Pseudoneoplastic Lesions of the Lungs and Pleural Surfaces

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18 Pseudoneoplastic Lesions of the Lungs and Pleural Surfaces

There is a limited group of pulmonary lesions that one can classify as pseudoneoplastic, but their conditions comprise a significant aggregation in absolute numbers. Some are categorized as malformative or reactive, including pulmonary hamartomas; selected inflammatory pseudotumors (“plasma cell granulomas”); tumefactive lymphoid hyperplasias; inflammatory or reparative conditions simulating carcinomas; unusual granulomatous reactions; tumefactive pleural plaques; and florid examples of mesothelial hyperplasia. Other clinical “pseudotumors” such as amyloidoma and rounded atelectasis1 are confused with neoplasms only by nonpathologists and are not included for discussion here. On the other hand, the variant of inflammatory pseudotumor now known as inflammatory myofibroblastic tumor demonstrates clonal characteristics and can rightly be regarded as a true neoplasm.2,3 Accordingly, it likewise has been omitted from this chapter.

Pulmonary Hamartoma

The term hamartoma is intended to denote tumefactive malformations that exhibit an architecturally abnormal relationship between tissue components that are appropriate to the organ site in which they arise.4 Other terms for these lesions in the lung include benign mesenchymoma, fibroma, chondroma, fibrochondrolipoma, fibrolipomyochondroma, hamartoma-chondroma, cartilage-containing tumor of the lung, adenochondroma, lipochondroadenoma, adenofibrolipochondromyxoma, and mixed tumor.5 Although in the past, chondroma has been used interchangeably with the lesion referred to here as hamartoma, they constitute distinct lesions and are discussed in Chapter 19.

Pulmonary hamartomas (PHs) have been encountered in approximately 0.25% of autopsies.6 They can arise both centrally and peripherally, and the latter are more common in men than women.710 Radiographically, hamartomas are typically found incidentally, usually in patients between 40 and 60 years of age; nevertheless, pediatric cases have also been reported.10 They are only rarely multiple. Hamartomas may coexist with primary or secondary malignancies of the lung.11,12 Under these circumstances, the hamartomatous lesions may be mistaken for intrapulmonary metastases or synchronous primary carcinomas, particularly if they lack internal calcification.

Macroscopically, most PHs are peripherally located, and they sometimes show a topographical relationship to small bronchi or bronchioles.1316 They rarely penetrate the visceral pleura.17 They are usually well-demarcated (Figs. 18-1 and 18-2) and range from several millimeters to 20 cm in diameter. The central form of hamartoma is encountered in association with large bronchi, as an endoluminal polypoid protuberance covered by intact mucosa.10 All hamartomas of the lung are lobulated, and their cut surfaces reflect their constituent cells (Figs. 18-3 and 18-4). Most of these lesions contain predominantly cartilaginous tissue and are therefore firm to hard, relatively homogeneous, and translucent when transected.

On histologic examination, PHs are manifested by mature mesenchymal tissues but with abnormal configurations. These elements are usually represented by hyaline cartilage, but fibrous tissue, smooth muscle, adipocytic components, and bone18 may be seen. Those masses lacking chondroid elements have sometimes been diagnosed as “intrabronchial lipoma,” “myxoma,” “leiomyoma,” or “fibroadenoma.”1316 During the growth of PHs, the mesenchymal portions of the lesion engulf and trap small tubular airways, and the latter structures thus spuriously appear to represent an integral part of the lesion (Figs. 18-5 and 18-6). Entrapped alveolar epithelium may also undergo cuboidal or low-columnar metaplasia. Epithelial hyperplasia and papillae may be present in the entrapped epithelium (Fig. 18-7). Indeed, the last of these changes can be prominent and bear a resemblance to placental tissue,19 a feature referred to as “placental transmogrification.” The presence of entrapped epithelium is one of the key distinguishing features of PH from “true” pulmonary chondroma. Transthoracic fine needle aspiration biopsy (FNAB) is a common method for the initial pathologic sampling of mass lesions in the lung. In fact, if PH is the favored diagnosis of the radiologist, FNAB is usually done with the anticipation that a thoracotomy can be avoided if that interpretation is correct. The cytologic features of PH include the presence of dispersed fusiform and stellate cells in a myxoid background, as seen histologically (see Fig. 18-7B). Chondroid material is also present in a majority of cases.2022

Nevertheless, FNAB of PH may, in fact, result in the very outcome it intends to avoid: namely, formal surgical resection because of a suspicion of malignancy. Some cytologic specimens of PH show atypical epithelial cells with enlarged nuclei, mimicking low-grade adenocarcinoma (see Fig. 18-7C), sometimes adjacent to stromal tissues resembling the pattern seen in some fibroadenomas of the breast in FNAB samples. This can easily lead to a false-positive interpretation of carcinoma.23 Surfactant-containing intranuclear inclusions can be seen in the trapped epithelium of PH,24 like those observed in bronchioloalveolar carcinomas, further suggesting the diagnosis of carcinoma.

