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

Chapter 19. Pseudoneoplastic Lesions of the Lungs and Pleural Surfaces

Mark R. Wick, MD, Timothy Craig Allen, MD, JD, Jon H. Ritter, MD, and Osamu Matsubara, MD

There is a limited group of pulmonary lesions that one can classify as pseudoneoplastic, but their conditions constitute a significant aggregation in absolute numbers. Some are categorized as malformative or reactive, including pulmonary hamartomas (PHs); selected inflammatory pseudotumors (IPTs) (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 IPT now known as inflammatory myofibroblastic tumor (IMT) demonstrates clonal characteristics and can rightly be regarded as a true neoplasm.^2,3 Accordingly, it has likewise 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, adeno- chondroma, 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.

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.^7-10 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 hamarto- matous 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.^13-16 They rarely penetrate the visceral pleura.¹⁷ They are usually well demarcated (Figs. 19.1 and 19.2) 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. 19.3 and 19.4). Most of these lesions contain predominantly cartilaginous tissue and are There fore firm to hard, relatively homogeneous, and translucent when transected.

Figure 19.1 Chest radiograph of pulmonary hamartoma shows, in this posteroanterior view, a well-circumscribed mass abutting the left cardiac border.

Figure 19.2 Computed tomography scan of the thorax shows a pulmonary hamartoma as a sharply demarcated nodular lesion near the right hilum.

Figure 19.3 Gross photograph of a pulmonary hamartoma shows a firm, homogeneous glistening white nodule that stands out from the lung cut surface.

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.^13-16 During the growth of PHs, the mesenchymal portions of the lesion engulf and trap small tubular airways; the latter structures thus spuriously appear to represent an integral part of the lesion (Figs. 19.5 and 19.6). Entrapped alveolar epithelium may also undergo cuboidal or low-columnar metaplasia. Epithelial hyperplasia and papillae may be present in the entrapped epithelium (Fig. 19.7). 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 (Fig. 19.7B). Chondroid material is also present in a majority of cases.^20-22

Figure 19.4 Another macroscopic image of a pulmonary hamartoma demonstrates internal lobulation and a glistening, translucent cut surface.

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 (Fig. 19.7C), 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.^27-30 ’Hiese 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.

Figure 19.5 Bronchiolar epithelium is entrapped by relatively mature chondroid and adipocytic tissues in this pulmonary hamartoma.

Figure 19.6 the juxtaposition of lesional mesenchyme (left) and trapped epithelium (right) is seen in this photomicrograph of a pulmonary hamartoma.

Figure 19.7 (A) Nodules of cellular mesenchymal tissue with a chondroid “aura” alternate with trapped and proliferating epithelial profiles in another example of pulmonary hamartoma. Chondroid hamartoma as sampled by fine-needle aspiration biopsy, with bland spindle cells surrounded by myxoid stroma (B). Other foci show bland cuboidal or low-columnar epithelial cells (C) and fragments of cartilage (D).

PH must be distinguished from primary or metastatic mesenchymal malignancies in the lungs, as well as primary or secondary biphasic sarcomatoid carcinomas.^31-34 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. 19.8), 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 composed only of 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 IPT of the lung has undergone scrutiny in the recent past and is now generally regarded as a true neoplasm composed of myofibroblasts.^2,3 ttat particular entity had been called the fibrohistiocytic subtype of pulmonary pseudotumor^38-40 but has now been renamed IMT.³ the lesion known as calcifying fibrous pseudotumor^41-44 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 anaplastic lymphoma kinase 1 protein.^45-47 Other lesions of the lung that have been included in the category of IPT—namely, plasma cell granuloma and hyalinizinggranuloma⁴⁶'⁵⁴—prob- ably do represent nonneoplastic 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 subsequent 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 the term 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 There of. Chest radiographs usually show a single, sharply marginated, round or oval mass (Fig. 19.9), but the edges of large lesions may be less well 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 are also 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 IPTs also exhibit areas of hemorrhage, necrosis, and/or calcification. Rarely IPTs comprise 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: 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.^58-61

Figure 19.8 the differential diagnosis in cases of pulmonary hamartoma includes metaplastic (sarcomatoid) carcinoma with a biphasic and partially chondroid configuration, as shown here.

