Pathology of the pleura: What the pulmonologists need to knowresp_1957

Transcription

1 INVITED REVIEW SERIES: PLEURAL DISEASE SERIES EDITORS: JOSÉ M. PORCEL AND Y.C. GARY LEE Pathology of the pleura: What the pulmonologists need to knowresp_1957 PHILIP T. CAGLE 1,2 AND TIMOTHY CRAIG ALLEN 3 1 Weill Medical College of Cornell University, New York, New York, 2 Department of Pathology, The Methodist Hospital, Houston, and 3 Department of Pathology, The University of Texas Health Science Center at Tyler, Tyler, Texas, USA ABSTRACT Primary and metastatic pleural neoplasms, and nonneoplastic pleural diseases, can have similar clinical, radiographic and gross features. However, treatments and prognoses of these diverse pleural conditions vary greatly. Accurate diagnosis of pleural disease is therefore extremely important, and histological interpretation of pleural biopsies is vital to rendering an accurate diagnosis. Smaller biopsies contribute to the difficulties in accurately characterizing pleural lesions, and immunostains are frequently employed in their assessment. Diffuse malignant mesothelioma, the most common primary pulmonary neoplasm, is rare; however, other less common primary pleural neoplasms, including solitary fibrous tumour, the most common benign primary pleural neoplasm, occur. These neoplasms are discussed. Also, non-neoplastic pleural diseases, including granulomatous pleuritis, eosinophilic pleuritis and fibrous and fibrinous pleuritis, among other diseases, are discussed. Key words: atypical mesothelial cell hyperplasia, mesothelioma, pleura, pleuritis, solitary fibrous tumour. biopsies may be extremely challenging due to several factors, including the marked range of sizes of pleural tissue received for examination (tiny needle biopsy specimens, thorascopic biopsy specimens, decortication excisions and extrapleural pneumonectomy specimens); sampling error and artefact formation; and the large degree in which benign and malignant neoplastic, as well as non-neoplastic, diseases display very similar or overlapping histological features. As biopsies are generally yielding smaller pieces of tissue, it behoves the pulmonologist to be aware of the limitations and difficulties inherent in the diagnosis of pleural disease on small biopsies. Immunostains are frequently necessary to assist the pathologist in rendering the correct diagnosis; however, immunostains should generally be performed in panels, and should be interpreted cautiously in order to best ensure correct diagnosis. Expert panels, including the United States and Canadian Mesothelioma Reference Panel and the International Mesothelioma Panel, may be helpful in diagnosing difficult cases. The following is a review of both neoplastic and non-neoplastic pleural diseases. INTRODUCTION Pleural diseases, both neoplastic (primary and metastatic) and non-neoplastic, exhibit similar clinical, radiographic and gross features, including pleural pain, pleural-based masses or pleural thickening, and pleural effusions. However, the treatments and prognoses of these diverse conditions vary greatly. As such, accurate diagnosis of pleural disease is critical, and histological interpretation of pleural biopsies is extremely important for correct diagnosis. Pleural The Authors: Drs Cagle and Allen are authors of numerous books, book chapters and articles on lung and pleural pathology. Dr Cagle is past president of the Pulmonary Pathology Society. Correspondence: Philip T. Cagle, Pulmonary Pathology, The Methodist Hospital, 100 Fannin, Houston, TX 77030, USA. pcagle@tmhs.org Received 1 February 2011; invited to revise 13 February 2011; revised 21 February 2011; accepted 22 February REVIEW Pleural effusion Pulmonologists frequently deal with pleural effusions. Although pleural effusions arise in a wide variety of diseases, over 90% of pleural effusions arise from about a dozen diseases. Diagnostic work-up and therapy will depend on the likelihood of these various diseases. 1 The gross appearance of pleural fluid may also be helpful. A grossly cloudy pleural effusions suggests chylothorax or an extremely cellular pleural effusion, such as one found with neoplastic disease. A grossly bloody pleural effusion is often caused by trauma, pneumonia, pulmonary embolism or a neoplasm. Common causes of pleural effusions are listed in Table 1. Cytological examination of pleural fluid is a routine procedure, and is a efficient method of confirming a malignant pleural effusion. The vast majority of doi: /j x