Electron microscopic studies of PH show primitive stellate fibroblastic cells with transitional forms to cartilaginous foci.25,26

Cytogenetic evaluations have demonstrated an abnormal karyotype in several instances, principally represented by an exchange of material among various chromosomes.2730 These data beg the question of whether PH might actually be neoplastic after all, but the clinical evolution of this lesion (see subsequent discussion) generally speaks against such a possibility.

PH must be distinguished from primary or metastatic mesenchymal malignancies in the lungs, as well as primary or secondary biphasic sarcomatoid carcinomas.3134 The presence of multinucleated cells, nuclear pleomorphism, necrosis, and mitotic activity is rare in PH, in contrast to these diagnostic alternatives. In histologically similar biphasic carcinomas (Fig. 18-8), keratin immunoreactivity is present both in the mesenchymal-like and the overtly epithelial components, whereas PH shows reactivity for epithelial markers only in trapped epithelial elements. True chondromas of the lung tend to be multiple and comprised of only cartilage, which is smoothly circumscribed. In contrast, PHs occur singly, and contain multiple tissue types and entrapped, invaginated epithelium.

PHs continue to enlarge slowly if left in place after diagnosis, but they rarely cause significant clinical difficulty. Simple excision of the lesions is typically performed today, especially with the availability of thoracoscopic video-assisted surgical techniques.35 Laser treatment has also been offered for patients with central PHs.36 The clinical result of these treatments is excellent in virtually all cases.

Returning to the question of whether PH might be neoplastic, Pelosi and colleagues have reported exceptional cases in which a malignancy appears to evolve from this lesion.37 In particular, these authors observed the patterns of malignant mixed tumor and malignant myoepithelioma in association with PH.

Inflammatory Pseudotumor—Plasma Cell Granuloma of the Lung

The most common form of the proliferative spindle cell lesion known as inflammatory pseudotumor (IPT) of the lung has undergone scrutiny in the recent past and is generally regarded currently as a true neoplasm composed of myofibroblasts.2,3 That particular entity had been called the fibrohistiocytic subtype of pulmonary pseudotumor3840 but has now been renamed inflammatory myofibroblastic tumor (IMT).3 The lesion known as calcifying fibrous pseudotumor4144 may represent a closely related entity, at least in some cases, and is bound to IMT by its common manifestation of a t(2;17) chromosomal translocation and a potential expression of the ALK-1 protein.4547 Other lesions of the lung that have been included in the category of IPT—namely, plasma cell granuloma and hyalinizing granuloma4654—probably do represent non-neoplastic masses with variable etiologies. Both of them are composed of inflammatory and mesenchymal cells, potentially including mature lymphocytes, plasma cells, mast cells, macrophages, eosinophils, fibroblasts, and myofibroblasts. There is also likely overlap between some of these lesions and those described in association with IgG4 sclerosing disease (see later discussion).

As just defined, the true incidence of pulmonary IPTs that are not IMTs is uncertain. IPTs are not commonly encountered in general surgical pathology practice, but their frequency is somewhat dependent on definitions. Some observers have used IPT broadly, to describe both circumscribed nodules and large irregular inflammatory masses, or segmental and lobar consolidations,55 whereas others have almost abandoned the term altogether, preferring a more descriptive diagnosis for most cases, such as organizing pneumonia.

This lesion shows no sex predilection and occurs over a broad age range, from 1 to 77 years, with a mean of 27 to 50 years.40 Approximately 50% of patients complain of cough, hemoptysis, shortness of breath, chest pain, or combinations thereof. Chest radiographs usually show a single, sharply marginated, round or oval mass (Fig. 18-9), but the edges of large lesions may be more ill-defined.56,57 Some IPTs involve the pleural surface and retract it as seen on computed tomography (CT) of the thorax57; as expected, these findings may falsely suggest the possibility of malignancy. Calcification and cavitation also are potentially present in IPTs, and these features may also be present in imaging.

Pulmonary IPTs range in size from 0.5 to larger than 30 cm.39,40 Most have well-defined margins macroscopically but do not have a true fibrous capsule, and the color and texture is variable. Those that contain numerous inflammatory cells are tan-white and fleshy, and those with a predominance of mesenchymal tissue are gray and firm. IPTs with secondary xanthomatization may be bright yellow and friable. Some IPT also exhibit areas of hemorrhage, necrosis, and/or calcification. Rarely IPTs are comprised of sessile intrabronchial masses, whereas others are attached to the pleura. In typical pulmonary IPT, the microscopic architecture of the lung is replaced by a fibroinflammatory proliferation. Depending on their dominant cellular elements and major growth patterns, IPTs may be subclassified into two types: namely, tumefactive organizing pneumonia-like and lymphoplasmacytic variants.39 These may simply represent different stages in the evolution of IPT, but recent publications suggest that lymphoplasmacytic IPT (LPIPT) is distinctive as part of systemic fibrosing autoimmune disorders that feature the presence of numerous IgG4-producing plasma cells.5861

