.^124,125 Moreover, the microscopic features of pleurotropic SC (PSC) are basically superimposable with those of biphasic or sarcomatoid mesotheliomas.

Figure 15.10 (A) Pseudoangiosarcomatous sarcomatoid carcinoma of the lung, demonstrating discohesion 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) Immunoreactivity for epithelial membrane antigen and for p63 protein (D) confirms the carcinomatous nature of the tumor.

Figure 15.11 (A) Inflammatory sarcomatoid carcinoma of the lung, showing brisk intratumoral and peritumoral chronic inflammation and (B) a bland proliferation of fibroblast-like cells at the periphery.

Figure 15.12 (A) Higher magnification of the tumor shown in Fig. 15.11 reveals nuclear atypia in the spindle cells. (B and C) the spindle cells are immunoreactive for keratin.

Even though There is no pragmatic clinical value in making the distinction between PSC 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 PSC with asbestos, and its etiology appears to be identical to that of “routine” forms of lung cancer.

Results of Adjunctive Pathologic Studies

Accounts of the electron microscopic and immunohistologic characteristics of pulmonary SC have not been altogether uniform. Some authors have preferred the view that such data in fact confirm the existence of true carcinosarcomas,^126-128 whereas others have felt that this information instead supports the concept of a pathologic continuum that is predicated on carcinoma in pure form.^14,16,42’^129-133 We strongly prefer the second of those opinions.

It is true that the sarcoma-like elements in SC of the airways do not uniformly exhibit the ultrastructural presence of intercellular junctions and tonofibrils, or immunoreactivity for keratin or epithelial membrane antigen (EMA) in fusiform and pleomorphic tumor cells. In fact, these generic markers of epithelial differentiation may be seen only extremely focally in such neoplastic components, and we have even seen isolated examples in which cell membrane-based EMA reactivity was obvious but keratin positivity was altogether absent. Humphrey et al. observed cytoplasmic tonofibrils or keratin positivity in the sarcomatoid elements of only 3 of 8 pulmonary SCs.¹⁴ However, it should be noted that the latter study was performed with a single hetero antiserum to high- molecular-weight keratin, representing a relatively insensitive means of immunodetection. In our previously published experience with SCs of the respiratory tract,³² 81% were ultrastructurally or immunohisto- chemically proven (with a mixture of monoclonal antikeratin antibodies [AE1/AE3/CAM5.2/MAK-6]) to be wholly epithelial in nature, and other authors have recorded similar findings at immunohistochemical and genetic levels of investigation.^129-135

The fact that features of epithelial differentiation are present at all in the sarcomatoid elements of these neoplasms strongly supports the premise that respiratory tract SC is a basically carcinomatous lesion in mesenchymal transition.¹³⁶ This concept has been well accepted in reference to dedifferentiated sarcomas of the soft tissue, in which clonal evolution is thought to account for a change in the morphology as well as the immunophenotype of the progenitor lesion.¹³⁷ Lessons learned in the latter sphere, and molecular biologic assessments of clonality in SCs,¹³⁸ have direct corollaries in the context under discussion here. We have observed the coexpression of vimentin (a primordial intermediate filament) in all examples of keratin-positive SC of the airways, and a minority of these lesions are additionally labeled for desmin (The intermediate filament of myogenous cells) and muscle-specific actin in the same cells that contain the other two filament proteins (Fig. 15.13).³² Collagen type IV is also seen surrounding individual tumor cells in most instances. Markers of neuroendocrine differentiation, such as chromogranin-A, CD57, and synaptophysin, might likewise be seen in selected lesions in their overtly epithelial components,^57,59 and S100 protein is apparent in foci resembling chondroid tissue by conventional microscopy.¹ In contrast, FLI-1 (Friend Leukemia-virus Integration-1) and CD31 are typically absent in PASC, whereas one or both of those endothelial determinants would be expected in true pleuropulmonary ^98,139 angiosarcomas.

Figure 15.13 Immunoreactivity for vimentin in sarcomatoid carcinoma of the lung. The tumor was also reactive for pan-keratin.

These accrued observations coincide with ultrastructural findings reported by Battifora in two cases of SC—which demonstrated the coincidence of desmosomes, tonofibrils, and collagen production in The same neoplastic cells—implying the presence of multilinear dif- ferentiation.¹⁴⁰ ttus SC can be viewed basically as an epithelial neoplasm with divergent mesenchymal differentiation, in which carcinoma cells acquire the potential to express a mesenchymal phenotype at light microscopic, ultrastructural, and immunohistologic levels. The pathogenetic bases for this peculiarity are currently unknown, but the practical deduction to be gleaned from this construct is that all SCs of the respiratory tract should be treated clinically as poorly differentiated carcinomas.

Wakely has reviewed the characteristics of pulmonary spindle cell tumors as seen in fine-needle aspiration biopsy specimens (Fig. 15.7).¹⁴¹ He concluded that adjunctive pathologic studies, such as those discussed earlier, were virtually mandatory before definitive diagnoses could be reached in that context.

Differential Diagnosis of Sarcomatoid Carcinoma

The differential diagnosis of SCs of the airways principally centers on the exclusion of true sarcomas, which are discussed later in this chapter. As a particular word of caution, it should be noted that synovial sarcoma (SS) and sarcomatoid mesothelioma may be very closely similar to SC as seen with the electron microscope or in immunophenotypic evaluations. The marked propensity for SS to affect children, adolescents, and young adults, its typical t(X;18) (p11.2;q11.2) cytogenetic aberration,^142,143 and nuclear labeling for TLE1 (transducin-like enhancer [of Split]-1) protein^144-147 (not seen in carcinomas) are crucial points in its distinction from SC of the upper airways. Of course, nuances of histologic appearances and radiographic characteristics are also valuable in this specific differential diagnostic setting. Similarly, roentgenologic findings are more helpful than morphologic observations in making the distinction between SC and spindle cell or biphasic mesothelioma. The ultrastructural profiles of the latter two lesions are again very similar, and, aside from selective reactivity for calretinin and podoplanin¹⁴⁸ in mesotheliomas, the same comment applies to their immunophenotypes.

Part II: True Primary Sarcomas of the Lung

Kaposi Sarcoma

The natural history of KS is a sad testimony to the global impact of the acquired immunodeficiency syndrome (AIDS). Before the 1980s, KS was a relatively rare neoplasm outside of Africa and the Mediterranean basin. Moreover, with relatively uncommon exceptions, this lesion was a cutaneous proliferation that uncommonly involved the viscera.¹⁴⁹ However, today, with particular regard to the intrathoracic organs, KS is, in most large metropolitan areas of the world, the most common of all pulmonary sarcomas.¹⁵⁰ Although initial presentation of this tumor in the bronchopulmonary tract was an almost-unknown phenomenon prior to the advent of AIDS, it is currently a well-recognized variation of the latter disease.¹⁵¹

Clinical Summary

In the context just mentioned, many patients with KS of the lung (KSL) are homosexual or bisexual men,^151-158 but they also include other high-risk groups for AIDS. Some examples are intravenous drug abusers, and persons who are seronegative for the human immunodeficiency virus (HIV) but become infected with human herpesvirus type 8 (HHV8). Most individuals with KS generally have other symptoms and signs of AIDS, such as weight loss, fever, night sweats, fatigue, lymphadenopathy, and opportunistic infections.¹⁵⁹ However, fever may be directly caused by KS in the lungs. There has been a case report of an AIDS patient with pulmonary KS and persistent pyrexia for which no source of infection was found, but which finally resolved after radiation therapy.¹⁶⁰ 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 are There fore relatively advanced at the time of diagnosis.¹⁶¹ Presenting complaints that are specific to the neoplasm include dyspnea, stridor (when endobronchial lesions are present), cough, and hemoptysis, which may be massive.¹⁵¹

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, KSL will be missed because the mucosa itself is uninvolved.¹⁶² 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. 15.14). An alveolar filling pattern is usually evident only if the patient has suffered hemoptysis and aspirated blood, but pleural eflusions or pneumothorax may be seen in cases where the lesion involves the serosal surfaces and the lung parenchyma.^163,164 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 images (MRIs) generally provide no more information than the chest radiographs. 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 a known tumor elsewhere.^152,153

Figure 15.14 A relatively nondescript reticulonodular interstitial infiltrate is seen on conventional (A) chest radiographs and (B) computed tomography, 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.

Figure 15.15 (A) Low-magnification image of pulmonary Kaposi sarcoma, showing a nodular proliferation of spindle cells and neovascular spaces (left) that permeates the pulmonary interstitium (right). (B) A transbronchial biopsy specimen of Kaposi sarcoma shows a spindle cell proliferation and interanastomosing vascular channels.

Pathologic Findings

As alluded to earlier, it is distinctly uncommon for the pathologist to be able to make a definitive diagnosis of KSL on a transbronchial biopsy specimen. Usually, a wedge biopsy is necessary, as obtained via video- guided thoracoscopy or a limited thoracotomy.¹⁶² 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 preexisting fibrous intrapulmonary septa, and it also concentrates around small tubular airways and blood vessels (Fig. 15.15). 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.^151,162 Extravasated erythrocytes and hemosiderin pigment are common in and around the tumor masses (Fig. 15.16). Pleural KS layers itself over the submesothelial mantle of connective tissue, effacing the mesothelium itself in doing so.

Mitotic activity is variable in pleural KSL, 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 HHV8 in approximately 85% of cases (Fig. 15.17)¹⁶⁵; it also labels for FLI-1¹⁶⁶ and podoplanin.¹⁶⁷

Therapy and Prognosis

Regardless of its occurrence in AIDS or in non-HIV-related cases, the presence of KS in the lung is prognostically ominous. Virtually all patients with visceral disease will die within 2 years, from infection if not from KS itself.^153,159,161 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. Chemotherapy regimens in the few published therapeutic trials designed specifically for pulmonary KS have primarily included Adria- mycin, bleomycin, and vincristine.^151,168170 Gill et al. found an 85% response with combination chemotherapy in a group of 13 patients.¹⁶⁹ Patients who benefited from this treatment included those who achieved at least partial responses. Complete response is defined by the following three criteria:

• direct bronchoscopy revealing complete disappearance of KS lesions in the tracheobronchial tree

• a normal chest x-ray

• resolution of all other sites of disease

A partial response is characterized by the same three points, except that the degree of resolution is not total.^168,169

Despite fairly good results with combination chemotherapy, patients with pulmonary KS do not show long survival. In the trial reported by Gill et al., the median survival for responders was slightly but significantly longer than that of nonresponders (10 vs. 6 months, respectively). However, considerable overlap between the two groups was present.¹⁶⁹

Other more experimental (and inconclusive) approaches have included the administration of zidovudine, interferon, and other antiviral compounds.^52,155,156 Radiotherapy may provide palliation of symptoms, but is noncurative. The most important piece of data in prognosticating cases of KSL is the serologic HIV status of the patient, inasmuch as AIDS is currently a uniformly lethal, albeit chronic, illness.