Figure 19.9 Plasma cell granuloma-type pulmonary inflammatory pseudotumor, which is seen in this chest radiograph as a large nodular mass in the right midlung field.

Figure 19.10 (A) Gross specimen showing pulmonary inflammatory pseudotumor with a circumscribed and internally homogeneous white-tan cut surface. (B) This photomicrograph of inflammatory pseudotumor of the lung shows an irregular interface with the surrounding parenchyma, multiple foci of chronic inflammation, and early sclerosis.

The organizing pneumonia-like variant shows intraalveolar lym- phohistiocytic inflammation and peripheral as well as central fibrosis (Figs. 19.10 and 19.11). 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. 19.12 and 19.13). 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.^58-61 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.^55-57,63-69 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 cases of LPIPT are probably part of a systemic autoimmune process.^58-61

Figure 19.12 "Mature” plasma cell granuloma-type pulmonary inflammatory pseudotumor demonstrates filling of the distal airspaces by densely collagenized stroma, with virtually no inflammation.

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 Mukensnabl),⁷⁵ the peculiar variant of lung cancer known as inflammatory sarcomatoid carcinoma (see Chapter 15),⁷⁶ 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 difluse 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 et al.⁸⁰ 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.^81-83 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.

Figure 19.13 (A and B) Sclerotic collagenous profiles fill alveolar spaces in this late-stage plasma cell granuloma-type pulmonary inflammatory pseudotumor. The image may resemble so-called hyalinizing granuloma.

Figure 19.14 Mycobacterial pseudotumor of the lung in a patient with acquired immunodeficiency syndrome, represented by a disorganized proliferation of spindle cells admixed with lymphocytes and histiocytes.

Mycobacterial Spindle-Cell Pseudotumor

Spindle-cell pseudotumors that are reactions to mycobacterial infection have been documented in several organ sites in immunosuppressed patients.^84-86 These proliferations show a close histologic resemblance to histoid leprosy,^87,88 and most reports have documented numerous intralesional mycobacteria (see Chapter 7). 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 comprise 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. 19.14-19.16). 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 myo fibroblastic 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.

Figure 19.15 This image of a pulmonary mycobacterial pseudotumor is reminiscent of the myofibroblastic tumor form of inflammatory pseudotumor of the lung.

Figure 19.16 Innumerable intralesional mycobacteria are present in the proliferating cells of a pulmonary mycobacterial pseudotumor, as seen in this Ziehl-Neelsen stain.

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.^84-86 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 16.

Figure 19.17 Computed tomography scan of a patient with Rosai-Dorfman disease. Note the accentuation of the bronchovascular bundles and pleural-based consolidation.

Figure 19.18 Gross photograph of lung tissue in Rosai-Dorfman disease (from the same patient as Fig. 19.17). Note the lymphangitic pattern of involvement.

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. 19.17) may show areas of pleural-based consolidation. Confluence of the infiltrates may yield mass-like densities in the lung fields as well (Fig. 19.18). 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 nonneoplastic 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. 19.19 and 19.20). The large histiocytes demonstrate a peculiar tendency to engulf intact, mature lymphocytes, representing a phenomenon known as lymphemperipolesis (Fig. 19.21). The overall image of foci of SHML in extranodal sites is There fore reminiscent of abnormal lymph nodes.^{91 the} immunophenotype of the lesional histiocytes is singular in that it features prominent reactivity for S100 protein (Fig. 19.22) 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 nonhistiocytic 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 immuno- histochemically 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.

Figure 19.19 (A) Rosai-Dorfman disease involving the lung, showing dense but heterogeneous lymphoid infiltrates with discrete, visible lymphoid aggregates. (B) Large pale histiocytes are visible at higher magnification.

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,^96-101 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

Figure 19.20 Rosai-Dorfman disease demonstrating the presence of large pale histiocytic elements associated with numerous small lymphocytes and plasma cells.

Figure 19.21 the large cells in Rosai-Dorfman disease contain numerous engulfed lymphocytes (lymphemperipolesis); this feature is characteristic of that condition but may be difficult to identify in the pulmonary manifestation.

Figure 19.22 (A and B) Intense immunoreactivity for S100 protein is seen in the lesional histiocytes of Rosai-Dorfman disease.