The organizing pneumonia-like variant shows intra-alveolar lymphohistiocytic inflammation and peripheral as well as central fibrosis (Figs. 18-10 and 18-11). Fibroblastic proliferation is admixed with fibrinoinflammatory exudate in alveoli, alveolar ducts, and bronchioles. The alveolar architecture is preserved in early lesions and the peripheral portions of “mature” IPT but is generally obscured by superimposed fibrous tissue, which tends to assume a whorled configuration (Figs. 18-12 and 18-13). Neutrophils are sometimes interspersed with the lymphocytes and plasma cells, and they may form intralesional microabscesses that result in small areas of cavitation. Alveoli bordering IPTs are often filled with foamy macrophages and mantled by hyperplastic pneumocytes. Multinucleated cells of the Touton type are sometimes present, as are foci of dystrophic calcification, osseous metaplasia, or myxomatous change. Lipoid pneumonia may develop adjacent to areas where IPTs have caused bronchial obstruction by intraluminal proliferation or impingement on an airway. Late in the evolution of IPTs and in their central aspects, the lung parenchyma is replaced by deposition of mature collagen in broad bundles that transect the lesion; it may sometimes assume a keloidal appearance.

In the LPIPT variant, plasma cells and lymphocytes comprise the bulk of the lesion; germinal centers and a paucicellular collagenous matrix may also be prominent.5861 Fibroblasts and xanthoma cells are usually relatively scant. To some degree, the two histologic subtypes of IPT do overlap one another morphologically. As mentioned earlier, the immunohistologic presence of numerous IgG4-positive plasmacytes tends to strongly favor a diagnosis of LPIPT. Other findings that may suggest LPIPT are the presence of endothelialitis, prominent organization, lymphangitic inflammatory infiltrates that are rich in plasma cells and histiocytes (with or without the presence of a mass), and fibrinous pleuritis. Prominently dilated lymphatic spaces, containing histiocytes that show emperipolesis of lymphocytes, may also be observed.

Neither form of IPT is composed of solid sheets of lymphocytes or plasma cells, tending to prevent diagnostic confusion with lymphoma or plasmacytoma. Nevertheless, rearrangement of the immunoglobulin heavy chain genes in a subset of LPIPT cases has been reported, raising the possibility that these particular lesions might be neoplastic or preneoplastic.62

Lymphocytic infiltration and scarring of vascular walls in some examples of IPT, often in association with organizing thrombi, have also been described.39 These changes may be secondary rather than a reflection of a primary vasculitic process. Usually, both kappa and lambda light chain immunoglobulins are detectable immunohistologically in the plasma cells, indicating a polytypic population51; lymphocyte subset markers similarly show an admixture of B cells and T cells.3

The specific etiologic factors underlying the development of pulmonary IPT are largely unknown. The premise that some cases represent a peculiar form of localized pneumonia has support from a history of a previous febrile illness with respiratory complaints in up to 40% of cases. Some case reports have suggested that there is an overlap in appearance between IPT and tumefactive pulmonary infections with aspergillus, rickettsiae, mycoplasma, various viruses, mycobacteria, Cryptococcus, corynebacteria, and other microorganisms.5557,6369 Rare examples have also been documented after trauma to the lung,70 and some cases arise from prior aspiration. As stated earlier, current hypotheses hold that some LPIPT are probably part of a systemic autoimmune process.5861

The differential diagnosis of pulmonary IPT has been partially cited previously. It includes plasmacytoma,71 malignant lymphoma,72,73 and lymphoid hyperplasia,74 selected examples of sclerosing hemangioma of the lung (called epithelial plasma cell granuloma-like tumors by Michal and Mukensnabl75), the peculiar variant of lung cancer known as inflammatory sarcomatoid carcinoma76 (see Chapter 14), and IMT.2,3 Among those conditions, plasmacytomas are recognized by their monotypism for cytoplasmic immunoglobulin, and selected lymphomas may also demonstrate this characteristic. Furthermore, malignant lymphomas are generally less well-circumscribed than IPTs and exhibit more cytologically monotonous infiltrates of atypical lymphoid cells. Localized and diffuse forms of pulmonary lymphoid hyperplasia are composed predominantly of mature lymphocytes, in contrast to the heterogeneous cellular composition of IPTs. Inflammatory sarcomatoid carcinoma can be separated from inflammatory simulators by its diffuse immunoreactivity for keratin, and IMTs contain significantly fewer IgG4-positive cells than those seen in IPTs.60 There is some minor difference of opinion as to whether pulmonary hyalinizing granuloma77 is a part of the spectrum of IPT in the lung. Pulmonary hyalinizing granuloma shows more lamellar hyalinized collagen than is seen in classical IPT. Hyalinizing granulomas of the lung are commonly multiple, whereas “usual” IPT is not.77 Sclerosing hemangiomas78 were once considered to be related to IPTs, but they are now appreciated as epithelial neoplasms with pneumocytic differentiation.79 The latter lesions may exhibit sclerosis, but they also contain aggregates of bland cuboidal cells together with micropapillary and angiomatoid areas. Inflammation is absent or scanty in sclerosing hemangiomas, and their constituent cells express thyroid transcription factor-179; those of IPT do not. Ledet and associates80 have examined the utility of immunostains for mutant p53 protein in the diagnostic separation of IPTs from low-grade intrapulmonary sarcomas. In their hands, p53 was restricted to malignant lesions, albeit with less than absolute sensitivity for such tumors.