Fibrosarcoma

Primary fibrosarcoma of the lung (FSL), like its soft tissue counterpart, is defined as a fibroblastic spindle cell neoplasm without any evidence of specialized cellular differentiation. Although it has been cited in the past, along with leiomyosarcoma, as the most common primary pulmonary sarcoma,¹⁷¹ FSL was, and probably still is, overdiagnosed.¹⁷² Two separate studies from the Mayo Clinic cited two different time- dependent incidence figures for FSL. From 1950 to 1978, it constituted 50% of all primary pulmonary sarcomas,¹⁷³ but only 20% in the decade 1980 to 1990.¹⁷⁴ As considered in previous chapter text, it is our belief that the great majority of pulmonary fibrosarcomas are actually SCs. Only those tumors that have been subjected to rigorous and specialized pathologic examination should be accepted as bona fide examples of this rare sarcoma variant.

Figure 15.17 Diffuse immunoreactivity is seen for herpesvirus 8-latent nuclear antigen-1 in Kaposi sarcoma of the lung.

Clinical Summary

Guccion and Rosen studied 13 cases of FSL, which were divided into endobronchial and intrapulmonary types.¹⁷¹ 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.¹⁷⁵ There was roughly an equal distribution by gender among endobronchial lesions; however, most intraparenchymal neoplasms occurred in men. All endobronchial FSLs in a series reported from the Armed Forces Institute of Pathology (AFIP) produced symptoms of cough, hemoptysis, or chest pain; some of the parenchymal cases did so as well.¹⁷¹ Thoracic imaging studies of FSL usually show discrete, homogenous masses. However, one reported pulmonary fibrosarcoma simulated a bronchogenic cyst clinically and radiographically.¹⁷⁶ Gladish et al.¹² 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 spindleshaped cells with a typical interdigitating growth pattern and discernible stromal collagenogenesis (Fig. 15.18). 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. 15.19). Mitotic activity is variable.

Figure 15.18 (A) Pulmonary fibrosarcoma, represented by a cellular proliferation of atypical spindle cells. (B) Nuclear anaplasia is apparent on high magnification.

Figure 15.19 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.^177-179

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 eventuating within 2 years.¹⁷¹ ttree cases seen at the Mayo Clinic between 1980 and 1990 occurred in young women whose lesions all recurred within 15 months following surgical excision.¹⁷⁴ In contrast, primary bronchopulmonary fibrosarcomas in children appear to have a relatively favorable prognosis and behave only as low-grade malignancies.^175,176 the five patients with pediatric FSL reported by Pettinato et al. 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.¹⁷⁵ 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 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,¹⁸⁰ but at least two cases have been reported as primary pulmonary examples.^181,182 HSCT has a distinctive morphologic appearance, featuring the multifocal presence of large rosette-like structures amidst a bland spindle cell proliferation (Fig. 15.20). The lesion has infiltrative borders, with no necrosis and only limited mitotic activity.

HSCT has a partial kinship with an Evans tumor (a low-grade fibromyxoid sarcoma)¹⁸³ 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.¹⁸² 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,¹⁸⁰ 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.

Primary Pulmonary Leiomyosarcoma

The most common anatomic locations for leiomyosarcomas in general are the uterus, gastrointestinal tract, and soft tissue, in order of relative frequency. Primary pulmonary leiomyosarcomas (PPLMS) are extremely uncommon and presumably take their origins from bronchial or pulmonary vascular smooth muscle. Only three cases of leiomyosarcoma were found among roughly 10,000 primary malignancies of the lung at one large American medical center between 1980 and 1990.¹⁷⁴ Because secondary pulmonary involvement by malignant smooth muscle tumors is a relatively frequent event, the diagnosis of PPLMS absolutely requires exclusion of an occult extrathoracic neoplasm presenting with a single “herald” metastasis to the lung.^184,185

Figure 15.20 (A) 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.

Clinical Summary

A series of 19 PPLMSs seen at the AFIP was divided into neoplasms that were predominantly endobronchial and others that were intraparenchymal, in analogy to pulmonary fibrosarcomas.¹⁷¹ the majority of these tumors in children are endobronchial in nature,^186,187 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 males. 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.¹⁸⁸ In contrast to carcinoma of the lung, leiomyosarcoma is not associated with cigare The 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. 15.21), sometimes with cavitation or cyst formation that is best seen by CT of the thorax.^171,189,190

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.¹⁹¹

Microscopy discloses histologic features that mirror those of leiomyosarcomas elsewhere in the body. On low-power magnification, there are interlacing fascicles of spindled cells that are arranged haphazardly, yielding a “whorled” appearance (Fig. 15.22). The neoplastic cells have cigar-shaped nuclei with blunt ends, a moderate amount of cytoplasm, and indistinct cell borders (Fig. 15.23). Fascicles cut in cross section demonstrate characteristic intracellular perinuclear lucencies.^191-194 Prominent myxoid stromal change may be observed.¹⁹⁵

Figure 15.21 Computed tomogram of the thorax showing primary leiomyosarcoma of the left lung.

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.¹⁹³ 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. 15.24). Immunoreactivity for desmin, muscle-specific actin, calponin, caldesmon, or smooth muscle actin is also characteristic of the tumor cells in PPLMS.¹⁹⁶

Figure 15.23 Cellular details are well seen in this primary pulmonary leiomyosarcoma.

Figure 15.24 Electron photomicrograph of pulmonary leiomyosarcoma, demonstrating cytoplasmic thin filaments, pericellular basal lamina, and cytoplasmic dense bodies.

Figure 15.25 Fine-needle aspiration biopsy of primary pulmonary leiomyosarcoma, showing loosely cohesive tumor cells with blunt-ended fusiform nuclei.

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 (Fig. 15.25).^197-199

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,^188,191-193 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.^171,173 However, pulmonary leiomyosarcomas appear to be relatively resistant to irradiation and chemotherapy.^188,194 Various prognostic variables have been discussed in connection with these lesions.^171,173 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, there fore, 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.¹⁷¹

Epithelioid Hemangioendothelioma

In 1975 Dail and Liebow reported the first cases of an unusual pulmonary neoplasm that they called intravascular bronchioloalveolar tumor (IVBAT). This name reflected their original hypothesis that the lesion in question was an epithelial tumor: specifically, a bronchioloalveolar carcinoma variant showing prominent vascular invasion.^200,201 Four years There after, Corrin et al. alternatively proposed an endothelial origin for this tumor based on the results of ultrastructural studies.²⁰² Subsequent evaluations by other authors have confirmed the vascular histogenesis of the IVBAT. Indeed, in 1982, Weiss and Enzinger described a series of soft tissue tumors that were histologically identical to IVBAT, and these authors were the first to use the term epithelioid hemangioendothelioma (EH) to emphasize their distinctively epithelioid cytologic features.²⁰³ In addition to the lungs and soft tissues, EH also primarily occurs in the bone and liver.²⁰⁴

Clinical Summary

EH of the lung is a neoplasm that arises predominantly in female patients; women account for roughly 80% of all cases.^201,205-210 It primarily occurs in young adults; approximately 50% are younger than 40 years of age and only 10% are older than 50 years at diagnosis.^204,211 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,^212,213 and it may simulate thromboembolic disease symptomatically as well.²¹⁴ Chest radiographs commonly show numerous, small nodular lesions throughout both lung fields (Fig. 15.26). There fore 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.²¹⁵

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 (Fig. 15.27).^201,205 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.²¹⁶ the neoplastic cell population is composed of plump, epithelioid cells, which are the histologic hallmark of EH (Fig. 15.28). They have centrally located, round-to-oval nuclei and 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.²¹⁷

Tumoral involvement of arterioles, venules, and lymphatics is variable within the tumor nodules and other distant sites. EH commonly shows an intraalveolar pattern of growth secondary to tumor extension through the pores of Kohn, and surgical margins may be, there fore, 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.^{202,205,218-222} Briefly, ultrastructural features of this tumor include cytoplasmic vacuoles, Weibel-Palade bodies (Fig. 15.29), cell membranous pinocytotic vesicles, and pericellular basal lamina.¹⁷² 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.^210,216 Weinrab et al. have also described labeling for CD10 in a majority of EH cases.²²³

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. 15.30).

A recurring cytogenetic finding in EH cases is a t(1,3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. It can be detected with conventional cytogenetic techniques or fluorescence in situ hybridization.²²⁴

Figure 15.26 Multiple nodular densities are seen throughout both lung fields (A) on plain film radiography and (B) computed tomography in this case of primary pulmonary epithelioid hemangioendothelioma. (C) Gross photograph of epithelioid hemangioendothelioma of the lung, in a wedge-excision specimen.

Figure 15.28 (A and B) the epithelioid nature of the tumor cells in pulmonary epithelioid hemangioendothelioma (PEH) is well seen in these photographs, as well as the myxofibrous stroma. (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.

Figure 15.29 (A and B) Numerous Weibel-Palade bodies, which have the appearance of lysosomal-like inclusions with internal striations, are present in epithelioid hemangioendothelioma in this electron photomicrograph. These organelles are the intracellular packaging sites for von Willebrand factor.

Figure 15.30 (A and B) Fine-needle aspiration biopsy of epithelioid hemangioendothelioma shows dispersed polygonal tumor cells, some of which contain cytoplasmic vacuoles.

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.^201,205 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.²¹⁸ 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.²¹⁶ 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,^201,219 and the presence of fusiform tumor cells.²⁰⁶

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.^225,226

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 et al. analyzed five cases of pulmonary EH for steroid hormone receptors by immunohistochemical methods, using paraffin-embedded material.²²⁷ 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 benefit in this setting.

Hemangiopericytoma and Intrapulmonary Solitary Fibrous Tumor

As first described in 1942 by Stout and Murray,²²⁸ hemangiopericytoma (HPC) is an uncommon, potentially malignant neoplasm that shows apparent differentiation toward the phenotype of pericytes. These are cells with long cytoplasmic processes that surround capillaries and serve a vasoregulatory function. HPC occurs most commonly in the deep muscles of the thigh, the pelvic fossa, and the retroperitoneum. However, 5% to 10% of all HPCs are said to present as primary pulmonary tumors.²²⁹ It must be remembered that the lungs and the bones are the anatomic sites that most frequently harbor metastases of HPC,²³⁰ and There fore a primary extrapulmonary tumor must be excluded before a diagnosis of a primary HPC can be rendered safely.