Figure 19.23 (A) This chest radiograph from a patient with idiopathic myelofibrosis shows a large intrapulmonary mass in the right lung field. It represented a nodule of extramedullary hematopoiesis (EMH). (B) Computed tomogram from another patient with β-thalassemia major, demonstrating multiple nodules of EMH in the lungs and thoracic soft tissues.

Fine-needle aspiration or needle biopsy of extramedullary hematopoiesis (EMH) demonstrates a variable mixture of erythroblasts, myeloid precursors, and megakaryocytes⁹⁹ (Figs. 19.23 and 19.24). These cell lines are usually recognizable as such in routine sections; however, should confirmation of their identity be desired, Leder stain and immu- nostains for glycophorin-A, myeloperoxidase, and CD61 can be used (Fig. 19.24).

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.

Figure 19.24 (A and B) Tumefactive extramedullary hematopoiesis (EMH) shows a mixture of erythroblasts, myeloid precursors, and megakaryocytes. The last of those cell types is the most diagnostic of the condition in conventionally stained sections. (C) Immunoreactivity for CD61 in the megakaryocytic component of EMH. (D) Myeloperoxidase positivity is apparent in the myeloid elements of EMH.

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 of 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 specimen of sputum or bronchial washing.^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 bronchi (Figs. 19.25 and 19.26).^109-116 As expected, a misdiagnosis of squamous carcinoma is the usual error in such instances.

Figure 19.25 Cytologic specimen from a bronchial brushing biopsy in a case of isolated granuloma of the lung, demonstrating markedly atypical squamoid cells with irregular nuclear chromatin, densely orangeophilic cytoplasm, and high nuclear-to-cytoplasmic ratios. These elements caused marked diagnostic consternation over the possibility of squamous carcinoma.

Figure 19.26 Atypical squamous metaplasia adjacent to an infarct.

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 pneumothorax (see also Chapter 6) (Figs. 19.27 and 19.28).^116-126 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 adenocarci- nomas.¹²⁸ Lower nuclear-to-cytoplasmic ratios, “scalloping” of cell borders, and focal intercellular “windows” in pseudoneoplastic glandlike profiles also typify atypical metaplasias.

Figure 19.27 Atypical groups of glandular cells are present in this bronchial washing specimen from a patient who had received chemotherapy for metastatic adenocarcinoma of the pancreas. They were thought to represent secondary involvement of the lung by tumor, ultimately proven to be postchemotherapy atypia.

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. 19.29). 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 reepithelialization 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. 19.30).

Peribronchiolar Metaplasia (Lambertosis)

As discussed in Chapter 9, 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. 19.31). When peribronchiolar metaplasia is seen in the setting of emphysema in a cigare The smoker, 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.^135-137

Figure 19.29 A disorganized proliferation of nerve fascicles is set in a fibromyxoid stroma in a posttraumatic bronchial neuroma.

Figure 19.30 Fibroepithelial polyp of the bronchus features squamous metaplasia of the mucosal epithelium, mantling a fibrovascular stalk that blends with the submucosal connective tissue. It is virtually identical histologically to an acrochordon of the skin.

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 are not recounted here.

Reactive Mesothelial Proliferations

In cytologic practice, reactive mesothelial lesions have often been given the descriptive but nebulous label atypical mesothelial cell proliferation.¹³⁸ However, because that terminology implies a possible connection with 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. 19.32 and 19.33).

Figure 19.31 This proliferation of bronchiolar epithelial cells is seen in the context of bullous emphysema in a smoker. It has been called peribronchiolar metaplasia (lambertosis) and can be confused with adenocarcinoma. Note uniform columnar cells with cilia.

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.^144-147

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 micro- villi.^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

Figure 19.32 (A and B) Markedly proliferative mesothelium in a patient with lupus erythematosus who had recurrent pleural effusions. Although this image is worrisome, the lesion was ultimately believed to be reactive in nature.

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, in our experience, these determinants have been shared by both pathologic entities. 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. 19.34), 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.

Figure 19.33 Solid sheets of reactive benign mesothelial cells are admixed with fibrin and inflammation. The cytologic features of the mesothelium caused concern over the diagnostic possibility of malignant mesothelioma.