Some examples of pulmonary IPT have been monitored for extended periods of time before excision or autopsy examination.8183 Information from these cases indicates that the lesions tend to remain stable or grow very slowly. Spontaneous resolution has also been documented, and a few lesions have shrunk after small incisional biopsy or administration of systemic corticosteroids or irradiation.81,83 Surgical removal is usually necessary to establish a definitive diagnosis of IPT, and, if the lesion has been completely excised, no further therapy is needed.56 Long-term follow-up of patients with pulmonary IPTs has revealed no untoward clinical events in such cases.

Mycobacterial Spindle Cell Pseudotumor

Spindle cell pseudotumors that are reactions to mycobacterial infection have been documented in several organ sites in immunosuppressed patients.8486 These proliferations show a close histologic resemblance to histoid leprosy,87,88 and most reports have documented numerous intralesional mycobacteria (see Chapter 6). Only one case of mycobacterial pseudotumor (MP) has been reported in the lung,89 although we have anecdotally encountered another example in a 41-year-old male patient with acquired immunodeficiency syndrome (AIDS).

Grossly, the lesions appear as yellow-gray nodules. They may show a predilection for small airways. Microscopically, the lesions are comprised of aggregates of spindle cells with a fascicular growth pattern and without significant atypia or mitoses. Scattered lymphocytes and plasma cells may be present, but overt granulomas are lacking. The cytoplasm of the spindle cells is “foamy” but may contain hemosiderin focally. The lesional cells are immunoreactive for lysozyme, with no labeling for S100 protein, keratin, actin, desmin, or von Willebrand factor. Ziehl-Neelsen staining shows innumerable acid-fast bacilli in the fusiform cells (Figs. 18-14 to 18-16). Most examples of MP in other anatomic locations have been related to Mycobacterium avium-intracellulare or Mycobacterium kansasii.

Another reported feature of MPs in other sites is a possible source of diagnostic error. That is, a reproducible cross-reaction has been seen with mycobacterial antigens using certain desmin antibodies,90 spuriously suggesting the presence of a myogenous proliferation. This observation is especially troublesome in the setting being discussed here, because smooth muscle or myofibroblastic tumors enter prominently into the differential diagnosis of MPs. However, a documented lack of immunoreactivity for actin and electron microscopic attributes that support histiocytic differentiation in MP argue against those alternative interpretations.

Other lesions that must be separated from pulmonary MP include Kaposi sarcoma, malignant fibrous histiocytoma, spindle cell melanoma, and neural proliferations.89 Obviously, acid-fast stains should be done in all spindle cell lesions from immunocompromised individuals, and these consistently confirm mycobacterial causation. In some instances, the nature of MP is more obvious because of overtly granulomatous foci in the lung tissue around the spindle cell lesion. Characteristics of malignancy such as necrosis, nuclear atypia, and pathologic mitoses are absent in MP.8486 Thus, diagnoses of pulmonary sarcomatoid carcinoma, malignant fibrous histiocytoma, or other sarcomas would be unlikely.

Pseudoneoplastic Hematolymphoid Processes

Lymphoid interstitial pneumonia and nodular lymphoid hyperplasia may both be regarded as pseudoneoplasms. They are discussed in Chapter 15.

Rosai-Dorfman Disease (Sinus Histiocytosis with Massive Lymphadenopathy)

Most frequently, Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy [SHML]) involves lymph nodes, but it may rarely involve the lung primarily.91,92 It can be seen in either sex and over a wide range of ages. Despite the name of this condition, lymphadenopathy does not always coexist with extranodal disease. When this condition affects the pulmonary parenchyma, it appears to have its epicenter in the hilar tissue and follows lymphatics peripherally into both lungs.91,93 Accordingly, chest radiographs show an accentuation of central bronchovascular markings and bilateral interstitial prominence. CT scans (Fig. 18-17) may show areas of pleural-based consolidation. Confluence of the infiltrates may yield masslike densities in the lung fields as well (Fig. 18-18). Interestingly, clinical evidence of associated immune dysfunction may be apparent, including autoantibody formation, polyarthritis, immune-complex glomerulonephritis, asthma, and juvenile diabetes mellitus. Fever, night sweats, and weight loss have also been reported.91 Justification for the classification of Rosai-Dorfman disease as non-neoplastic comes from molecular data indicating its polyclonal nature.91 Nevertheless, this condition may occasionally coexist with solid malignancies, including carcinomas of the lung.94,95 Such an association could arise, at least in part, from the aforementioned immunologic dysfunction in SHML.