The currently recommended classification scheme for mesenchymal neoplasms has merged HPC with solitary fibrous tumor (SFT).²³¹ Hence, for all intents and purposes, the two entities are considered to be closely related if not identical, and the abbreviation of HPC-SFT will be used in reference to that tumor group.

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 and as old as 73 years have been reported.^232,233 Some tumors are detected incidentally on radiographic studies without causing pulmonary symptoms; six of 18 cases in one series fit this scenario.²³⁴ Alternatively, presenting symptoms may include hemoptysis, chest pain, cough, and dyspnea, and more rarely, pulmonary osteoarthropathy.²³⁴ Rare examples of HPC-SFT are completely intrapulmonary in location, and some even involve the tracheobronchial tree.^235,236 This tumor type has also been reported to arise potentially in transplanted lungs.²³⁷

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.”²³⁸ No other pathognomonic features are evident in chest roentgenograms, CT scans, and MRIs of the lung.^233,239 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.²⁴⁰ 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. 15.31) that does not cause compression atelectasis.²³⁹

Figure 15.31 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, and areas of internal necrosis and hemorrhage. Histologic sections typically show a relatively monomorphous cellular proliferation that surrounds thin-walled, anastomosing vascular channels that are lined by a single endothelial layer. These blood vessels often (but not always) assume gaping “staghorn” or “antler-like” configurations (Figs. 15.32 and 15.33). The population of neoplastic cells is uniform, with oval compact nuclei and ill-defined cytoplasm.¹⁹¹ 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.^230,234,241

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 HPC by ultimate exclusion.²²⁸ the histologic differential diagnosis includes SC, SS, fibrous histiocytomas, leiomyosarcoma, and mesenchymal chondrosarcoma,²⁴¹ and distinctions between these neoplasms are best made by ancillary studies.

Figure 15.32 Pulmonary hemangiopericytoma, showing ill-defined clusters of bluntly fusiform tumor cells and prominent stromal blood vessels.

Figure 15.33 (A) "Staghorn”-shaped blood vessels in primary pulmonary hemangiopericytoma (HPC). (B) Individual tumor cells are invested by reticulin fibers in HPC (reticulin stain method).

Figure 15.34 Immunoreactivity for CD99 is seen in pulmonary hemangiopericytoma- solitary fibrous tumor. CD34 and bcl-2 protein are usually present in this tumor as well.

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.^178,230 HPC-SFT is a neoplasm that demonstrates a relatively restricted group of immunoreactants; these include vimentin, collagen type IV, CD34, CD99, CD57, bcl-2 protein, and STAT6 protein, the last of which is the most specific marker (Fig. 15.34).^242,243 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.

Therapy and Prognosis

As is true of 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 et al., and should There fore be avoided at all costs.²³³ Chemotherapy and irradiation have not been shown to be consistently effective adjuvant modalities, but they may have some role to play in management.^244,245 A study by Jha et al. on the general role of radiation therapy in treating HPC-SFT showed that postoperative irradiation was useful for local tumor control, for salvage therapy after local recurrence, and for palliation.²⁴⁶ Tumors less than 5 cm in maximum dimension exhibit a better response than those that are larger than 10 cm.²⁴⁷

As mentioned above, HPCs are in general well known for their unpredictable biologic behavior. Postoperative survival has ranged from 10 weeks to 18 years.^233,247 Even with apparently complete surgical resection, HPC-SFT recurs locally in approximately 50% of cases within 2 years,^234,240 and later recurrences are seen as well; distant metastasis, however, is uncommon.²⁴¹

Clinical and histologic features that have been cited as prognostically useful^232,240,241 include the presence of symptoms at presentation; mitotic activity of more than four 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.²³² 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.²³⁴

Malignant Fibrous Histiocytoma

MFH (now commonly called pleomorphic sarcoma, not further specified) is a common, extensively studied soft tissue sarcoma of older adults that develops most frequently in the extremities and the retroperitoneum. In a series of 200 cases by Weiss and Enzinger,²⁴⁸ the lungs were the most common site of metastases. ’Hius exclusion of an occult soft tissue tumor is once again necessary before a diagnosis of primary pulmonary malignant fibrous histiocytoma (PPMFH) can be made. A review of Mayo Clinic cases found only four examples among 10,134 tumors arising in the lung.¹⁷⁴ Currently, there are fewer than 75 reported cases of PPMFH in the English literature.^249-262

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.^249,258 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.²⁵⁷

Pathologic Findings

Most examples of PPMFH are intraparenchymal, but occasional endobronchial lesions have also been observed.²⁴⁹ ttere is apparently no predilection for any particular lobe of either lung. These tumors are usually large, ranging up to 25 cm in maximum dimension,²⁶¹ with an average size of 6 to 7 cm. They are well circumscribed, lobular, and white-tan, and not uncommonly 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. 15.35). As the name malignant fibrous histiocytoma 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. 15.36). 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.¹⁷⁸

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.¹² Immunohistochemical and electron microscopic studies can be employed to separate these pathologic entities.^250-254,261 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 immu- nohistologic analyses.¹⁷⁸

Figure 15.35 (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 15.36 This example of primary pulmonary malignant fibrous histiocytoma shows a more epithelioid cell population that could cause diagnostic confusion with poorly differentiated carcinoma.

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.²⁶² Adjunctive chemotherapy and irradiation have not proven to be effective in the few published cases of PPMFH in which these treatments have been employed.^249,259,261 In one series of 22 examples,²⁴⁹ 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, survivals as long as 5 to 10 years have been documented in a few patients with PPMFH_.^249,251

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.²⁶¹

Rhabdomyosarcoma

For practical purposes, primary rhabdomyosarcoma of the lung (RMSL) is a tumor that is confined to the pediatric population. In adults, tumors resembling rhabdomyosarcoma are almost invariably examples of SC,¹ and this fact should be borne in mind in interpreting all but the most recent literature on this topic. Moreover, this is another sarcoma type that much more commonly arises outside of the lungs, and the probability that one is dealing with metastasis to the pulmonary parenchyma is There fore important to remember.

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 under 10 years of age.^263-266 At least one lesion, documented by Choi et al., was seen in a child with neuro- fibromatosis.²⁶⁷ Symptoms and signs of RMSL may be nonspecific, including cough, wheezing, and dyspnea, or the patient may present with spontaneous pneumothorax.²⁶⁸ 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 text).^264,265,269 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.²⁶⁹

Roentgenographic studies may demonstrate a single, nondescript, intraparenchymal mass that is homogeneous on CT or MRI analyses, 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 previously, 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.

Figure 15.37 (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.

Pulmonary rhabdomyosarcomas have most often assumed an embryonal or an alveolar growth pattern^264,265 (Figs. 15.37 and 15.38), although pleomorphic tumors, which are usually encountered in the soft tissues of adults, have been reported in the lung as well.²⁷⁰ These neoplasms are typically composed of small round cells that are configured in one of three ways. These include solid sheet-like clusters with no further distinguishing morphologic attributes; discohesive 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).²⁷¹ 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.

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 previously. 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. 15.39). 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.²⁷² 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. 15.40), or Z-band protein.^273-275 Vimentin is also uniformly found, but markers of epithelial differentiation, such as keratin and EMA, must be absent to make the diagnosis of RMSL.

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.^263-270 However, there are no controlled studies to determine whether or not 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.²⁷⁶

Chondrosarcoma of the Respiratory Tract

Chondrosarcomas are uncommon but well documented in the supporting tissues of both the upper and lower airways. Indeed, although cartilaginous malignancies are usually observed in the proximal long bones of adults, visceral lesions of this type have been reported in a variety of locations. As one would expect, there are few if any examples of primary pulmonary chondrosarcoma (PPCS) that involve the most distal portion of the respiratory tract, because cartilaginous support for the bronchi ends at the level of subsegmental bronchi.^277,278 Accordingly, most PPCSs affect the trachea and major bronchial divisions,^279-282 and chondrosarcomas that are seen in the peripheral lung fields should be carefully examined radiologically to make certain that they are not extensions of contiguous bony lesions in the sternum, vertebral bodies, or ribs.

In contrast to statements pertaining to other sarcoma morphotypes in the lung, it is virtually unknown for chondroid malignancies to metastasize while they are still occult in peripheral osseous or soft tissue sites. Thus once a pathologic diagnosis of chondrosarcoma has been established for a lesion that clearly involves the airway, it may safely be considered to have arisen at that location.

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.^279,280 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.²⁷⁷

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 manifest simply as sharply circumscribed, lobulated masses (Fig. 15.41) that may contain flecks of central calcification or cystic change.²⁸²

Figure 15.39 Electron photomicrograph of pulmonary rhabdomyosarcoma, showing cytoplasmic sarcomeric differentiation with formation of Z-bands.

Figure 15.40 Nuclear immunoreactivity for Myo-D1, shown here, is another general feature of rhabdomyosarcoma.

Figure 15.41 Plain chest film showing chondrosarcoma arising from the carina, represented by a rounded mass that projects into the left lung field.

Figure 15.42 Excisional gross specimen of carinal chondrosarcoma, demonstrating obvious bluish foci of cartilaginous differentiation.

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, PPCS has an irregular peripheral macroscopic interface with the lung (Fig. 15.42); it exhibits at least modest nuclear pleomorphism, nuclear crowding, and cellular binucle- ation and does not contain respiratory epithelial profiles (Fig. 15.43).^277,279 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 Mesenchymal chondrosarcomas,^278,283 represented by small cell neoplasms of childhood with a resemblance to Ewing sarcoma (Fig. 15.44), 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. Other singular subtypes of chondrosarcoma are the dedifferentiated form, in which low-grade chondroid tissue is juxtaposed to a highly anaplastic pleomorphic tumor component (Fig. 15.45), and the extraskeletal myxoid variant, which is typified by cords of epithelioid cells with eosinophilic cytoplasm, in a myxoid stroma. The latter lesion demonstrates the presence of an ETSR1-ATF1 fusion gene (Fig. 15.46). Both of these types of chondrosarcoma have been reported only rarely as a primary pulmonary lesion.^284-286

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.²⁸⁰ 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: a tumor size of 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.

Primary Pulmonary Synovial Sarcoma

Although SS is primarily a peripheral soft tissue tumor, it is also potentially seen as a primary pleuropulmonary lesion. Published reports of approximately 150 cases have now attested to that fact.^{142,143,196,287-293} Because of the range of histologic and radiographic appearances associated with SS, it enters into differential diagnosis with several other neoplasms in the lung and pleura.