2 Pathology of the pleura 431 Table 1 Common causes of exudative and transudative pleural effusions Exudative pleural effusions Metastatic malignant neoplasms to the pleura Infections, including viral, bacterial, mycobacterial and fungal Drugs, including nitrourantoin, amiodarone and methotrexate, among others Collagen vascular diseases, including rheumatoid arthritis, systemic lupus erythematosus and Sjogren s syndrome Radiation therapy Sarcoidosis Pancreatitis Transudative pleural effusions Congestive heart failure Myxoedema Cirrhosis Peritoneal dialysis Superior vena cava syndrome neoplasms involving the pleura are caused by metastatic tumours. Malignant pleural effusions are frequently hypercellular, and may contain small clusters of tumour cells arranged in murules, solid clusters, papillae or acinar structures. Production by the malignant cells of mucin in adenocarcinomas, or keratin or intercellular bridges in squamous cell carcinomas, may assist in making an accurate diagnosis. In many cases, a two-cell population of cells may be identified cytologically, with one cell population composed of neoplastic cells, and the second composed of mesothelial cells. Many metastatic neoplasms to the pleura are adenocarcinomas, and immunostains are frequently employed to assist in determining the primary tumour site. A panel of immunostains is also helpful in determining tumour type and primary site in cases of poorly differentiated pleural neoplasms identified cytologically. Molecular studies such as PCR are increasingly being employed with pleural cytology specimens to assess malignant pleural effusions. In pleural cytology specimens exhibiting markedly reactive mesothelial cells, for which the diagnosis of diffuse malignant mesothelioma (DMM) is being entertained, it is almost always impossible to definitively determine whether such cytological findings represent markedly reactive mesothelial cells or DMM cells. In some cases, malignant cells from DMM may appear relatively uniform. In these cases, a biopsy or excision is required in order to render a definitive diagnosis of either reactive mesothelial cell hyperplasia or DMM. Immunostains are of no benefit in distinguishing reactive mesothelial cell hyperplasia and DMM. Neoplastic pleural diseases Neoplasia in the pleura is common, and metastatic tumour to the pleura is by far the most common neoplasm within the pleura. 2,3 Nonetheless, primary pleural neoplasms occur. DMM is rare; however, it is the most common primary pleural neoplasm. Other rare pleural mesotheliomas, including localized malignant mesothelioma (LMM) and welldifferentiated papillary mesothelioma (WDPM), occur and must be differentiated. 4 6 Solitary fibrous tumour (SFT) is the most common benign primary pleural neoplasm. Other benign and malignant neoplasms occur rarely in the pleura. 2,3 Metastatic disease to the pleura Metastases to the pleura occur much more frequently than primary pleural neoplasms, causing approximately pleural effusions in the USA each year, as compared to DMM, which causes approximately 1500 pleural effusions each year. 7 This is a ratio of over 130 pleural metastases for each primary pleural DMM. Metastases to the pleura exhibit characteristics, including pleural effusions, pleural thickening and pleural-based masses, found with primary pleural neoplasms and reactive pleural processes. Common metastases to the pleura include lymphoma, lung cancer and breast cancer; however, malignancies from any primary may metastasize to the pleura. Diagnosis is generally made on needle core biopsies and cytology specimens; however, occasionally a thorascopic biopsy is required to render adequate tissue for diagnosis. Even in patients with a known primary neoplasm, pleural sampling may be necessary to confirm the presence of the metastasis, to exclude a reactive process mimicking cancer, or to exclude a second primary malignancy. Immunostains are frequently employed to supplement histology in evaluating pleural biopsies. Often, the neoplasm s histological pattern can yield a differential diagnosis that can guide the selection of appropriate immunostains to be performed on the often limited tissue sample of the pleural neoplasm. Small blue cell neoplasms metastatic to the pleura include small cell carcinoma, lymphoma, melanoma, carcinoid tumour and atypical carcinoid tumour, and lobular breast carcinoma, among other neoplasms. Differential diagnosis of a clear cell histological pattern on pleural biopsy includes papillary pattern pulmonary adenocarcinoma, papillary renal cell carcinoma and papillary thyroid carcinoma, among other papillary cancers. Clear cell neoplasms that frequently metastasize to the pleura include clear cell renal cell carcinoma, clear cell pulmonary adenocarcinoma and squamous cell carcinoma, and clear cell carcinoma of the ovary, among other clear cell neoplasms. 