Figure 19.34 Nuclear immunoreactivity for putatively mutant p53 is present in epithelioid cells in this cell block. This finding has been used by some observers to support the diagnosis of mesothelioma over one of reactive mesothelial hyperplasia.

In view of the poor outcome of most patients with mesothelioma and limited options 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 Immu- nohistologic differences have been outlined earlier. 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, which 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 muci- carmine 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. 19.35). 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. 19.36).^157-163 ’Hiere 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 HPPs have an increase in commercial-type amphibole asbestos content in the lungs.^157-163 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. ’Hiose 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” arrangement (Fig. 19.37).¹⁶² 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. 19.38).

Figure 19.35 This posteroanterior chest film demonstrates a large nodular mass in the right lateral pleura with internal calcification. It represents a pseudotumoral fibrohyaline pleural plaque in a patient with occupational-level asbestos exposure.

Figure 19.36 Gross image of fibrohyaline pleural plaques, represented by well-demarcated sessile white-yellow fibrous thickening.

Figure 19.37 Photomicrograph of a fibrohyaline pleural plaque, showing a "basket weave" configuration of laminated, markedly hypocellular mature collagen. The surface of the plaque contains chronic inflammatory cells.

Figure 19.38 Another example of a fibrohyaline pleural plaque, containing internal foci of dystrophic calcification.

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 immu- nophenotype 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.

ttere 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. ’tteir 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.^169-171 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.

Figure 19.39 Diffuse pleural fibrosis, showing an organized deposition of hypocellular, fully mature collagen in the visceral pleura. The medium-power image demonstrates a vaguely lamellated appearance; capillaries are relatively numerous and oriented vertically to the pleural surface.

Microscopically, DPF is characterized by the deposition of bland, hypocellular fibrous tissue in the pleura without the basket weave pattern of hyaline plaques (Fig. 19.39). 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. 19.40). 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 in DPF (Fig. 19.40C), a characteristic that is lost in DM.

Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.

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Multiple Choice Questions

1. Which ONE of the following mesenchymal tissue types is not potentially seen in pulmonary hamartomas (PHs)?

A. Smooth muscle

B. Striated muscle

C. Fat

D. Cartilage

E. Bone

ANSWER: B

2. Which ONE of the following microscopic features separates PH from true chondroma of the lung?

A. The level of intralesional vascular density

B. The degree of cartilaginous cellularity

C. The presence of entrapped epithelium

D. Mitotic activity

E. Lesional calcification

ANSWER: C

3. Which of the following statements concerning PHs is/are TRUE?

A. They may coexist with primary or secondary malignant lung tumors.

B. Most are peripherally located in the lungs.

C. Some of them may show cytogenetic aberrations.

D. Rarely, carcinomas may develop in them.

E. All of the above

ANSWER: E

4. Which of the following is a “true” inflammatory pseudotumor (IPT) of the lung?

A. Hyalinizing granuloma

B. IgG4 sclerosing disease

C. Tumefactive organizing pneumonia

D. All of the above

E. None of the above

ANSWER: D

5. Which ONE of the following is NOT a potential radiographic characteristic of “true” pulmonary IPTs?

A. A markedly stellate configuration

B. Central cavitation

C. Internal calcification

D. Subpleural location

E. Potential size of more than 30 cm

ANSWER: A

6. The type of “true” inflammatory pulmonary pseudotumor that is called “tumefactive organizing pneumonia” potentially shows which of the following microscopic features?

A. Intraalveolar lymphohistiocytic inflammation

B. Central scarring

C. Fibrinoinflammatory exudate

D. Pneumocytic hyperplasia and atypia

E. All of the above

ANSWER: E

7. Lymphoplasmacytic-type “true” pulmonary IPT may manifest all of the following histologic characteristics EXCEPT:

A. Plasma cells containing IgG4

B. Intralesional endothelialitis

C. Lymphangitic inflammatory infiltrates

D. Metaplastic cartilaginous tissue

E. Fibrinous pleuritis

ANSWER: D

8. “True” pulmonary IPTs may be associated with which ONE of the following?