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-quarter of all patients were asymptomatic.²⁸⁷ 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. 15.47), which may arise in any segment of any pulmonary lobe. However, some cases will show flocculent or particulate calcification on plain film radiographs or computed tomograms. Cystic change may also be noted, and a minority of lesions are clearly associated with a major bronchus.142,143,287-292

Figure 15.43 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 15.44 (A and B) Mesenchymal chondrosarcoma of the lung, showing a juxtaposition of chondroid islands and undifferentiated small round tumor cells.

Figure 15.45 Dedifferentiated chondrosarcoma of the lung, demonstrating a low-grade "parent” component (top of figure) and an abruptly juxtaposed anaplastic sarcomatous derivative There of (bottom of figure).

Figure 15.46 An intrapulmonary sarcoma with features of extraskeletal myxoid chondrosarcoma is shown here. In a fine-needle aspirate and a biopsy specimen (leftpanels), the tumor cells are arranged in cords and set in a myxochondroid stroma. The tumor shows rearrangement of the EWSR1 gene in a fluorescent in situ hybridization preparation (right panel).

Figure 15.47 Computed tomography scan of primary pulmonary synovial sarcoma showing a large mass in the right hemithorax.

Pathologic Findings

The gross and microscopic spectrum of SSs of the lung parallels that seen in similar tumors of peripheral soft tissue.²⁹⁴ Macroscopically, one sees a fleshy, ill-circumscribed mass in virtually any intrapulmonary location (Fig. 15.48). Classically, biphasic SS is composed of fascicles of compact spindle cells arranged in interweaving or herringbone fascicles, punctuated by clefts or overtly gland-like spaces that are lined by cuboidal to low columnar tumor cells (Fig. 15.49).²⁹⁵ 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 gland-like 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. 15.50) or 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. 15.51) is recognized.²⁹⁴

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 gland-like differentiation, or sheets of small round cells.²⁸⁷ Monophasic spindle-cell SS is more common by far (Fig. 15.52), 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.²⁷³ Another key feature of the recognition of monophasic spindle cell SS is the presence of a “staghorn” or “mooseantler” pattern of intratumoral vascularity.²⁹⁴ Divergent differentiation, simulating osteogenic, neural, or squamous lesions, is another pathologic facet of monophasic SS that may cause diagnostic consternation.²⁸⁷

Figure 15.48 Grossly, primary pulmonary synovial sarcoma exhibits a fleshy tan-grey cut surface.

Figure 15.49 (A) Photomicrograph of biphasic synovial sarcoma of the lung. The tumor contains gland-like epithelial structures punctuating a neoplastic spindle cell proliferation. Diagnostic confusion with biphasic sarcomatoid carcinoma is possible. (B) Immunostaining for pan-keratin highlights the overtly epithelial glandular component of this neoplasm.

Figure 15.50 Stromal calcification is present in this pulmonary synovial sarcoma.

Figure 15.51 Another variant of biphasic synovial sarcoma of the lung contains solid epithelial cell nests, admixed with spindle cell areas.

Electron microscopy and immunohistology have shown that SS is actually an epithelial proliferation, with ultrastructurally well-formed junctional complexes between the tumor cells.^273,294 Reticulin stains are often useful in outlining epithelioid cell clusters when they are present but indistinct. Immunostains for keratin and EMA (Fig. 15.53) 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.²⁹⁴ Another extremely useful marker is TLE-1; it is a nuclear protein that is observed in virtually all cases of SS (Fig. 15.54)^144-147; There is some sharing of reactivity for TLE-1 with neural neoplasms,¹⁴⁶ 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. 15.55), which can be assessed using traditional cytogenetic techniques or fluorescence or chromogenic in situ hybridization (FISH/CISH).^142,143 This karyotypic aberration produces a selective fusion transcript known as SYT-SSX, and the polymerase chain reaction (PCR) can be employed to detect it diagnostically, using suitable primer pairs of nucleotides.^147,292

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 or FISH 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 Fig. 15.56.

Figure 15.52 (A to C) Monophasic 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.

Figure 15.53 Immunoreactivity for epithelial membrane antigen (A) and pan-keratin (B) is potentially seen in monophasic synovial sarcoma (MSS). (C) Electron microscopy of MSS demonstrates attachment complexes between the fusiform tumor cells, consistent with their epithelial nature.

Therapy and Prognosis

The long-term outlook for patients with SS of the lung is guarded at best. In a series reported by Zeren et al., 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.²⁸⁷ 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.²⁹⁴

Figure 15.54 Nuclear immunoreactivity for transducin-like enhancer [of Splitj-1 is a selective marker for synovial sarcoma of both monophasic and biphasic types, among all sarcoma morphotypes.

Figure 15.55 Fluorescent in situ hybridization preparation from primary pulmonary synovial sarcoma, showing the t(X; 18) chromosomal translocation that typifies this neoplasm. The green signal corresponds to a segment of chromosome 18; the red signal corresponds to a segment on the X chromosome.

Essary et al.²⁹⁶ 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.

Other Primary Pulmonary Sarcomas

In addition to those tumors that have been previously considered, there are other sarcoma morphotypes that may be encountered in the lungs.

Figure 15.56 Decision tree for the immunohistochemical diagnosis of synovial sarcoma. 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; +, positive; -, negative.

These include liposarcoma (Fig. 15.57),^297-299 angiosarcoma,^259,300,301 malignant peripheral nerve sheath tumor,^302,303 osteosarcoma,³⁰⁴ angio- matoid fibrous histiocytoma (Fig. 15.58),³⁰⁵ and alveolar soft parts sarcoma (Fig. 15.59).^306-309 Fewer than 25 cases of each of these neoplasms have been documented in the literature, making it impossible to present their clinicopathologic attributes as if they were thoroughly studied and well characterized.

However, a few generalizations do appear to be appropriate. First, liposarcomas and malignant schwannomas of the lung have usually been documented as tumors that have an endobronchial component, potentially producing airway obstruction. In contrast, this feature is not part of the profile of either angiosarcoma or osteosarcoma. Secondly, both angiosarcoma-like and osteosarcoma-like epithelial neoplasms are vastly more common in the respiratory tract than true sarcomas with those respective microscopic patterns.¹ Thus the pathologist must be certain to address the likelihood of SC under such circumstances. Finally, therapy for those rare lesions in this category that have proven to be primary in the lungs is completely anecdotal and has been based on extrapolation from treatment used for histologically similar neoplasms in osseous and soft tissue sites.

Part III: Primary Malignant Melanomas of the Lung

Melanomas arising primarily in the lung are extraordinarily rare; the literature contains sparse reports on this topic.^{310- 327} the largest series is from the AFIP, consisting of eight cases seen over a period of many years.³¹⁰ Although rigorous criteria have been proposed for primary malignant melanoma of the lung (PMML), this interpretation cannot be established with absolute certainty because of the well-known capacity for spontaneous regression of primary melanomas in mucosal or cutaneous sites. To consider a diagnosis of PMML seriously, there obviously must be no prior history of a potentially malignant pigmented tumor of the skin or ocular uveal tract. Moreover, clinical examination for possibly occult melanomas in the integument, nailbeds, eyes, nasal cavity, paranasal sinuses, oral cavity, esophagus, anus, rectum, vulva, and leptomeninges should not show any extrapulmonary lesions. In fact, some authors have suggested that a case of PMML can be regarded as bona fide only retrospectively, after a postmortem examination has excluded another source of a primary melanoma.^311-313 Hence, it is self-evident that this diagnosis can never be considered irrefutable during life.

As to the fundamental question of the origin of primary melanoma in the respiratory tract, some have stressed that the tracheobronchial tree is, in fact, of endodermal derivation—in similarity to the oral cavity and the esophagus—where well-documented primary melanomas have originated.³¹³ Nonetheless, these tumors are generally thought to be neuroectodermal, and their presence in endodermal or mesodermal sites is There fore problematic with reference to “classical” histogenetic theory. We instead subscribe to the “stem cell” theory of neoplasia, wherein embryologic constructs are essentially irrelevant, to explain the phenomenon under discussion here. In that vein, it is interesting that some benign proliferations of the lung also demonstrate partial or global melanocytic differentiation: namely, clear-cell “sugar” tumor, angiomyolipoma, and lymphangioleiomyomatosis.^328-332

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.^310-327 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 studies.

Figure 15.57 (A) Pleomorphic liposarcoma of the right lung, represented by a large rounded mass in the right hemithorax on this lateral plain-film radiograph. (B) Gross photograph of pleomorphic pulmonary liposarcoma, showing a yellow-white, lobulated cut surface. (C) Photomicrograph of pleomorphic pulmonary liposarcoma, demonstrating obvious lipoblastic differentiation among a population of cells with markedly heterogeneous nuclear profiles.

Figure 15.58 (A) Angiomatoid (malignant) fibrous histiocytoma (AFH) of the lung, showing a central blood lake (right of figure), a zone of relatively monomorphic spindle cells, and a cuff of mature lymphocytes (left of figure). This tumor manifests either a t(12,16)(q13;p11) or a t(12,22)(q13;p12) chromosomal translocation, yielding FUS-ATF1 and EWSR1-ATF1 fusion genes, respectively. (B) Perls staining of AFH shows abundant deposits of hemosiderin amidst the tumor cells, providing a potentially helpful finding in differential diagnosis with other spindle cell lesions.

Figure 15.59 (A) Alveolar soft part sarcoma (ASPS), primary in the lung, comprising well-defined nests of loosely apposed epithelioid cells with prominent nucleoli and eosinophilic cytoplasm. This tumor exhibits a recurrent der(17) chromosomal aberration, related to a nonreciprocal t(X;17)(p11.2;q25) translocation. (B) Fine-needle aspiration biopsy of ASPS, showing dyshesive large round cells with fluffy amphophilic cytoplasm. (C) Nuclear immunoreactivity for the TFE3 protein is present in ASPS, related to the t(X;17) translocation. (D) ASPS contains crystalloid cytoplasmic inclusions by electron microscopy; these structures are thought to represent aggregates of myogenous proteins. ([B] Courtesy Dr. Paul Wakely, Columbus, Ohio).