7 It is noteworthy that the most recent (7th edition), American Joint Committee on Cancer (AJCC) Cancer Staging Manual has reclassified lung cancer patients with pleural invasion from stage IIIB (T4) to stage IV (M+). 8 It further separates metastatic lung cancer into two groups, pleural metastases (M1a) and other visceral metastases (M1b). The AJCC Cancer Staging Manual s reclassification is based on significant survival differences; it notes that patients with pleural

3 432 dissemination of lung cancer, either as a pleural nodule or as a malignant pleural effusion, exhibit similar survival as patients with contralateral lung nodules; and that patients with distant metastases exhibited significantly worse survival. 8 Diffuse malignant mesothelioma DMM is a rare neoplasm; however, it is the most common primary pleural neoplasm, with approximately 2000 cases occurring in the USA each year. 9 The majority are caused by prior occupational exposure to asbestos. Approximately 80% of pleural DMMs in men are caused by asbestos exposure; that percentage is lower for women. There are two groups of fibrous silicate minerals that are termed asbestos: amphiboles and serpentines. The amphiboles amosite and crocidolite have been established as causes of DMM; however, the role of other asbestos fibres as causative of DMM is controversial. 10 Also, besides occupational exposure to asbestos, other exposures, including environmental exposures, have been shown to cause DMM. 11 The latency period from first exposure to asbestos to the diagnosis of DMM can be 30 years or more. The extensive use of asbestos in construction, shipbuilding and other areas during the 20th century led to high numbers of DMM diagnoses during the 1970s and 1980s. Although incidences of DMM caused by these exposures has probably peaked, given its long latency period, diagnoses of asbestos-related DMM are expected to continue to be made Chest radiation therapy is another potential cause of pleural DMM. DMM is a lethal, treatment-resistant neoplasm that carries a bleak prognosis, with most patients dead within a year of diagnosis, and essentially all dead within 2 years of diagnosis. Therapeutic options, including radical pleurectomy, radiation and chemotherapy, have given very limited or no survival benefit. The medical legal ramifications of the diagnosis of DMM, with the potential for compensation in toxic tort litigation, along with its rarity, makes its accurate diagnosis extremely important. 9 Any approach to diagnosing a pleural lesion has to consider two differential diagnostic problems: first, differentiation between DMM and a metastatic neoplasm or other primary pleural neoplasm must be considered; second, differentiation between DMM and reactive mesothelial cell hyperplasia or pleural fibrotic lesion must be considered. The first concern is challenging; however, the second can be extremely difficult and vexing as well. With small pleural biopsies, differentiation may in some cases be impossible. DMM often present in older men with dyspnoea, chest pain and unilateral pleural effusion. DMM is grossly characterized by diffuse nodules that ultimately spread over the pleural surface to encase the lung in a rind-like manner. The gross presentation varies; in some cases a prominent tumour mass or masses may be present; however, spread of tumour along the pleural surface is necessary for the diagnosis of pleural DMM. In other cases, DMM widely invades the chest wall and lung, making surgical PT Cagle and TC Allen therapy impossible. DMMs may also metastasize to local or distant sites. Radiological and surgical confirmation of the growth pattern along the pleural surface is important for diagnosing DMM; however, other primary pleural neoplasms and metastatic neoplasms to the pleura may grow in a manner mimicking pleural DMM. As such, the characteristic pleural surface and rind-like growth of a pleural neoplasm is not in and of itself diagnostic of pleural DMM. The diagnosis of pleural DMM is one of the most difficult in all of pathology. Small specimen size, separation from metastatic neoplasms to the pleura, separation from reactive pleural lesions, and marked variation in DMM histological patterns, are all factors contributing to the difficulty in diagnosis. The significant medical legal repercussions of the diagnosis of DMM also give import to correct diagnosis of DMM. Along with clinical and radiological correlation, histological examination, almost always including immunostains, is necessary for the accurate diagnosis of DMM. DMM occurs in a wide variety of histological patterns, making its diagnosis, as well as its distinction from reactive pleural lesions and numerous metastatic neoplasms with similar histological features, often challenging. 