A. Infection with Candida species

B. Inhalation of aerosolized bat dung

C. Autoimmune disease

D. Congenital adenomatoid malformations

E. Use of intravenous gadolinium as an imaging agent

ANSWER: C

9. All of the following conditions belong in the histologic differential diagnosis of mycobacterial pseudotumor (MP) of the lung EXCEPT:

A. Kaposi sarcoma

B. Metastatic carcinomas

C. Adenovirus pneumonia

D. Schwann cell proliferations

E. Fibrous histiocytomas

ANSWER: C

10. Histologically, MP of the lung resembles which ONE of the following skin disorders?

A. Erythema multiforme

B. Histoid leprosy

C. Cutaneous larva migrans

D. Granuloma faciale

E. Mucha-Habermann disease

ANSWER: B

11. All of the following are potentially associated with pulmonary Rosai-Dorfman disease EXCEPT:

A. Evidence of systemic autoimmunity

B. A central pattern of hilar and lung involvement

C. Polyarthritis

D. Schistocytic anemia

E. Lymphadenopathy

ANSWER: D

12. Histologic differential diagnosis in pulmonary Rosai-Dorfman disease includes all of the following disorders EXCEPT:

A. Metastatic carcinoma

B. Hodgkin lymphoma

C. Erdheim-Chester disease

D. Large-cell non-Hodgkin lymphoma

E. Pneumonia caused by Legionella micdadei

ANSWER: E

13. The large lesional cells in pulmonary Rosai-Dorfman disease are immunoreactive for all of the following markers EXCEPT:

A. Lysozyme

B. Alpha-1antichymotrypsin

C. CD1a

D. S100 protein

E. CD68

ANSWER: C

14. All of the following disorders are potentially associated with extramedullary hematopoiesis (EMH) in the lung and pleura EXCEPT:

A. Gaucher disease

B. Idiopathic myelofibrosis

C. Gilbert syndrome

D. Chronic hemolytic anemia

E. Hemoglobin C disease

ANSWER: C

15. Which ONE of the following “special” stains is potentially helpful in recognizing the cellular constituents of EMH?

A. CD2

B. CD141

C. Chloroacetate esterase

D. Pinkerton stain

E. Methenamine silver

ANSWER: C

16. An “acceptable” level for false-positive diagnoses of carcinoma in respiratory cytology specimens is:

A. 0.25% or less

B. 1%

C. 5%

D. 10%

E. None of the above ANSWER: A

17. All of the following conditions are potential causes of false-positive diagnoses of carcinoma in respiratory cytology specimens EXCEPT:

A. “Occult” pulmonary infarcts

B. Granulomatous infections of the lung

C. Prior thoracic irradiation

D. “Shedding” from carcinoma of the oropharynx

E. Bronchopathia osteoplastica

ANSWER: E

18. Which ONE of the following is a pseudoneoplastic pathologic lesion that is potentially encountered after trauma to, or inflammation of, the large airways?

A. Necrotizing sialometaplasia

B. Paragonimiasis

C. Chromomycosis

D. Oxalosis

E. Argyria

ANSWER: A

19. “Lambertosis” of the peripheral lung parenchyma may be confused histologically with:

A. Small-cell neuroendocrine carcinoma

B. Well-differentiated adenocarcinoma

C. Sarcomatoid carcinoma

D. Metastatic clear-cell carcinoma

E. Squamous cell carcinoma

ANSWER: B

20. At a histologic level, biopsies of “fibrous pleurisy” could conceivably be misinterpreted as:

A. Metastatic fibrolamellar hepatocellular carcinoma

B. Leiomyosarcoma

C. Hodgkin lymphoma of the pleura

D. Desmoplastic mesothelioma

E. Low-grade fibromyxoid sarcoma (Evans tumor)

ANSWER: D

Case 1

eSlide 19.1

A 54-year-old man had a 35-pack-year cigare The smoking history. He presented for screening chest radiographs as part of a general physical examination, and a 3.5-cm mass was seen in the right lower lobe. It had irregular borders and was judged to be “moderately suspicious” for malignancy by the radiologist. Fine-needle aspiration was nondiagnostic, and a thoracoscopic wedge excision of the lesion was done.