Pathologic specimens of the lung or lymph nodes in SHML demonstrate comparable morphologic findings. Dilated lymphatic spaces in the pulmonary parenchyma contain large pale histiocytes with abundant amphophilic cytoplasm, surrounded by lymphoid infiltrates that are punctuated by germinal centers and fibrous septa (Figs. 18-19 and 18-20). The large histiocytes demonstrate a peculiar tendency to engulf intact, mature lymphocytes, representing a phenomenon known as lymphemperipolesis (Fig. 18-21). The overall image of foci of SHML in extranodal sites is therefore reminiscent of abnormal lymph nodes.91 The immunophenotype of the lesional histiocytes is singular in that it features prominent reactivity for S100 protein (Fig. 18-22) and CD45 in the absence of CD1a. Labeling for CD68, lysozyme, MAC387, and alpha-1-antichymotrypsin may also be observed.

Differential diagnoses in cases of SHML potentially include metastatic carcinoma, metastatic melanoma, Erdheim-Chester disease, large cell lymphoma, and Hodgkin lymphoma.91,92 The large tumor cells in the non-histiocytic conditions in this list differ from those in SHML immunohistologically, by their reactivity for keratin (in carcinoma), MART-1/melan-A (in melanoma), CD3 or CD20 (in non-Hodgkin lymphoma), and CD30 (in Hodgkin lymphoma). Practically speaking, with the exception of Erdheim-Chester disease—which is immunohistochemically indistinguishable from SHML and also characterized by bland histiocytes—all of the other conditions also show a much higher degree of cytologic atypia than that seen in SHML. Thus, special diagnostic studies are usually not required to make the cited distinctions.

The clinical course of Rosai-Dorfman disease is unpredictable. A comprehensive summary91 noted that patients with more than one site of extranodal disease and obvious immune dysfunction more often suffered significant morbidity and even mortality from this condition. Spontaneous remissions have been seen as well. Treatment is individualized, with antineoplastic therapy being reserved for those patients with serious organ dysfunction.

Extramedullary Hematopoiesis

In patients who have preexisting disorders of myelopoiesis, such as idiopathic myelofibrosis, hemoglobinopathies, severe hemolytic anemias, or Gaucher disease,96101 myeloid tissue that has been nascent since infancy can potentially reappear in several extramedullary sites. The lung and pleura are included in that list. If the proliferation of such elements is sufficient, it may manifest itself as discrete masses within visceral structures or serosal surfaces, often imitating neoplasms radiographically.100

Fine needle aspiration or needle biopsy of extramedullary hematopoiesis (EMH) demonstrates a variable mixture of erythroblasts, myeloid precursors, and megakaryocytes99 (Figs. 18-23 and 18-24). These cell lines are usually recognizable as such in routine sections; however, should confirmation of their identity be desired, Leder stain and immunostains for glycophorin-A, myeloperoxidase, and CD61 can be used (see Fig. 18-24).

The clinical course of patients with pulmonary EMH depends on management of the underlying hematologic disorders. If normal medullary hematopoiesis can be improved or restored, the condition often regresses spontaneously. In cases where tumefactive EMH is symptomatic, local ablative therapy can be considered. However, the lesions in question may be a major source of circulating blood elements, and so this intervention should be used with caution.

Very uncommonly, EMH may serve as the seed bed for extramedullary leukemic transformation.102

Pseudoneoplastic Changes as a Consequence Of Lung Injury

Exfoliative cytology of the respiratory tract has been used effectively for several decades in the diagnosis of pulmonary disorders.103 Nonetheless, inherent shortcomings in this method have been well-documented, and some of them relate to the potential for the overdiagnosis of benign reparative or inflammatory conditions in the lungs as neoplastic. The incidence of this eventuality should be less than or equal to 0.25% of all cytologic specimens according to accepted standards.104 Generally speaking, similar pitfalls accompany the interpretation of small transbronchial biopsy specimens in surgical pathology.

There are several possible reasons for mistakes in the cytologic diagnosis of malignancy in the lung. One may simply misinterpret reparative conditions or inflammatory epithelial atypia as carcinoma, but this should be rare.105,106 Another potential source of confusion is the shedding or artifactual introduction of malignant cells from the mouth or upper airway into a sputum or bronchial washing specimen.107,108 Both of these scenarios are troublesome only if there are accompanying abnormalities on chest films that might cause clinicians to consider a neoplasm diagnostically. Thus, it is obvious that radiologic data are essential to optimal cytopathologic interpretation.

However, there are some mass lesions that may, under selected circumstances, incite benign but atypical epithelial proliferations in the surrounding lung. Exfoliated cells in these cases may thus be mistaken as carcinomatous. The underlying conditions associated with this trap include symptomatically “occult” pulmonary infarcts, granulomas, and bronchiectasis with surrounding pneumonia, typically associated with atypical squamous metaplasia in adjacent bronchi109116 (Figs. 18-25 and 18-26). As expected, a misdiagnosis of squamous carcinoma is the usual error in such instances.