15 DMMs have three histological types: epithelioid, biphasic (or mixed) and sarcomatoid (Figs 1 3). Both histological types, epithelioid and sarcomatoid, can be further divided into a variety of subtypes, each of which introduce additional differential diagnostic considerations. 15 Many DMMs are composed of more than one histological pattern, and DMMs diagnosed on larger specimens are more likely to be termed biphasic than those diagnosed on small tissue biopsies. Epithelioid DMMs are tumours consisting predominantly of polygonal, cuboidal or oval cells; and sarcomatoid DMMs are tumours predominantly consisting of neoplastic spindle cells. Biphasic DMMs by definition consist of both an epithelioid component and a sarcomatoid component. The differential diagnosis of epithelioid DMM primarily includes reactive mesothelial hyperplasia, other epithelioid primary pleural neoplasms and epithelioid metastatic neoplasms to the pleura. The differential diagnosis of sarcomatoid DMM primarily includes fibrous pleuritis, other sarcomatoid primary pleural neoplasms and sarcomatoid neoplasms metastatic to the pleura. Desmoplastic DMM is a subtype of sarcomatoid DMM composed predominantly of a fibrous neoplasm. Differential diagnosis of desmoplastic DMM generally includes fibrous pleuritis and pleural plaque. The histological types and subtypes of DMM are listed in Table 2. Differentiation of pleural diffuse malignant mesothelioma and reactive pleural lesions As mentioned above, one of the most difficult differential diagnostic problems with pleural DMM is separating epithelial DMM from reactive mesothelial proliferations, and separating sarcomatoid DMM from fibrous pleuritis. 16,17

4 Pathology of the pleura 433 Table 2 Histological types and subtypes of diffuse malignant mesothelioma 15 Epithelioid type Tubulopapillary Acinar Solid (both well-differentiated and poorly-differentiated) Clear cell Adenomatoid Deciduoid Signet ring cell Adenoid cystic Small cell Sarcomatoid type Sarcomatous (fibrosarcomatous, osteosarcomatous, chondrosarcomatous) Desmoplastic Lymphohistiocytoid Biphasic (mixed) type Other types Pleomorphic Transitional Reactive epithelial proliferations of mesothelial cells occur in a variety of clinical settings and may cause pleural thickening that mimics pleural DMM clinically, radiologically and grossly. Reactive epithelial proliferations pathologically include both simple mesothelial hyperplasia and atypical mesothelial hyperplasia. Both line the pleural surface, and atypical mesothelial hyperplasia may exhibit architectural features mimicking pleural DMM, such as tubular lumens and papillary structures. Entrapment of reactive mesothelial cells within areas of chronic pleuritis may mimic DMM. 16 Histological features that support invasive pleural DMM over entrapped reactive mesothelial cells within organizing pleuritis include obvious invasion of DMM mesothelial cells into underlying tissues, cellular nodules with stromal expansion, full thickness cellularity with atypical mesothelial cell throughout the thickness of the organizing pleuritis, and obvious malignant cytological features such as atypical mitotic features and markedly pleomorphic tumour cell nuclei. 16 In contrast, histological features that support entrapment of reactive mesothelial cells within organizing pleuritis over invasion of pleural DMM include lack of obvious invasion, active fibrin deposition with associated active inflammation, linear arrangement of individual mesothelial cells and small glands, simple nonbranching mesothelial glandular structures, and large amounts of stroma separating proliferating reactive mesothelial cells (Figs 4 7). 