Pathologic Findings

In several reported cases of PMML, the lesions have been centered in large airways, including the trachea and major bronchi.^{310,316,318,319} 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. 15.60). Indeed, divergent differentiation into chondroosseous-like tissue has been reported in melanomas.³³³

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 et al.³³⁴ and Yamada and colleagues³³⁵ 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 pan-keratin (often used as an internal control in carcinoma cases), the alternative possibility of melanoma should be considered. In that context, it is worth noting that a pigmented variant of primary pulmonary neuroendocrine carcinoma has indeed been reported.³³⁶

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 (Fig. 15.61).^310,313 Electron microscopic studies showing the presence of cytoplasmic premelanosomes (Fig. 15.62), or immunohistochemical negativity for keratin and labeling for S100 protein, HMB-45 antigen, melan-A/MART-1, PNL2, or tyrosinase, are useful in confirming the presence of melanocytic differentiation³¹⁰ and excluding the differential diagnoses of anaplastic carcinoma or sarcoma.

Figure 15.60 (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.

Figure 15.61 In situ malignant melanoma of the bronchial mucosa. The tumor cells are scattered throughout the epithelium randomly.

Therapy and Prognosis

Before assigning a diagnosis of probable PMML, one must undertake thorough dermatologic examination, as well as extensive radiologic and endoscopic assessments.^322,325-327 Those measures are designed to detect an occult primary mucocutaneous melanoma in another location. De Wilt et al. also considered the scenario in which pathologists confront a possible diagnosis of intrapulmonary melanoma in intraoperative consultation.³²⁷ 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.

Most documented cases of PMML have fared extremely poorly, with the majority of patients dying within 1 year of diagnosis.^{310- 327} Reid and Mehta reported one individual who survived 11 years after surgery³¹⁶; 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 that case is doubtful as a verifiable PMML. Most patients have undergone surgical resections of their tumors, although a few have received irradiation or chemotherapy.³¹¹ 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 event. Whether the advent of new biologic agents, with activity against melanoma, will alter that situation remains to be seen.

Figure 15.62 Electron photomicrograph of malignant melanoma, demonstrating the presence of cytoplasmic premelanosomes. These inclusions are diagnostic.

Part IV: Sarcomas of the Pulmonary Arterial Trunk

Although it is technically not part of the respiratory tract, the pulmonary arterial trunk is an appropriate topic for this discussion that centers on intrathoracic mesenchymal malignancies. For more than 75 years, it has been known that this vascular segment may serve as the point of origin for sarcomas with diverse histologic features, and clinical manifestations that are just as variable.³³⁷ To date, approximately 200 cases of pulmonary trunk sarcoma (PTS) have been documented.^12,337-361

Figure 15.63 (A) Computed tomographic image showing a mass within the pulmonary trunk representing pulmonary trunk sarcoma. (B) Another pulmonary trunk sarcoma as seen at autopsy.

Clinical Summary

Patients with PTS are adults in middle life or beyond, and There is 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.^341,342 Patients often complain of intractable cough, progressive dyspnea, and dull chest pain that may increase with exertion; cardiac tamponade has rarely been observed.³³⁹ 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.^344,345 However, cardiac imaging studies demonstrate no evidence of ventricular hypokinesis or perfusion abnormalities.³⁵⁶

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.³³⁷ However, current imaging modalities are now capable of revealing the tumor in question rather easily (Fig. 15.63).³⁵⁶ It takes the form of a partially obstructing, endoluminal mass at the level of the right ventricular outlet or above it, and 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.^357,358

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 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. 15.64), whereas others are anaplastic tumors that defy easy classification under the microscope (Fig. 15.65).³³⁷ The proffered pathologic interpretations in the literature on PTS include such diagnoses as undifferentiated sarcoma, angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibromyxosarcoma, fibrosarcoma, chondrosarcoma, osteosarcoma, hemangioendothelioma, MFH, and malignant mesenchymoma.^12,337-361 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 15.64 This pulmonary trunk sarcoma has a low-grade fibromyxoid image.

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 of malignant fibrous histiocytoma. However, some low-grade fibromyxoid variants can closely simulate an intracardiac myxoma or organizing mural thrombus.³³⁷ Close attention to morphologic detail is the only certain method for distinguishing between such possibilities.

Figure 15.65 These microscopic images of a case of pulmonary trunk sarcoma demonstrate (A) one area that resembles malignant fibrous histiocytoma histologically, (B) whereas another focus in the lesion shows obvious formation of osteoid. The exact nosologic classification of such tumors is often difficult.

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 SS, spindle cell sarcomas of various lineages (Fig. 15.66), pleomorphic sarcomas (Fig. 15.67), and small round-cell tumors (Fig. 15.68) have superimposable microscopic images in such preparations. Thus ancillary diagnostic methods are necessary to make specific diagnoses in those neoplastic categories.

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.³⁵⁹ 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.

Figure 15.66 Generic fine-needle aspiration biopsy image of spindle cell sarcoma.

Figure 15.67 Generic fine-needle aspiration biopsy image of pleomorphic sarcoma.

Figure 15.68 Generic fine-needle aspiration biopsy image of small round-cell sarcoma

Figure 15.69 (A) Computed tomography image and (B) gross photograph of localized sarcomatoid mesothelioma.

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.^337,345 An exception to the latter statement is embodied in a report by Tavora et al., who suggested that low-grade myofibroblastic PTS had a distinctly better prognosis than other histotypes.³⁶⁰ 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.³⁶¹ 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.

Part V: Tumors of the Pleura

Sarcomatoid Malignant Mesothelioma (See Also Chapter 21)

Clinical Summary

Regardless of histologic subtype—sarcomatoid or otherwise— The clinical features of intrathoracic mesothelioma are the same.^362-364 Malignant mesothelioma of the pleura typically affects adult men, although women and children are certainly represented in the patient population with this neoplasm.^364,365 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. 15.69). Later in the clinical course, encasement of the lung by confluent neoplastic tissue is seen (Fig. 15.70).

In likeness to examples of peritoneal mesothelioma that have been linked causally to chronic recurrent peritonitis in the context of familial Mediterranean fever,³⁶⁶ 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.³⁶⁷ In those instances, 85% to 90% of patients will show the presence of pleural plaques or pleural calcifications, or quantitative pulmonary asbestos fiber burdens clearly in excess of the background, serving as tangible markers of such exposure.^368-374 ttose findings are much 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.

Figure 15.70 An extrapleural pneumonectomy specimen in this case demonstrates circumferential encasement of the lung by tumor tissue and extension into the interlobar septa.

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.^375,376 Substantial recent interest has centered on the potential role of simian virus-40 in this setting,³⁷⁷ but conclusions on whether that agent is indeed causative are still unsettled. At least 30% of pleural mesotheliomas are idiopathic.³⁶⁷

Figure 15.71 (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 15.72 (A) Another example of sarcomatoid mesothelioma is more anaplastic cytologically, simulating the appearance of pleomorphic sarcomas. This attribute is also visible in a fine-needle aspiration biopsy specimen (B).

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 There tofore included epithelioid, biphasic, and sarcomatoid mesotheliomas.^{364,378,379 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).³⁷⁸ 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 malignant mesothelioma (MM)—with epithelioid and sarcoma-like elements— primary SS of the pleura is an important diagnostic alternative.¹¹ 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,³⁸⁰ or immunoreactivity for TLE-1, its separation from MM can be extremely challenging. This is so because the immunophenotypes of the two tumors are otherwise so similar.³⁸¹

Monophasic sarcomatoid mesothelioma potentially simulates a range of spindle cell sarcoma morphotypes that may affect the pleura (Figs. 15.71 and 15.72), again including monophasic SS, but also fibrosarcoma, MFH, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.^382-386 Pseudo- mesotheliomatous 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.

In specific reference to sarcomatoid mesotheliomas, the basic histologic image of such lesions is virtually identical to that associated with SC of the lung.^387-392 Indeed, cases in which a tumor mass involves both the peripheral lung and the pleura will require immunohistologic or molecular evaluation in order for a distinction to be made with definition between those tumor types.³⁹³ 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.

Figure 15.73 (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.

Lymphohistiocytic mesothelioma^394,395 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.^396-402 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. 15.73). 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.⁴⁰¹

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, FISH/CISH, the PCR using appropriately chosen primers, and traditional cytogenetic evaluations.^{362-374,403,404}

Although most attention has been paid in recent years to the immunohistochemical separation of epithelioid MM from metastatic adenocarcinoma,^405,406 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 pan-keratin, or keratin 5/6, or both); EMA; thrombomodulin; HBME-1; calretinin; Wilms tumor gene product-1 (WT-1); podoplanin; 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.⁴⁰⁷ 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.⁴⁰⁸

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, WT-1, podoplanin, and calretinin assume much greater value in the differential diagnosis of sarcomatoid MM (Fig. 15.74).^148,407,409 the principal interpretative alternatives are those of true sarcoma, sarcomatoid pseudomesothe- liomatous carcinoma, or malignant SFT; 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.^410,411

Figure 15.74 Diffuse immunoreactivity is seen in this sarcomatoid mesothelioma for podoplanin, with antibody D2-40.

FISH or PCR 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.^380,381 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. 15.75). Rarely, localized sarcomatoid mesotheliomas may also resemble SFTs of the pleura⁴¹²; in those cases, immunoreactivity for CD34, or CD99, or both, tends to exclude a diagnosis of MM.⁴¹³

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.^362,363,414 the sarcomatoid type of mesothelioma appears to be the most aggressive, and it is associated with only a brief survival after diagnosis.²⁴³ A peculiarity of this neoplasm is its tendency to grow through surgical defects in the chest wall, represented by either 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.⁴¹⁵ Treatment is generally supportive, inasmuch as irradiation and chemotherapy produce little survival benefit.⁴¹⁶ Extrapleural pneumonectomy is still a controversial surgical approach to mesothelioma; its proponents claim a definite decrease in mortality in the operative group, as compared with stage- and age-matched controls managed by other means.⁴¹⁷ However, those observations have not been supported by other studies.⁴¹⁸ Some authors have suggested that the expression of aquaporin-1 by the tumor cells in epithelioid mesotheliomas is a relatively favorable prognostic marker.⁴¹⁹

Figure 15.75 This electron photomicrograph of sarcomatoid mesothelioma shows an intercellular attachment-plaque (left center), but There are otherwise no specialized markers of epithelial differentiation.

Primary Pleural Sarcomas

Sarcomas are as rare in the pleura as they are in the lungs. Most neoplasms that take the generic appearance of malignant mesenchymal tumors in the serosae of the thorax are, in actuality, epithelial lesions. They may either represent metastatic SCs or variants of malignant mesothelioma, as considered previously. In addition, there are only a limited number of definable clinicopathologic entities to consider in this specific anatomic location. These include fibrosarcoma, malignant solitary (localized) fibrous tumor of the pleura, leiomyosarcoma, SS, Askin malignant thoracopulmonary small round-cell tumor, PPB, KS, EH, and angiosarcoma. Extraordinarily rare examples of granulocytic sarcoma (extramedullary tumefactive acute myeloid leukemia),⁴²⁰ malignant peripheral nerve sheath tumor (Fig. 15.76),³⁸⁶ mesenchymal chondrosarcoma,⁴²¹ extraskeletal myxoid chondrosarcoma (Fig. 15.77),⁴²² liposarcoma,^423,424 and extraosseous osteosarcoma^425,426 have been documented as apparently primary pleural tumors, but information on such lesions is anecdotal.