Another more heterogeneous collection of diseases that may imitate adenocarcinoma in cytologic samples or small biopsies includes radiation pneumonitis, postchemotherapy atypia in alveolar lining cells, bronchiectasis, pulmonary infarcts, viral pneumonias of various types, pulmonary vasculitides, lung injury caused by toxic chemicals, noninfectious interstitial pneumonitides, diffuse alveolar damage, and recurrent pneumothorax116126 (see also Chapter 5) (Figs. 18-27 and 18-28). These conditions are again most misleading in the context of localized radiographic abnormalities in the lungs and when details of the clinical setting are not provided. Moreover, because of the broad roentgenographic spectrum of such tumors as bronchioloalveolar adenocarcinoma, including an imitation of uncomplicated pneumonia,127 the study of chest films is, unfortunately, an imperfect safeguard in this specific setting. In general, pseudomalignant glandular pulmonary metaplasias show greater cellular heterogeneity than that seen in true adenocarcinomas.128 Lower nuclear-to-cytoplasmic ratios, “scalloping” of cell borders, and focal intercellular “windows” in pseudoneoplastic glandlike profiles also typify atypical metaplasias.

It is also important to realize that special techniques, such as immunostains for tumor-associated glycoprotein-72 (with the antibody B72.3), are not able to make the distinction in question and may even contribute further to misdiagnosis.129 Indeed, there are no universally effective methods to avoid mistakes in the cytologic or biopsy diagnosis of pulmonary malignancy. Patients and clinicians should probably be apprised of that reality.

Traumatic neuroma, a discrete injury-related tumefactive lesion of the bronchial mucosa,130,131 may occur spontaneously (e.g., after aspiration of food), or as a result of instrumentation-induced injury of the airway. Histologically, it shows a disorganized proliferation of mucosal nerve bundles, set in a fibrous or fibromyxoid stroma (Fig. 18-29). A mechanistically related process is that of necrotizing sialometaplasia, caused by inflammatory damage to, and pseudocarcinomatous metaplasia of, the bronchial glands.132 Yet another bronchial lesion that has been documented after injury to the lung is the fibroepithelial polyp. It may represent the end result of re-epithelialization of polypoid intraluminal granulation tissue in the airway lumen. When it is ultimately excised, a fibroepithelial polyp shows variable degrees of squamous metaplasia mantling a central fibrovascular polyp, which emanates from the bronchial submucosa (Fig. 18-30).

Peribronchiolar Metaplasia (Lambertosis)

As discussed in Chapter 8, peribronchiolar metaplasia (also known as Lambertosis) is a condition wherein metaplastic bronchiolar epithelium extensively colonizes adjacent alveolar spaces.133,134 Occasionally, this process may be so marked as to raise serious concern over the histopathologic diagnosis of adenocarcinoma (Fig. 18-31). When peribronchiolar metaplasia is seen in the setting of emphysema in cigarette smokers, that worry is heightened even further. Nevertheless, the metaplastic elements in peribronchiolar metaplasia are more columnar than those of bronchioloalveolar carcinoma, and not as atypical as those of ordinary pulmonary adenocarcinomas. Focal retention of ciliation in the cells of peribronchiolar metaplasia further supports its reactive benign nature, inasmuch as cilia virtually exclude a diagnosis of carcinoma.

Pseudoneoplastic Lesions of the Pleural Surfaces

Pseudoneoplastic lesions of the pleura comprise a relatively small group. Perhaps the most common of them is principally seen by cytopathologists: namely, mesothelial hyperplasia in pleural effusion specimens. Indeed, cytologic simulators of malignancy encompass such a wide variety of entities that they cannot be addressed completely in this text. We will consider selected aspects of this topic, but for a more complete discussion, the reader should consult comprehensive treatises on cytopathology.135137

The microscopic classification of mesothelial lesions can be challenging, both in cytology and surgical pathology. Pertinent problems in this area include the distinction of reactive proliferations from mesothelioma or metastatic carcinoma and the separation of benign and malignant lymphocytic effusions. Approaches to the last of these topics are identical to techniques discussed earlier in reference to pulmonary lymphoid lesions and will not be recounted here.

Reactive Mesothelial Proliferations

Reactive mesothelial lesions have often been given the descriptive but nebulous label of atypical mesothelial cell proliferation in cytologic practice.138 However, because that terminology implies a possible connection to malignancy, or, at least, premalignancy, we do not advocate its use. Rather, one should simply state that mesothelial cells are hyperplastic or reactive if their morphologic features are clearly benign.139 Such proliferations are associated with a number of underlying pathologic conditions, including cirrhosis, anemia, viral infections, connective tissue diseases, prior radiation, reactions to bronchogenic carcinomas or pleural metastases, recurrent pneumothoraces, and a variety of chronic pleural infections.126,140 An adequate clinical history is obviously necessary to the accurate interpretation of pleural tissue samples. Cytologic features that favor malignancy include the presence of papillae or other architectural complexities, obvious nuclear atypia, necrosis, and pathologic mitotic figures.135,141 There are contrasting criteria for the recognition of reactive or hyperplastic mesothelial lesions.142 They are characterized only by superficial entrapment of mesothelial cell nests in the pleural stroma, an intense inflammatory infiltrate that is densest near the pleural surface, vascular proliferation with few associated spindle cells, an absence of overt nuclear atypia, and a lack of atypical mitoses (Figs. 18-32 and 18-33).