16 Tables 3 and 4 list microscopic features suggesting benignity and malignancy, respectively. Fibrous pleuritis may mimic sarcomatoid DMM, especially desmoplastic DMM. These diseases can show significant histological overlap. Histological features supporting sarcomatoid DMM over fibrous pleuritis include obvious invasion of underlying tissues by neoplastic spindle cells, bland necrosis, frankly sarcomatoid areas within the lesion, and distant metastases. Table 3 Microscopic features suggesting a benign mesothelial proliferation Lack of obvious invasion by mesothelial cells Active deposition of fibrin and associated acute inflammation Mesothelial cells are arranged in linear arrays and small, simple, non-branching gland-like structures Mesothelial cells are generally arranged parallel to the surface of the pleura and separated by abundant stroma In cases with highly cellular areas of mesothelial cell proliferations, the areas do not extend into underlying pleural fibrous tissue Parallel arrays of capillaries are arranged perpendicular to the surface of the pleura Table 4 Microscopic features suggesting a malignant mesothelial proliferation Unequivocal invasion of mesothelial cells into underlying lung parenchyma or chest wall is the most reliable feature for the diagnosis of diffuse malignant mesothelioma Collections of mesothelial cells, epithelioid or sarcomatoid, with unequivocally malignant cytological characteristics, including abnormal mitotic figures, markedly atypical tumour cell nuclei and frankly sarcomatoid area Obvious tumour nodularity Bland necrosis Atypical cells distributed throughout the entirety of the thickened pleura with approximately the same degree of cellularity from superficial to deep In many cases, extensive sampling will be necessary to render an accurate diagnosis. In some cases, differentiation between epithelioid DMM and reactive mesothelial hyperplasia, and between sarcomatoid DMM and fibrous pleuritis, may not be able to be determined. For epithelioid lesions, the diagnosis of atypical mesothelial proliferation is appropriate. In cases of both epithelioid and sarcomatoid lesions, additional tissue may be necessary in order to render an accurate diagnosis. Another lesion encountered rarely is rounded atelectasis. Also termed folded lung or Blesovsky syndrome, rounded atelectasis is often associated with asbestos exposure. Other identified causes of rounded atelectasis include silicosis, posttuberculosis and drug-related. It is often asymptomatic. Typically involving the lower lobes, rounded atelectasis consists of thickened pleura beneath which there is a generally well-circumscribed area of markedly atelectatic lung parenchyma. It may be bilateral. Most measure less than 5 cm. Radiographic imaging of rounded atelectasis are typically characteristic. In occasional cases where it is mistaken for a peripheral pulmonary neoplasm, PET scan shows a metabolically inactive lesion

5 434 Localized malignant mesothelioma LMMs are extremely rare discrete, circumscribed, sessile or pedunculated pleural neoplasms with histological and immunohistochemical features identical to DMM. 2,4,22,23 LMMs are frequently identified incidentally, and clinical and radiological correlation is necessary for accurate diagnosis. These tumours are usually amenable to surgical excision with good overall prognosis. Grossly, pleural LMMs are wellcircumscribed solitary, pedunculated or sessile tumours that arise from the parietal or visceral pleura. LMM may recur and may metastasize, ultimately causing patient death. All three mesothelioma types occur epithelioid, sarcomatoid and biphasic. Type does not correlate with survival. LMMs are characterized by being identical histologically, ultrastructurally and immunohistochemically, with DMM. However, LMM does not spread along the pleura in a manner characteristic of DMM. Indeed, even microscopic evidence of tumour away from the main tumour mass automatically removes LMM from the differential diagnosis; these tumours are DMMs with a dominant tumour mass. 2,4,22,23 Well-differentiated papillary mesothelioma WDPM is a rare neoplasm that may arise in the pleura. 2,5,6 Occupational exposure to asbestos has not been found to be a definitive cause of WDPM. WDPMs most commonly arise as a neoplasm of low malignant potential in the peritoneum of young to middle-aged women; however, WDPMs arise in men and women. WDPMs may also arise in the pericardium and tunica vaginalis testis. WDPM patients typically behave as benign tumours, with patients surviving a number of years even after tumour recurrence. Nonetheless, occasional cases of WDPM behave more aggressively and cause patient death relatively quickly. While some WDPM patients may present with ascites, abdominal pain, pleural effusion, pneumothorax or chest pain, WDPMs are frequently identified incidentally at the time of abdominal surgery. Grossly, WDPMs generally arise as multifocal tumour nodules, but may occasionally be solitary lesions. 