Pleural Fibrosarcoma and Malignant Solitary Fibrous Tumor

A review of the literature on serosal neoplasms reveals few examples of well-documented primary pleural fibrosarcoma (PPFS).^427,428 the latter is somewhat arbitrarily distinguished from malignant solitary fibrous tumor (MSFT) of the pleura^429,430 by its clinical growth pattern, which is diffuse rather than localized. However, in other respects, these two tumor entities are virtually identical to one another; in fact, some examples of PPFS have apparently evolved from SFT of the pleura.^431-436 Although some authors prefer to separate malignant fibrous tumors of the pleura into “true” fibrosarcoma and MFH-like tumors,⁴³⁷ all of these lesions will herein be considered as a single group because of their closely similar clinicopathologic attributes.

Figure 15.76 (A) Malignant peripheral nerve sheath tumor of the pleura, showing variation in cellular density and a tendency for nuclei to align themselves in parallel. (B) the tumor is immunoreactive for CD56.

Clinical Summary

Pleural fibrosarcoma and MSFT arise in adult patients over a wide range of ages (15 to 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.^429,430 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.^438,439 It appears that pleural sarcomas have no association with prior asbestos exposure (in contradistinction to a proportion of malignant mesotheliomas).³⁹⁰ Other potential etiologies of these lesions are unsettled at the present time, but some authors have reported a possible pathogenetic linkage to chronic tuberculous pleuritic and prior pyothorax.^440,441

Figure 15.77 (A) Extraskeletal myxoid chondrosarcoma (EMCS) of the pleura, resembling epithelioid mesothelioma. Cords of tumor cells are set in a myxoid stroma. (B) the tumor cells contain intrareticular microtubules, a singular finding in EMCS.

Radiographic studies in cases of PPFS commonly demonstrate the presence of a unilateral pleural effusion, which may be massive.^438,442 In addition, a dominant mass and diffuse but irregular thickening of the pleura are usually evident and are especially well seen with CT or MRI studies.⁴⁴² Based on clinical data, it is not possible to distinguish PPFS from diffuse malignant mesothelioma, 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 lobulated (Fig. 15.78).⁴³⁸ 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.^431,438

Pathologic Findings

The macroscopic appearance of PPFS is virtually identical to that of diffuse malignant mesothelioma, that is, 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.^431-439 On the other hand, MSFTs are sessile or pedunculated localized masses that are most often seen in the upper portions of either hemi- thorax. They have bosselated, fleshy, tan-gray cut surfaces, usually with foci of spontaneous necrosis and hemorrhage (Fig. 15.79).^431,438

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. 15.80). The neoplastic cells may be arranged in a storiform fashion and show moderately to markedly pleomorphic cytologic features, calling to mind the histologic attributes of MFH.^427,438 In other cases, they are aligned in a fascicular herringbone configuration, as in pulmonary fibrosarcomas (Fig. 15.81). 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 blander spindle-cell aggregates are enmeshed in hyalinized, keloidal-type collagen.⁴³⁸ A “staghorn” stromal vascular pattern is common in such areas as well.

Figure 15.78 Computed tomography image showing left pleural-based mass, which proved to be a malignant solitary fibrous tumor.

Figure 15.79 Gross photograph of excised malignant solitary fibrous tumor of the pleura demonstrating internal foci of necrosis.

Figure 15.80 (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 15.81 (A) Herringbone pattern of densely cellular growth and mitotic activity are present in this localized malignant solitary 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. 15.82). 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.^427,431,432 In contrast, true mesotheliomas (including sarcomatoid variants) uniformly express epithelial markers.³⁸⁹ In contrast to benign SFTs, some MSFTs may lack immunoreactivity for CD34, bcl-2 protein, CD99, and STAT6.⁴³⁶

Therapy and Prognosis

PPFS is not often treatable by surgical means, owing to 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 may also involve the pericardium and produce cardiac embarrassment.⁴⁴³ Actuarial 1-year survival was only 39% in one series where multimodality therapy was employed.⁴³⁷

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.⁴³⁸ 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 There fore 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.³⁹⁰ Irradiation and chemotherapy do not appear to offer any benefits in this setting and may even shorten the survival of patients with MSFT.⁴³⁸

Figure 15.82 (A) Fibrosarcoma-like malignant solitary fibrous tumor of the pleura comprising cells that ultrastructurally resemble fibroblasts (B).

Figure 15.83 Gross photograph of primary pleural leiomyosarcoma, showing a localized lesion with a fleshy, white-gray cut surface.

Figure 15.84 Fascicular spindle cell growth is evident in this primary pleural leiomyosarcoma.

Primary Pleural Leiomyosarcoma

Leiomyosarcomas are extremely rare as primary pleural neoplasms, with less than 25 well-documented cases in the literature.^444-446 Only one series of such tumors has been reported, by Moran and colleagues.⁴⁴⁴

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. 15.83).⁴⁴⁵ Some examples have encased the lung completely, simulating malignant mesothelial tumors.⁴⁴⁴

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. 15.84). Necrosis is also frequently encountered as well. The tumors invade the lung parenchyma or the soft tissues of the chest wall, or both.

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. 15.85). Immunohistologically, pleural leiomyosarcomas are reactive for vimentin, desmin, muscle- specific actin, caldesmon, calponin, and alpha-isoform actin (Fig. 15.86),⁴⁴⁴ 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.

Therapy and Prognosis

Because of the rarity of these lesions, only anecdotal information is available on the biology of primary pleural leiomyosarcomas. Moran et al. advocated surgical ablation but found that two of five such lesions they studied could not be resected completely.⁴⁴⁴ the merits of adjuvant therapeutic modalities are as yet unstudied.

Figure 15.85 Cytoplasmic skeins of thin filaments, punctuated by dense bodies, are seen in this electron photomicrograph of primary pleural leiomyosarcoma.

Figure 15.86 Immunoreactivity for caldesmon is apparent in primary pleural leiomyosarcoma.

Askin Tumor (Primitive Neuroectodermal Tumor) and Desmoplastic Small Round-Cell Tumor

In 1979 Askin and colleagues described a peculiar thoracic neoplasm that was seemingly limited to children, adolescents, and young adults.⁴⁴⁷ This lesion arises from the pleura or the extrapleural intercostal soft tissue and was originally named the “malignant small cell tumor of the thoracopulmonary region.” Since then, it has become known more simply as the Askin tumor, or alternatively, thoracopulmonary primitive neuroectodermal tumor (TPNET) because the neoplasm has been shown to exhibit neuroepithelial differentiation.^448-459 Before its seminal description, it is likely that this lesion was included among cases of Ewing sarcoma of the thorax or peripheral neuroblastoma.⁴⁶⁰ Primary PNET of the lung is considered elsewhere in this monograph, but the Askin tumor is technically considered to be separate from that entity and will There fore be discussed at this point. A related neoplasm is known as desmoplastic small round-cell tumor (DSRCT) of the serosal surfaces. It was originally described in the peritoneum, and is more common There by far, but several examples have been described in the pleura as well.^461-463

Figure 15.87 Askin tumor (primitive neuroectodermal tumor) of the right hemithorax in a young child, as seen in a computed tomography scan.

Clinical Summary

Askin tumor and DSRCT demonstrate a peak incidence during the second decade of life (mean age 15 years) and show a slight male predilection. Isolated cases of TPNETs in infants and in older adults have also been documented.^461-467 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.⁴⁴⁸ Although they have been confused with classical neuroblastoma in some reports, Askin tumors and DSRCTs are not associated with elevations of catecholamine metabolite levels in the urine or blood, nor do they produce the opsoclonus-myoclonus syndrome.^456,464

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. 15.87). TPNETs and DSRCTs often reach a size greater than 10 cm at the time of initial diagnosis, and they demonstrate ill-defined interfaces with the subjacent lung or surrounding tissues.⁴⁶⁸

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.⁴⁵⁶ At a macroscopic level, TPNET is lobulated with fleshy, relatively soft, tan-gray cut surfaces (Fig. 15.88) that may show foci of hemorrhage and necrosis.³³⁰ Microscopically, it exhibits cellular monomorphism, with round-to-oval nuclei, even distribution of chromatin, indistinct nucleoli, and variable mitotic activity (Fig. 15.89). Stromal blood vessels are numerous and form a discernible network within the tumor mass; matrical hemorrhage also may be manifest.^447-464 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 (Fig. 15.90).^447,448 Histochemically, the Askin tumor may or may not contain abundant glycogen with the PAS method (Fig. 15.91), although in the original series on this lesion, only PAS-negative neoplasms were accepted to facilitate separation from classical Ewing sarcoma.

Figure 15.88 Partial excision of the lesion yielded a fleshy mass demonstrating internal foci of necrosis.

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 an Askin tumor (Fig. 15.92). The growth pattern is also more organoid than in conventional TPNET.^461-463 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. 15.93),⁴⁶² and ultrastructural studies also support the presence of bifid epithelial-myogenic differentiation.

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 SS, HPC, 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 (Fig. 15.94).^448,469 By electron microscopy, they demonstrate blunt cytoplasmic processes that contain dense-core granules or microtubules; these characteristics are seen in classical neuroblastoma as well, but not in other small round-cell tumors.⁴⁵⁶

Figure 15.89 (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 shows primitive cytoplasmic extensions that contain neurosecretory-type or synaptic vesicles. (D) Immunoreactivity for CD99 (MIC2 protein) is also present.

Figure 15.90 Primitive intercellular rosettes are present in this Askin tumor (primitive neuroectodermal tumor).

Figure 15.91 Diffuse reactivity is seen with the periodic acid—Schiff stain in an Askin tumor, reflecting the presence of abundant cytoplasmic glycogen.