Despite an almost-universal reference to cytologic atypia in the literature on mesothelioma, nuclear aberrations in mesothelioma are often unimpressive. Conversely, cytologic atypia may be striking in reactive mesothelium.143 In general, the cytologic criteria associated with malignant mesothelioma include an elevated nuclear-to-cytoplasmic ratio, irregularity of the nuclear membranes, and coarsely clumped chromatin.141 However, even by morphometric evaluation, conflicting results regarding such features have been reported.144147

Several attributes of mesothelial cells are potentially shared by both benign and malignant proliferations in cytologic samples. They include cytoplasmic vacuolization, binucleation or multinucleation, and a brush-border pattern that extends over the entire free surface of the cells, correlating with the ultrastructural finding of elongated microvilli.135,141 Reactive cells generally tend to exfoliate singly or in small groups; on the other hand, large formations, including morular structures with “knobby” cellular outlines or papillary structures, raise the likelihood of mesothelioma.141,148 A similar comment applies to uniformly dense mesothelial hypercellularity in an effusion specimen. It should also be understood that the comments just offered apply only to epithelial or biphasic subtypes of malignant mesothelioma, because sarcomatoid variants rarely shed into body cavities. If effusions are present in the latter cases, they usually contain only inflammatory cells and reactive but cytologically benign mesothelial cells.149 The largely hypothetical concept of “mesothelioma in situ” has been introduced for putatively malignant but microscopic lesions limited to the pleural surface.150,151 The distinction of this condition from florid but reactive mesothelial proliferations is unsettled diagnostically.

Immunohistochemistry has limited value in the separation of reactive and malignant mesothelial cells.152 Some analyses have suggested that purely epithelioid mesotheliomas show dense plasmalemmal labeling for epithelial membrane antigen and vimentin,153 whereas benign mesothelial cells lack both markers. Nevertheless, these determinants have been shared by both pathologic entities in our experience. Both cell types are consistently negative for carcinoembryonic antigen, tumor-associated glycoprotein-72, and CD15 (all of which are expected in carcinomas), and positive for HBME-1, calretinin, WT1, podoplanin, and keratin 5/6.141,154 Although this panel of reactants is useful in distinguishing adenocarcinoma from mesothelioma, it cannot separate benign and malignant mesothelial lesions.

Interest has also arisen regarding the immunostaining of mesothelial lesions for selected gene products that might be correlated with malignancy. In particular, mutant p53 proteins have been assessed in that context, with the expectation that they would be present in malignant mesothelioma but not in benign pleural proliferations.155,156 In fact, when they are immunoreactive for p53 protein, reactive mesothelia usually shows weak nuclear labeling or both cytoplasmic and nuclear staining that should raise suspicion of a spurious result.156 In contrast, mesotheliomas can exhibit convincing and intense nuclear reactivity (Fig. 18-34), but up to 40% are completely nonreactive for p53.155 Although p53 protein immunotyping may provide adjunctive diagnostic information, we believe that it should not be used in isolation. It must be integrated with morphologic findings as well as radiographic details.

In view of the poor outcome of most mesothelioma cases and limited option for its treatment, diagnostic circumspection is appropriate in this context. It would be very undesirable to label a patient with a reactive proliferation as having a mesothelioma, and, with the passage of time, true examples of that tumor will declare themselves clinicopathologically.

More clear-cut criteria are available for the distinction between reactive mesothelium and metastatic carcinoma.142 Carcinomatous effusions often feature a distinctly dimorphic cellular population, although this may be subtle in cases of mammary or gastric cancers.135 Immunohistologic differences have been outlined above. Periodic acid/Schiff stains, performed with and without diastase digestion, label neutral mucins in at least 50% of metastatic adenocarcinomas but not in mesothelial proliferations. Some intracytoplasmic vacuoles in mesothelial cells also contain hyaluronic acid that may stain with the Alcian blue method at pH 2.5; it is digestible with hyaluronidase. Such inclusions may show weak cross-reactivity with mucicarmine stains, potentially causing a mistaken diagnosis of carcinoma. However, spurious mucicarmine staining again disappears after hyaluronidase treatment, unlike the pattern of adenocarcinoma.

Tumefactive Hyaline Pleural Plaques

Hyaline pleural plaques (HPPs) are important because of their value as markers of above-background asbestos exposure (Fig. 18-35). Moreover, they occasionally may simulate the radiographic and pathologic appearances of selected mesothelial neoplasms or metastases of malignant tumors in the pleural space.