2,5,6 Tumour nodules measure millimetres to centimetres in greatest dimension, and commonly confer a velvety appearance to the surface of the involved serosa. Tumour nodules may have a tan to off-white central area of scarring. Microscopically, WDPMs consist of papillae with a single layer of bland flat, cuboidal, or columnar epithelioid cells lining broad central fibrovascular cores (Figs 8,9). WDPMs are not characterized microscopically with prominent mitotic figures, haemorrhage or necrosis. Solid or tubular histological patterns may be identified. WDPMs do not show deep invasion; however, limited invasion may be seen in some cases. 2,5,6 Because of their markedly differing therapies and prognoses, differentiation of WDPM from DMM is critical. Papillae found within the papillary areas of DMMs show typically thin papillary cores with centrally placed blood vessels, lined by neoplastic mesothelial cells with variable numbers of mitotic figures and prominent nucleoli. With small biopsy samples showing a WDPM-like microscopic pattern, differentiation between WDPM and a focus of papillary pattern DMM may be extremely difficult or impossible, and extreme care must be taken in order to avoid misdiagnosis. 2,5,6 Solitary fibrous tumour PT Cagle and TC Allen Pleural SFT is the most common benign primary pleural neoplasm, and the second most common primary pleural neoplasm after DMM. 2,24 Also termed localized fibrous tumour, SFTs may arise in various extrapleural sites, including retroperitoneum and head and neck. Previously erroneously believed to arise from mesothelial cells, SFTs are neoplasms arising from submesothelial fibroblasts or mesenchymal cells. Malignant SFTs occur, discussed below. Occupational exposure to asbestos has not been shown to be an aetiological factor in the development of SFT. SFTs arise in men and women of all ages, and may occur in children. Most cases are identified incidentally; however, chest pain may be a presenting symptom. Up to 20% of patients may present with Pierre-Marie-Bamberg syndrome, characterized by digital clubbing and hypertrophic pulmonary osteoarthropathy. Approximately 5% of patients exhibit Doege-Potter syndrome, characterized by refractory hypoglycaemia caused by increased secretion of insulin-like growth factor by the tumour. Both syndromes typically abate following excision of the SFT. 2,24 Grossly, SFTs arise from the visceral or parietal pleura, and may be pedunculated or sessile. SFTs vary in size; however, larger tumours, such as those greater than 10 cm in greatest dimension, are more likely to be malignant. SFTs are off-white to tan-gray on cut section. Extensive areas of necrosis or haemorrhage are not characteristic of SFTs, and suggest malignancy. Microscopically, SFTs exhibit several histological patterns, including the patternless pattern, cellular pattern and haemangiopericytoma-like pattern (Figs 10,11). The cells are typically spindled. Mitotic figures, haemorrhage, increased cellularity, necrosis and severe nuclear atypia are not characteristic of SFT, and suggest malignancy. In cases that are microscopically difficult, immunostains may assist in diagnosis. SFTs are typically immunopositive with CD34, vimentin, CD99 and Bcl-2; and immunonegative with keratin, S-100 and CD31. The vast majority of benign SFTs are cured by wide excision. 2,24 Although reports vary greatly, about one-third of SFTs are malignant SFTs. Malignant SFTs of the pleura, in contrast to benign SFTs, often present symptomatically with cough, dyspnoea, chest pain and pleural effusion. Malignant SFTs are typically large neoplasms, often greater than 10 cm in greatest dimension at the time of diagnosis. 2,3,24 Grossly, malignant SFTs resemble benign SFTs; however, wide areas of necrosis and haemorrhage, not typical of benign SFT, may be present. Microscopically and immunohistochemically, malignant SFTs resemble their

6 Pathology of the pleura 435 Figure 1 Epithelioid diffuse malignant mesothelioma showing tubular and papillary patterns of tumour. Figure 4 Chronic fibrous pleuritis showing reactive features including capillaries arranged perpendicular to the pleural surface, and decreasing cellularity toward the base of the pleural thickening. Figure 2 Sarcomatoid diffuse malignant mesothelioma showing spindle cell tumour cells. Figure 5 Reactive mesothelial cell hyperplasia showing simple, linear tubular structures arranged parallel to the pleural surface. Figure 3 Biphasic diffuse malignant mesothelioma showing a mixture of epithelioid and sarcomatoid tumour cell patterns within the tumour. Figure 6 Bland necrosis within a sarcomatoid diffuse malignant mesothelioma.