Immunohistochemically, TPNET is related to classical Ewing tumor-PNET in that it shows consistent reactivity for synaptophysin as well as CD99.⁴⁷⁰ DSRCT is more variable with regard to its positivity for both of those markers.^471,472 the Askin tumor may be distinguished from neuroblastoma immunophenotypically; the former lesion is reactive for both beta₂-microglobulin and CD99,⁴⁶² whereas the latter tumor is not. Among PNET, DSCRCT, and neuroblastoma, only DSCRT labels for WT-1 (Fig. 15.95).⁴⁷³,⁴⁷⁴

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.⁴⁴⁸ 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 that are similar to those employed for Ewing sarcoma.^449,475 Stage III and IV Askin tumors and DSRCTs are probably best managed nonsurgically because There are no data to support a role for debulking surgery in such circumstances.⁴⁴⁸

Figure 15.92 (A and B) Desmoplastic small round-cell tumor of the pleura, in which angular cell groups composed of cells like those of an “ordinary” primitive neuroectodermal tumor (Figs. 15.53 to 15.55) are set in a markedly fibrous stroma. They are dyshesive and monomorphic in a fine-needle aspiration biopsy specimen (C).

Figure 15.93 the neoplastic cells in desmoplastic small round-cell tumor of the pleura are concurrently immunoreactive for keratin (A) and desmin (B).

Figure 15.94 the characteristic t(11,22) chromosomal translocation of a primitive neuroectodermal tumor is seen in a spectral-karyotypic preparation (A), and a fluorescent in situ hybridization preparation, using break-apart probes (B).

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^376,476) in approximately 1% of cases, and Farhi et al. described several examples of postchemotherapy myelodysplastic syndrome and acute leukemia in this context.⁴⁷⁷

Pleuropulmonary Blastoma

Until 1988, a group of anaplastic mesenchymal tumors of the peripheral lung and pleura in children had been grouped together under the rubric of pediatric pulmonary blastoma. Nonetheless, Manivel et al.⁷⁷ showed that such lesions differed from typical PBs in adults, which comprise a subset of SCs. The childhood tumors were found to be more often primary in the pleura; they also showed a histologic resemblance to soft tissue sarcomas. Because of these important points of difference from adult PBs, the pediatric lesions were reclassified as PPBs.

Figure 15.95 Nuclear immunoreactivity for Wilms tumor-1 (WT-1) protein is apparent in pleural desmoplastic small round-cell tumor.

Clinical Summary

PPBs arise most often in the first decade of life, without a distinct preference for males or females.⁴⁷⁸ However, isolated examples have been reported in adult patients as well.^{77-83,479-490} Cough, chest pain, weight loss, dyspnea or tachypnea, and spontaneous pneumothorax are the most common presenting complaints of PPB.^77,485 Evidence of a pleural effusion may also be found on physical examination, and a small subset of patients present with acute, rapidly progressive respiratory embar- rassment.⁴⁹¹ It is clear that this neoplasm may be part of certain cancer families, in which other soft tissue sarcomas and cystic nephromas may be seen in other members.^{81,82,485,487} 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, nasal chondromesenchymal hamartomas, and thyroid hyperplasia.^492,493 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.⁴⁹⁴

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 studies (Fig. 15.96). Some examples may show focal internal calcification, and types I and II PPB (see subsequent chapter text) demonstrate obvious internal cyst formation (Fig. 15.97).^{77,485,488,495,496}

Pathologic Findings

PPB is grossly cystic or fleshy and tan-pink-gray upon 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 coworkers^80,485,492 have subclassified PPBs into three groups, based on the extent of cystic change that they demonstrate. Type I tumors are cystic; type II lesions are mixed solid and cystic; and type III PPBs are predominantly solid (Figs. 15.98 to 15.100). Cystic foci in type I PPB 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 (see Chapter 5).^495,497

Figure 15.96 Computed tomogram of pleuropulmonary blastoma in a young adult, showing partial effacement of the right hemithorax.

Figure 15.97 Multilocular internal cystic change is apparent in this pleuropulmonary blastoma, as seen in a high-resolution computed tomography scan.

Microscopically, one sees a heterogeneous mixture of growth patterns that are admixed with one another in various solid regions of these tumors.⁴⁸⁶ Some foci resemble MFH (Fig. 15.101); others take on a rhabdomyosarcomatous appearance; and still other areas have the features of primitive neuroepithelial tumors, fibrosarcoma, liposarcoma, chondrosarcoma, or osteosarcoma.^77,485 In the past, some observers applied the term malignant mesenchymoma to PPB, but such a designation is no longer used. Importantly, epithelial foci are absent in PPB, in contrast to their indisputable presence in so-called adult PB.^77,80,485 Immunohistochemical and ultrastructural studies demonstrate findings that are in accord with the aforementioned microscopic features, and they again fail to reveal epithelial characteristics in PPBs.^77,80

Figure 15.98 (A and B) Gross photographs of type I pleuropulmonary blastoma, demonstrating extensive cystic change in the lesions. (C) the cyst walls contain primitive mesenchymal tissue as well as elements with rhabdomyoblastic features (D and E), which are immunoreactive for desmin (F).

Figure 15.99 (A) Gross photograph of type II pleuropulmonary blastoma, the solid areas of which (B) resemble the microscopic image of pleomorphic sarcoma.

Figure 15.100 (A) Type III pleuropulmonary blastoma, represented by a solid mass (A). This particular tumor has a nondescript spindle cell constituency (B). (Courtesy Dr. D. Ashley Hill, Washington, DC).

Fine-needle aspiration biopsies typically show dyshesive, pleomorphic cells from PPBs (Fig. 15.102). Immunohistologic studies are required to assess the presence of lineage-related markers in such elements.

Hill et al. have suggested that a proportion of cystic type I PPBs evolve into types II or III over time in a sizable number of cases.⁴⁹⁶ Type I tumors show the presence of primitive mesenchymal tissues mantling intralesional cysts, beneath a cytologically bland lining of respiratory epithelium (Figs. 15.103 and 15.104). Rhabdomyosarcomatous and chondrosarcoma-like elements are common in types II and III PPB.⁴⁹²

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.⁴⁸⁶ the absence of keratin in PPB excludes PB, other forms of carcinoma, mesothelioma, and germ cell tumors from further consideration.

Therapy and Prognosis

PPB is a rare tumor; There fore 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 intensive irradiation and chemotherapy.^485,492 Because of the histologic characteristics of the tumor, which are like those of de novo soft tissue sarcomas, it would seem appropriate to employ potent drug combinations that are directed toward the various histologic components of PPB (e.g., rhabdomyosarcoma, MFH, osteosarcoma). Surgical debulking of the tumor mass can also be considered. Morphologic findings in PPBs have been related 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.^80,485,492 Interestingly, Wright has also reported a case wherein successive recurrences of a PPB showed progressive transformation from type I to type III morphology.⁴⁹⁰ Priest and colleagues have reported a singular tendency for PPB to demonstrate metastases to the brain and other central nervous system sites (Fig. 15.105).⁴⁹⁸ ttat complication is observed in 11% of type II cases and 54% of type III cases.

Figure 15.101 Another type III pleuropulmonary blastoma is more pleomorphic microscopically.

Figure 15.102 Bizarre, large, dyshesive spindle cells are seen in this fine-needle aspiration biopsy specimen of type III pleuropulmonary blastoma.

Figure 15.103 (A) Solid, alveolar rhabdomyosarcoma-like growth in type III pleuropulmonary blastoma, showing immunoreactivity for fast-muscle myosin (B).

Vascular Sarcomas of the Pleura

As mentioned previously, angiosarcoma, KS, and EH may take origin in the pleura as well as in the pulmonary parenchyma. The general clinicopathologic attributes of these lesions were described in previous text. It is notable that the most common initial sign of angiosarcoma and KS of the pleura is the presence of a bloody pleural effusion (Fig. 15.106).³⁰⁰ Gross examination of the tumor at thoracotomy or thoracoscopy shows multiple soft, hemorrhagic, red-violet, nodular pleural implants in examples of angiosarcoma and KS. On the other hand, EH is virtually identical to malignant mesothelioma at a macroscopic level (Fig. 15.107); histologic and immunohistochemical studies are necessary to distinguish between them.^499,500 As is true of their intrapulmonary counterparts, KS and angiosarcoma of the pleura are associated with a dismal prognosis,^501-505 whereas patients with EH may survive for prolonged periods of time.⁴⁹⁹

Figure 15.104 A chondroid area is present in this pleuropulmonary blastoma.

Figure 15.105 Metastasis of pleuropulmonary blastoma to the brain, as seen in a magnetic resonance image of the head.

Figure 15.106 (A) A pleural tumor is seen in the right hemithorax on this computed tomography scan, with an associated pleural effusion. (B) Fine-needle aspiration biopsy of the lesion shows modestly cohesive malignant epithelioid cells, also seen in a concurrent biopsy (C). Immunoreactivity for CD31 (D) establishes the diagnosis of epithelioid angiosarcoma of the pleura.

Figure 15.107 Gross (A) and microscopic (B) images of primary epithelioid hemangioendothelioma (EHE) of the pleura, closely resembling those of epithelioid mesothelioma. However, EHE is immunoreactive for CD31 (C), unlike mesothelioma. ([A] Courtesy Dr. Victor Roggli, Durham, North Carolina.)

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Multiple Choice Questions

1. Which of the following procedures is/are used in modern pulmonary medicine to obtain tissue specimens from the lungs?

A. Bronchoscopy

B. Video-assisted thoracoscopy

C. Fine-needle aspiration

D. Surgical wedge biopsy

E. All of the above

ANSWER: E

2. Which ONE of the following statements is FALSE?

A. Procurement of clinical and radiologic information is diagnostically more helpful in neoplastic lung disease, compared with nonneoplastic disorders.

B. Specimen size and quality affect the level of diagnostic certainty.

C. Descriptive diagnoses are acceptable in lung pathology.

D. Fine-needle aspiration biopsy of the lung has acceptable specificity and sensitivity compared with diagnosis of pulmonary neoplasms.