Many studies have linked asbestos exposure to the emergence of fibrohyaline plaques (Fig. 18-36).157163 There is also a variable but generally low incidence of these lesions in routine necropsies. Asbestos fibers are absent in the plaques themselves, and, if present, are seen only in the subjacent pulmonary parenchyma. Most patients with bilateral HPP have an increase in commercial-type amphibole asbestos content in the lungs.157163 The number of fibers is greater than that in the general population but less than the number found in individuals with asbestosis. Unilateral plaques may also be seen in patients with asbestos exposure, but these plaques may also develop as a consequence of chronic pleural irritation of any type. They are commonly associated with infections such as tuberculosis or empyema, chronic or recurrent pleural hemorrhage, and chest wall trauma.162

HPPs are most often detected in individuals older than 50 years of age, most commonly in men. Those lesions associated with occupational asbestos exposure show an average latency of 20 years or more from the time of initial dust inhalation.162,163 HPPs characteristically arise in the lower thorax (especially the diaphragm) and preferentially involve the parietal pleura, often with a parallel orientation to the ribs. Much less commonly, they may affect the pericardial surfaces.158 Individuals with HPPs lack symptoms that are directly related to the plaques themselves, and the lesions are regarded as tissue reactions rather than a true disease process. Most associated pulmonary function abnormalities are due to accompanying emphysema or interstitial lung disease.157 Plain films have limited sensitivity for the detection of uncomplicated HPPs, but this statistic increases markedly if the plaques are calcified. The use of CT has greatly improved the ease with which these lesions are recognized.164

The typical pattern of HPP features hypocellular, dense bundles of hyalinized collagen, often with a “basket weave” arrangement162 (Fig. 18-37). Chronic inflammation may be present in and around the lesion and, in some cases, acute inflammation or fibrin deposition may be seen on the pleural surface. These changes likely reflect the proposed mechanism of formation of the lesion: namely, that of recurrent and organizing pleuritis. Dystrophic calcification is often evident pathologically (Fig. 18-38).

The main pathologic diagnostic alternative in cases of HPP is that of localized desmoplastic mesothelioma (DM). This tumor shares many of the microscopic characteristics of HPP; both are composed of relatively bland cells that are separated by dense bands of collagen. Nevertheless, there is greater cellularity in DM, at least focally, with areas of storiform growth and a greater degree of nuclear pleomorphism.165 Necrosis is also possible in mesothelioma but does not occur in HPP. Involvement of the visceral pleura or diffuse effacement of the pleural space are features usually associated with DM, and they argue against an interpretation of HPP. Adjunctive studies are of very little use in this context. Immunoreactivity for mutant p53 protein is more likely in DM but is not restricted to this lesion.166 Furthermore, a substantial portion of DM cases are completely p53-negative, mirroring the expected immunophenotype of HPP.

Although some solitary fibrous tumors of the pleura may contain keloidal collagen like that seen in HPPs,167 they show much greater cellularity and a dissimilar histologic pattern overall. Furthermore, a solitary fibrous tumor typically presents as a localized, polypoid intrapleural mass rather than a sessile plaque; it is also immunoreactive for CD34, CD99, or bcl-2 protein (unlike HPP) and has no causal relationship to asbestos exposure.

There is no indication for surgical removal of HPPs, except in those rare cases where their radiologic images cause clinical concern over a possible diagnosis of malignancy. Their possible relationship to bronchogenic carcinoma or mesothelioma has been examined, as reviewed elsewhere.168 The plaques themselves appear not to be precursor lesions for malignancies but are simple markers of dust exposure.

Diffuse Pleural Fibrosis

A pathologic process related to HPPs is diffuse pleural fibrosis (DPF; also known as fibrous pleurisy or chronic fibrosing pleuritis). It may be associated with connective tissue disorders, such as lupus erythematosus or rheumatoid arthritis, as well as chronic infections and asbestos exposure.169171 DPF often involves the visceral pleura and may produce apical fibrous “capping” analogous to that seen in association with bullous emphysema. In extreme cases, obliteration of the pleural space may eventuate.

Microscopically, DPF is characterized by the deposition of bland, hypocellular fibrous tissue in the pleura, without the “basket weave” pattern of hyaline plaques (Fig. 18-39). The lesional tissue often demonstrates an increase in vascularity—with vertically oriented capillaries—and may contain scattered foci of chronic inflammation, including plasma cells, lymphocytes, and histiocytes (Fig. 18-40). An associated exudate may be apparent on the luminal pleural surface.

The differential diagnosis centers on the exclusion of DM. The clinicopathologic similarities of DM and DPF are even closer than the likenesses between DM and HPP, because both DM and DPF have the ability to encase the lung in a “rind” of tissue.163 However, DPF lacks the level of cellularity, nuclear atypia, hypovascularity, potential necrosis, and invasive growth of DM. Special studies are generally noncontributory to this diagnostic separation. However, a routine keratin stain may highlight invasion of tumor into pleural fat in cases of DM, and a Verhoeff–van Gieson elastic stain may be illustrative in showing preservation of elastic tissue layering in the pleura (see Fig. 18-38) in DPF, a characteristic that is lost in DM.

Self-assessment questions related to this chapter can be found online on the Expert Consult site for this title.

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