7 436 PT Cagle and TC Allen Figure 7 Pankeratin stain highlights epithelioid diffuse malignant mesothelioma tumour cells invading chest wall adipose tissue. Figure 11 Cellular area within a solitary fibrous tumour, without any mitotic figures, haemorrhage, marked nuclear atypia or pleomorphism, or necrosis. Figure 8 Well-differentiated papillary mesothelioma showing broad papillary structures with fibrous cores and lining epithelioid cells. Figure 12 Area of necrosis within a malignant solitary fibrous tumour, abutting an area of cellular tumour. Figure 9 Higher power of well-differentiated papillary mesothelioma showing relatively uniform lining epithelioid cells and blood vessels within the fibrous cores. Figure 13 Marked nuclear atypia within a malignant solitary fibrous tumour cell. Figure 10 Patternless pattern of solitary fibrous tumour. benign counterparts. There are four microscopic criteria that are necessary in order to render the diagnosis of malignancy in an SFT, including: (i) increased tumour cellularity, often with overlapping and crowding of cells; (ii) increased mitotic figures, specifically greater than four per 10 high power fields; (iii) necrosis; and (iv) marked tumour cell nuclear atypia or pleomorphism (Figs 12,13). 2,3,24 Malignant SFTs typically recur and metastasize, often causing patient death. Complete respectability with a wide surgical margin gives the best prognosis in patients with malignant SFT, and may be curative. Nonetheless, patients with malignant SFT require close follow up. 2,3,24

8 Pathology of the pleura 437 Other rare primary pleural neoplasms Although a detailed discussion is beyond the scope of this review, there are numerous primary pleural neoplasms, both benign and malignant, that occur rarely or very rarely. 2,3 These include benign tumours such as calcifying fibrous pseudotumour, schwannoma, lipoma and adenomatoid tumour; and malignant neoplasms including synovial sarcoma, angiosarcoma, primary effusion lymphoma, pleuropulmonary blastoma, malignant small cell tumour of thoracopulmonary region (also termed Askin Tumour and primitive neuroectodermal tumour), liposarcoma and desmoplastic small round cell tumour, among other rare and very rare primary pleural neoplasms. The reader is referred to this review s references for more detailed discussion of these various entities. 2,3 Non-neoplastic pleural diseases Fibrous and fibrinous pleuritis Fibrous and fibrinous pleuritis are common pleural conditions typically arising from infections, including viral, fungal, bacterial and mycobacterial infections; drug reactions, pneumothorax or haematothorax; underlying lung conditions such as pneumonia, tumours and abscesses; and trauma or previous surgery. 25,26 Microscopically, fibrinous pleuritis is an acute reaction, showing variably thick areas of fibrin deposition along the surface of the pleura. Over time, fibrinous pleuritis is followed by fibrous pleuritis, showing variably thick areas of fibrous tissue containing fibroblasts and loose stroma, along with capillaries and a variable mixed chronic inflammatory cell infiltrate, lining the pleural surface. Often, both fibrinous and fibrous pleuritis occur together, as acute conditions begin to organize. With infections, leukocytoclastic necrosis (so-called dirty necrosis) may occur. Fibrous pleuritis may also contain areas of mesothelial cell hyperplasia which, as discussed above, may occasionally be so prominent as to mimic malignancy. 25,26 Localized pleural fibrosis Localized pleural fibrosis may occur in the form of pleural plaques, apical caps or nodular histocytic hyperplasia. Pleural plaques may or may not be associated with occupational exposure to asbestos. Chronic fibrous pleuritis of various aetiologies may also cause pleural plaques. Microscopically, pleural plaques show a characteristic basket weave pattern of dense collagen. Apical caps are scars of elastic tissue often identified in patients with history of empyema. Apical caps are thought to probably be caused by local ischaemia. Often an incidental finding associated with tumour or inflammation, nodular histocytic hyperplasia is characterized by variably sized nodules consisting of histocytes and associated reactive mesothelial cells which, in some cases may mimic neoplastic proliferations. 25,27,28 Granulomatous pleuritis and eosinophilic pleuritis Granulomatous pleuritis is a type of chronic fibrous pleuritis containing granulomatous inflammation, which may include well-formed caseating or noncaseating granulomas. Its aetiology is typically infectious, specifically tuberculosis or fungal. As special stains for acid-fast and fungal organisms are frequently negative, pleural culture is recommended at the time of biopsy when granulomatous pleuritis is considered. 