E. The marginal quality of any given lung biopsy specimen can be described in the surgical pathology report.

ANSWER: A

3. Which ONE of the following statements is TRUE?

A. Flexible bronchoscopy began in the United States in the late 1980s.

B. Rigid bronchoscopy is no longer performed in Asia.

C. Flexible bronchoscopy requires general anesthesia.

D. Flexible bronchoscopy is best used for examination of the proximal airways.

E. Flexible bronchoscopes have smaller bores than rigid bronchoscopes.

ANSWER: E

4. Modern flexible bronchoscopes:

A. Allow the operator to visualize sixth-order bronchi

B. Are commonly equipped with a cupped forceps

C. May produce biopsies that sometimes include bronchial cartilage

D. None of the above

E. A, B, and C

ANSWER: E

5. Biopsy specimens that are obtained in the bronchoscopy suite:

A. Should ideally be air-dried before submission to the laboratory

B. Can alternatively be placed in fixative solution or transport medium by the bronchoscopist

C. Should be wrapped in sterile dry gauze pads before sending them to the laboratory

D. Are unsuitable for immunohistochemical studies

E. All of the above

ANSWER: B

6. Currently, the standard fixative for lung biopsy specimens is:

A. Ethylene glycol

B. Methacarn

C. Ten percent formalin

D. Bouin solution

E. A mixture of 20% formalin and 80% ethanol ANSWER: C

7. Which of the following statements about bronchoscopy specimens is TRUE?

A. They are subject to relatively little artifact due to biopsy technique.

B. Air-drying helps preserve open alveolar spaces in them.

C. The optimal number of tissue pieces in them depends on the disease process.

D. Fungal cultures cannot be performed using them.

E. All of the above

ANSWER: C

8. In transbronchial lung biopsy techniques, which of the following statements is TRUE?

A. Cupped forceps are not used.

B. The jaws of the forceps should be open when it is first placed in the airway.

C. Biopsies are obtained at end-inspiration of the respiratory cycle.

D. The pieces of tissue that are obtained have a smooth cylindrical shape.

E. Tissue fragments measure 2 to 3 mm in diameter.

ANSWER: E

9. In obtaining specimens for cytopathology, which ONE of the following statements regarding the bronchial brushing technique is TRUE?

A. It uses an instrument resembling a miniature paintbrush.

B. Contents of the brush are washed onto glass slides with ethanol.

C. Resulting slides cannot be stained with Wright-Giemsa reagents.

D. Papanicolaou stain is often applied to the slides.

E. Immediate fixation of slides in 10% formalin is recommended.

ANSWER: D

10. Molecular characterization of lung tissue can be accomplished using:

A. Bronchial washing specimens

B. Transbronchial biopsy specimens

C. Open lung biopsy specimens

D. All of the above

E. None of the above

ANSWER: D

11. Bronchoalveolar lavage specimens are obtained:

A. After filling the airways of both lungs with sterile saline and waiting 5 minutes

B. Only from adult patients

C. For purposes of tumor diagnosis

D. To evaluate possible lung infections

E. From patients who may have surfactant abnormalities

ANSWER: D

12. In the transbronchial fine-needle aspiration technique of Wang and Terry, the aspirate sample is washed from the biopsy needle with:

A. Air

B. Saline

C. Plasma

D. Ethanol

E. Michel solution

ANSWER: A

13. Which ONE of the following statements regarding rigid bronchoscopy is TRUE?

A. It can be done in an outpatient setting in a physician’s office.

B. It is no longer performed in the United States.

C. Relatively large foreign bodies can be extracted with it.

D. Necrotic lung tumors should not be accessed with it.

E. It was introduced as a new method in the year 1925 and abandoned in 1995.

ANSWER: C

14. Which of the following statements regarding thoracentesis is TRUE?

A. They are performed for relief of symptoms in cases of pleural effusion.

B. They yield specimens that can be kept unspoiled at 4°C for several hours..

C. They can be used for chemical and enzymatic analyses.

D. They are suitably performed in cases of suspected intrapleural tumor.

E. All of the above ANSWER: E

15. Why is it advisable for histotechnologists to prepare four to six unstained glass slides of small tissue specimens?

A. They can be used later for biochemical analysis of the tissue.

B. The medicolegal risk attending these specimens mandates that all of them should be sent out for extramural consultation.

C. The tissue can be scraped off the slides to reconstruct the lesion they contain in three dimensions.

D. All of the above

E. None of the above

ANSWER: E

16. In the clinical procedure abbreviated as “VATS,” what does the “V” stand for?

A. Virtual

B. Vacuum

C. Video

D. Vesalius

E. Vivisection

ANSWER: C

17. Which of the following statements regarding open wedge biopsies of the lungs is/are TRUE?

A. Intercollegial consultation is strongly recommended.

B. They are performed primarily for the treatment of peripheral lung cancers that measure greater than 5 cm in diameter.

C. One biopsy specimen from one lung is acceptable for diagnosis.

D. They are inferior to transbronchial biopsies for diagnosis of interstitial lung diseases.

E. They can now be done without general anesthesia.

ANSWER: A

18. Which of the following methods can be performed very successfully using paraffin blocks of lung tissue?

A. Electron microscopy

B. Flow cytometry

C. Molecular cytogenetic studies

D. Microbiological cultures

E. All of the above

ANSWER: C

19. What is the recommended method for performing frozen section microtomy on fresh lung tissue?

A. Freezing a 5- to 6-mm thick slab of tissue cut with a fresh scalpel

B. Embedding the fresh tissue in agar

C. Infusing the specimen with Bouin solution using a needle and syringe

D. Slow-freezing the specimen with a drop in temperature of no more than 5°C per minute

E. Filling the airways with latex before cutting the sections ANSWER: A

20. Which of the following techniques can be used to optimize fixation and histologic visualization of atelectatic lung tissue?

A. Shaking the specimen in a sealed container that is half full of fixative

B. Removing all surgical staples before fixation and prosection

C. Adding a small volume of carbonated water to the fixative solution

D. Insufflating the tissue with fixative using a needle and syringe, after removing surgical staples

E. All of the above

ANSWER: E

Case 1

eSlide 15.1

This 65-year-old man has a 50-pack-year cigare The smoking history. He presented with shortness of breath and was found to have a large right pleural effusion radiographically. Computed tomography of the thorax confirmed that finding and showed multinodular thickening of the right pleura. No masses were evident in the lung parenchyma. Cytological studies of right thoracentesis fluid were nondiagnostic, and a thoracoscopic biopsy of the right pleura was performed. The patient has no history of prior tumors.

Discussion

Histologic examination showed a neoplastic proliferation of markedly atypical fusiform and pleomorphic cells in the pleural space. There was no involvement of the lung parenchyma, and no asbestos bodies were found There in. Immunostains for pan-keratin yielded multifocal reactivity in the lesional cells, whereas others for calretinin, WT-1, and podoplanin were negative. Expression of BAP-1 was retained in the tumor. These findings were felt to best support a diagnosis of pseudomesotheliomatous sarcomatoid carcinoma, presumably of pulmonary origin. The patient is undergoing chemotherapy currently.

(See the section “Special Variants of Sarcomatoid Carcinoma of the Lung” in Part 1 of Chapter 15 of edition 3.)

Case 2

eSlide 15.2

A 41-year-old woman presented with left-sided pleuritic-type chest pain. Radiographs showed a left pleural effusion and a pleural-based mass in the lower hemithorax. Fine-needle aspiration biopsy of the lesion revealed the presence of a spindle-cell proliferation that was felt to be malignant. Accordingly, an open thoracotomy and partial pleu- rectomy were performed.

Discussion

Histologic evaluation demonstrated a densely cellular neoplasm comprising fusiform cells, with high nuclear-to-cytoplasmic ratios. Based on the microscopic appearance, the differential diagnosis was principally centered on localized mesothelioma versus monophasic synovial sarcoma versus sarcomatoid carcinoma. Immunostains of the tumor showed multifocal reactivity for pan-keratin, and diffuse labeling for epithelial membrane antigen, CD99, and Transducin-Like Enhancer [of Split]-1. Other stains for Wilms tumor gene product-1 and podoplanin were nonreactive. A polymerase chain reaction-based assay showed the presence of SYT-SSX fusion transcripts in the tumor cells. These results were interpreted as diagnostic for synovial sarcoma.

(See the section “Primary Pleural Sarcomas” in Part V of Chapter 15 of edition 3.)

Case 3

eSlide 15.3

A 39-year-old man presented with deeply seated right-sided chest pain. He had previously been completely healthy. Radiographs of the thorax showed multiple nodular densities through the right lung field, ranging in diameter up to 3 cm. A thoracoscopic wedge biopsy was obtained.

Discussion

Histologic evaluation demonstrated a multifocal proliferation of compact epithelioid cells that were set in a myxofibrous stroma. Some of the

cells contained intracytoplasmic vacuoles, and they were arranged in groups and single-file arrays. Immunostains for pan-keratin were negative, whereas others for CD31, CD34, and FLI-1 were reactive with the tumor cells. Fluorescence in situ hybridization studies demonstrated the presence of a WWTR1-CAMTA1 gene fusion product. These results supported the diagnosis of epithelioid hemangioendothelioma.

(See the section “Epithelioid Hemangioendothelioma” in Part II of Chapter 15 of edition 3.)

Case 4

eSlide 15.4

A 44-year-old man developed a persistent cough. Chest radiographs showed a right parahilar mass measuring 4 cm in maximal dimension. The lung fields were otherwise clear. Fine-needle aspiration biopsy of the lesion demonstrated the presence of an obviously malignant pleomorphic spindle-cell tumor, and a right lower lobectomy was performed subsequently.

Discussion

Histologic assessment revealed a pleomorphic spindle-cell tumor in which the lesional cells were arranged haphazardly or in fascicles. No pigment was visible in them, and There were no intramucosal tumor cells in bronchi. Immunostains for pan-keratin and p63 were completely negative, whereas others for S100 protein and SOX10 showed diffuse and strong labeling of the tumor cells. Focal staining for HMB45 was also seen. A V600E BRAF mutation was present in the lesion. These results supported the diagnosis of malignant melanoma. A thorough examination of the skin surface and mucosae subsequently revealed no lesions. It is unclear at this point whether the tumor arose primarily in the lung, or whether it represented a solitary metastasis of a regressed melanoma. The patient is currently receiving therapy with dabrafenib, and he appears to be tumor-free.

(See the section “Part III. Primary Malignant Melanomas of the Lung” of Chapter 15 of edition 3.)

Case 5

eSlide 15.5

A 3-year-old girl developed obvious dyspnea on exertion, and showed tachypnea at rest as well. Chest radiographs revealed a huge right-sided intrathoracic mass that markedly compressed the lung. Thoracotomy and debulking surgery were performed. The patient’s mother had a sex-cord stromal tumor of the ovary, and her maternal grandmother had a cystic nephroma of the kidney in childhood.

Discussion

Sections of the mass show a pleomorphic spindle-cell neoplasm, with some cellular elements resembling rhabdomyoblasts. No epithelial component is apparent. Immunostains demonstrated diffuse reactivity for CD56, and a proportion of the tumor cells were also positive for desmin, myogenin, and vimentin. No reactivity was seen for pan-keratin, epithelial membrane antigen, or p63. The patient and her maternal family members were found to have a constitutive mutation in the DICER-1 gene. These data supported the diagnosis of pleuropulmonary blastoma, type III (solid type). Chemotherapy was administered after surgical debulking, but the patient died 2 years There after.

(See the section “Pleuropulmonary Blastoma” in Part V of Chapter 15 of edition 3.)