Discussion

Immunostaining for pankeratin showed no neoplastic elements in this basically inflammatory mass, IgG4 stains were unremarkable, and fluorescence in situ hybridization (FISH) studies for ALK rearrangement were negative. The patient had had two prior episodes of bronchopneumonia, and it was felt that the current lesion represented a focus of unresolved tumefactive organizing pneumonia. The alternative interpretations of IgG4-related fibrosclerosing disease, inflammatory myofibroblastic tumor, and inflammatory sarcomatoid carcinoma were eliminated by the stated results.

(See section on inflammatory pseudotumor-plasma cell granuloma in Chapter 19.)

Case 2

eSlide 19.2

A 49-year-old man had a 27-pack-year cigare The smoking history. During a routine health assessment, he was found to have a 3-cm mass in the left upper lobe. It had smooth contours and was felt by the radiologist to represent a pulmonary hamartoma. A fine-needle aspiration biopsy was obtained, showing atypical epithelial cells that mantled small stromal fragments. Possible malignancy could not be excluded, and a thoracoscopic excision of the lesion was done.

Discussion

Histologic evaluation showed the features of typical chondroid hamartoma.

(See section on pulmonary hamartomas in Chapter 18.)

Case 3

eSlide 19.3

A 62-year-old man with a long history of cigare The smoking and emphysema underwent a right middle lobectomy for biopsy-proven squamous cell carcinoma. In the sections of nontumoral lung parenchyma that were obtained, this lesion was found.

Discussion

The focus shown here is a typical example of so-called peribronchiolar metaplasia (PBM), also known as lambertosis. The cytologic features of this lesion are bland and There fore unlike those of “atypical adenomatous alveolar hyperplasia” and noninvasive adenocarcinoma (formerly bronchioloalveolar carcinoma). Having recently studied PBM immu- nohistochemically, Brown concluded that it has characteristics more in keeping with pneumocytic metaplasia than with a bronchiolar proliferation (see https://core.ac.uk/download/pdf/196979.pdf).

(See section on peribronchiolar metaplasia-lambertosis in Chapter 18.)

Case 4

eSlide 19.4

A 55-year-old woman with long-standing systemic lupus erythematosus developed shortness of breath. Radiographs of the thorax showed a large right pleural effusion but no mass lesions or pleural thickening. Thoracentesis and cytologic examination of pleural fluid showed a lymphocyte-rich effusion that also contained numerous mesothelial cells, which were judged to show modest cytologic atypia. Thoracoscopy with biopsy of the parietal pleura was done.

Discussion

This specimen demonstrates a proliferation of mesothelial cells, which in some foci form micropapillary structures. Their cytologic features are bland. A BAP1 immunostain demonstrated retained expression of that protein in the lesional cells. Taken together, these features were felt to represent mesothelial hyperplasia rather than mesothelioma. (See section on reactive mesothelial proliferations in Chapter 18.)

Case 5

eSlide 19.5

A 65-year-old man had developed rheumatoid arthritis when he was 23. In January 2011, he presented with shortness of breath and was found to have a left pleural effusion. It was drained by thoracentesis but recurred several times. Cytologic evaluations of the pleural fluid revealed no evidence of malignancy. In March 2013, thoracic radiographs again showed an effusion as well as diffuse left pleural thickening. Because of concern over the possibility of mesothelioma, a thoracoscopic pleural biopsy was done.

Discussion

Microscopic examination of the biopsy demonstrated laminated pleural fibrosis, with evenly spaced blood vessels distributed throughout the lesion. There were no areas of hypercellularity, and the parietal pleural fat was not involved. Immunostains for p53 were negative in the lesional cells, and BAP1 and p16 were both retained in immunohistologic and FISH studies. These results were felt to support the diagnosis of chronic fibrous pleuritis (fibrous pleurisy). Surgical decortication of the left lung was undertaken, along with augmented medical therapy for the patient’s rheumatoid arthritis. Three years later, he was much improved and no longer had a pleural effusion.

(See Hwang HC, Pyott S, Rodriguez S, et al. BAP1 Immunohisto- chemistry and p16 FISH in the diagnosis of sarcomatous and desmoplastic mesotheliomas. Am J Surg Pathol. 2016;40:714-718. See also the section on diffuse pleural fibrosis [fibrous pleurisy] in Chapter 18.)