26 Eosinophilic pleuritis is a fibrinous or fibrous pleuritis characterized by the additional finding of increased numbers of eosinophils. Eosinophilic pleuritis is a characteristic feature of spontaneous pneumothorax in young adults. Associated biopsy tissue of lung and pleura often shows pulmonary honeycombing with associated bullae or bleb formation. Other aetiologies of eosinophilic pleuritis include drug reactions, infections and lymphangioleiomyomatosis. Haematothorax and pneumothorax of various aetiologies may also cause eosinophilic pleuritis. 26 REFERENCES 1 Light RW. Clinical diagnosis of pleural disease. In: Cagle PT, Allen TC, Beasley MB (eds) Diagnostic Pulmonary Pathology, 2nd edn. Informa, New York, 2008; Guinee DG, Allen TC. Primary pleural neoplasia: entities other than diffuse malignant mesothelioma. Arch. Pathol. Lab. Med. 2008; 132: Granville L, Laga AC, Allen TC et al. Review and update of uncommon primary pleural tumors: a practical approach to diagnosis. Arch. Pathol. Lab. Med. 2005; 129: Allen TC, Cagle PT, Churg AM et al. Localized malignant mesothelioma. Am. J. Surg. Pathol. 2005; 29: Butnor KJ, Sporn TA, Hammar SP et al. Well-differentiated papillary mesothelioma. Am. J. Surg. Pathol. 2001; 25: Galateau-Salle F, Vignaud JM, Burke L et al. Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases. Am. J. Surg. Pathol. 2004; 28: Cagle PT, Allen TC (eds). Metastatic cancer. In: Frozen Section Library: Pleura. Springer, New York, 2010; Edge SB, Byrd DR, Compton CC et al. American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th edn. Springer, New York, 2010; Cagle PT, Allen TC (eds). Diffuse malignant mesothelioma. In: Frozen Section Library: Pleura. Springer, New York, 2010; Marchevsky AM, Wick MR. Current controversies regarding the role of asbestos exposure in the causation of malignant mesothelioma: the need for an evidence-based approach to develop medicolegal guidelines. Ann. Diagn. Pathol. 2003; 7: Bourdes V, Boffetta P, Pisani P. Environmental exposure to asbestos and risk of pleural mesothelioma: review and metaanalysis. Eur. J. Epidemiol. 2000; 16: Connelly RR, Spirtas R, Myers MH et al. Demographic patterns for mesothelioma in the United States. J. Natl. Cancer Inst. 1987; 78: Nishimura SL, Broaddus VC. Asbestos-induced pleural disease. Clin. Chest Med. 1998; 19: Peto J, Decarli A, La Vecchia C et al. The European mesothelioma epidemic. Br. J. Cancer 1999; 79:

9 Allen TC. Recognition of histopathologic patterns of diffuse malignant mesothelioma in differential diagnosis of pleural biopsies. Arch. Pathol. Lab. Med. 2005; 129: Cagle PT, Churg A. Differential diagnosis of benign and malignant mesothelial proliferations on pleural biopsies. Arch. Pathol. Lab. Med. 2005; 129: Mangano WE, Cagle PT, Churg A et al. The diagnosis of desmoplastic malignant mesothelioma and its distinction from fibrous pleurisy: a histologic and immunohistochemical analysis of 31 cases including p53 immunostaining. Am. J. Clin. Pathol. 1998; 110: Younis WG, Dernaika TA, Jones KR et al. Rounded atelectasis with atypical computed tomography findings. Respir. Care 2006; 51: Stathopoulos GT, Karamessini MT, Sotiriadi AE et al. Rounded atelectasis of the lung. Respir. Med. 2005; 99: Arakawa H, Honma K, Saito Y et al. Pleural disease in silicosis: pleural thickening, effusion, and invagination. Radiology 2005; 236: Bloom CI, Wilson GE. Rounded atelectasis and respiratory compromise secondary to pergolide use. Respirology 2009; 14: PT Cagle and TC Allen 22 Laga AC, Allen TC, Bedrossian C et al. Cancers of the pleura. In: Cagle PT (ed.) Color Atlas and Text of Pulmonary Pathology, 2nd edn. Lippincott Williams & Wilkins, New York, 2008; Churg A, Allen TC. Localized pleural tumors. In: Cagle PT, Allen TC, Beasley MB (eds) Diagnostic Pulmonary Pathology, 2nd edn. Marcel Dekker, New York, 2009; England DM, Hochholzer L, McCarthy MJ. Localized benign and malignant fibrous tumors of the pleura. A clinicopathologic review of 223 cases. Am. J. Surg. Pathol. 1989; 13: Laga AC, Allen TC, Cagle PT. Fibrous and fibrinous pleuritis. In: Cagle PT (ed.) Color Atlas and Text of Pulmonary Pathology, 2nd edn. Lippincott Williams & Wilkins, New York, 2008; Laga AC, Allen TC, Cagle PT. Specific forms of pleuritis. In: Cagle PT (ed.) Color Atlas and Text of Pulmonary Pathology, 2nd edn. Lippincott Williams & Wilkins, New York, 2008; Choi YL, Song SY. Cytologic clue of so-called nodular histiocytic hyperplasia of the pleura. Diagn. Cytopathol. 2001; 24: Yousem SA. Pulmonary apical cap: a distinctive but poorly recognized lesion in pulmonary surgical pathology. Am. J. Surg. Pathol. 2001; 25: