Pathology of Diffuse Malignant Mesothelioma and Other Mesothelial Neoplasms of the Pleura

12/8/2014 Pathology of Diffuse Malignant Mesothelioma and Other Mesothelial Neoplasms of the Pleura

http://emedicine.medscape.com/article/2078767-overview 1/4

Pathology of Diffuse Malignant Mesothelioma andOther Mesothelial Neoplasms of the Pleura

Author: Alain C Borczuk, MD; Chief Editor: Philip T Cagle, MD more...

Updated: Dec 10, 2013

DEFINITIONMalignant mesothelioma is an aggressive cancer that arises from mesothelial cells, which make up the normal liningof the pleura, pericardial, and abdominal cavity.

EPIDEMIOLOGYMesothelioma is an uncommon malignancy, with an incidence rate of less than 1 case per 100,000 population.Pleural malignant mesothelioma is more than twice as common in men as in women.

ETIOLOGY

Mesothelioma is associated with exposure to asbestos.[1] Specifically, amphibole-type asbestos (amosite, crocidolite,anthophyllite, tremolite, actinolite) is associated with the highest risk of subsequent disease. Another mineral fiber,erionite, has been found to cause mesothelioma in Turkey. A significant interval or latency between exposure anddevelopment of disease has been noted, with an interval of over 20 years associated with the highest relative risk.However, the attributable risk of asbestos in mesothelioma development varies by sex and location of themesothelioma, with asbestos exposure having the highest relationship to male sex and pleural disease.[2]

LOCATIONThe pleural space is the most common location for mesothelioma. The tumor lines the chest cavity along the pleuralspace and can surround and encase the lung. Tumor can also involve the pericardium as either a primary orsecondary site. Mesothelioma can also occur in the peritoneal space and in the tunica vaginalis, all mesothelial-linedstructures.

CLINICAL FEATURES AND IMAGINGPatients with pleural mesothelioma often present with respiratory complaints (dyspnea), which can be related topleural effusion in many cases. Chest pain can also be a presenting symptom. Some patients are asymptomatic withan incidentally discovered effusion. Physical examination findings, when present, generally relate to pleural effusion.

Various methodologies can be used to image the chest in malignant mesothelioma. Chest radiography may beuseful in identifying pleural effusion, and masses/pleural thickening can be suggested with this method. CT scanningcan better delineate and more accurately define the changes seen on chest radiography, including pleuralthickening, pleural effusion, and reduced lung volumes. MRI may also be useful. Positron emission tomography(PET) scanning has been used to assess the extent of disease.

For more, see Malignant Mesothelioma Imaging.

GROSS FINDINGSThe classic description of malignant pleural mesothelioma is a thickening in the pleural space with encasement ofthe lung by a rindlike visceral pleura (see image below).

Figure 1 An autopsy lung case with diffuse thickening of the pleura causing compression of the underlying lung tissue.

The tumor can form additional small nodules over the diaphragmatic surfaces or other less involved areas in a givencase. Hyalinized pleural plaques, which are white platelike thickenings over the parietal pleura and diaphragmaticsurface, can become invaded by mesothelioma.

Rare cases of malignant mesothelioma are characterized by a single mass lesion without the diffuse thickening orsatellite nodules. This is called localized malignant mesothelioma.

MICROSCOPIC FINDINGSThe major growth patterns of malignant mesothelioma are epithelioid and spindled. Tumors of pure epithelioidhistology can have patterns described as papillary (cells growing along exophytic fronds with vascular cores),tubulopapillary (a mixture of glandlike formations and papillary structures), and solid (see image below).



Figure 2 This histologic section stained with hematoxylin and eosin shows papillary structures on the right and a transition to amore solid pattern on the left.

The cells of mesothelioma often have deceptively uniform nuclei with moderate amounts of cytoplasm; the mitoticrate is often low. These are factors that can make cytologic detection of disease especially difficult and can result insignificant diagnostic challenges in tissue samples of reactive pleural conditions.

Histologic variants of malignant mesothelioma, epithelioid type, include cystic growth patterns and cells thatresemble decidual cells and variants that resemble small cell carcinoma. Some cases can have abundantextracellular matrix, and rare cases can produce intracellular mucin.

Tumors with spindled cell histology are called sarcomatoid. This group of tumors can be composed of spindled cellswithout further characterization or differentiation, which is the most common spindled pattern. However, some casescan have very bland spindled cells with minimal atypia amid abundant acellular collagen in a storiform pattern, andthis variant is called desmoplastic mesothelioma when the pattern represents 50% of the tumor.[3]

Well-differentiated papillary mesothelioma represents a proliferation of bland mesothelial cells along fibrovascularcores (papillary architecture), and they are often incidentally discovered growths in the abdominal cavity, althoughthey can also occur in the chest. These are more common in women and are not associated with asbestos exposure.These can have superficially infiltrative growth, but not deeply invasive growth into skeletal muscle or fat, and can bemultifocal. While they can recur, these proliferations generally have a very indolent behavior (see image below).

Well differentiated papillary mesothelioma is characterized with a single layer of bland cuboidal cells lining fibrovascular cores, asdemonstrated in this image.

Benign cystic mesothelioma is composed of multilocular, sometimes multifocal, mesothelial cysts lined by flat tocuboidal mesothelial cells. They occur more commonly in the abdomen but can be seen in the chest. They may beassociated with prior surgery. While these lesions can recur, only very rare cases have been associated withsubsequent mesothelial malignancy.

Fibrous mesothelioma is an obsolete term used to describe a solitary fibrous tumor not of mesothelial origin. Thisdoes not refer to sarcomatoid mesothelioma.

IMMUNOHISTOCHEMISTRYThe diagnosis of malignant mesothelioma is confirmed using immunohistochemistry tests. As the differentialdiagnosis is often with adenocarcinoma, a combination of markers indicating mesothelial origin and antiepithelialorigin are used.

Markers of mesothelial differentiation include calretinin and WT1 (nuclear), as well as cytokeratin 5/6 and D2-40(podoplanin). None of these markers is sufficiently sensitive or specific to be used alone; a minimum of 2 mesothelialmarkers is recommended, although more are needed in some cases.

Markers of carcinomatous differentiation include MOC31, BG8, CEA, CD15, B72.3, and BEREP4. Again, none ofthese markers is sufficiently specific for adenocarcinoma to be used alone; a minimum of 2 carcinoma markers isrecommended, and many cases require a larger panel. Since lung adenocarcinoma is often among the differentialdiagnoses, thyroid transcription factor 1, which is positive in lung adenocarcinoma and negative in mesothelioma,can be helpful.

Other markers of potential use include PAX8 to distinguish mesothelioma from renal cell carcinoma and femalegenital tract adenocarcinoma and p63 to distinguish from squamous cell carcinoma.

MOLECULAR/GENETICSThe cytotoxic effect of asbestos on cells and the subsequent effects on cellular survival have been implicated in thepathogenesis of malignant mesothelioma. Specifically, generation of reactive oxygen molecules has been shown tocause DNA damage and activation of NFKB and AP-1 pathways found to enhance cellular survival. Interestingly,activating oncogenic mutations (eg, EGFR, KRAS) have not been described in mesothelioma, and mutationsotherwise commonly seen in solid tumors, such as p53 mutation, are not described in malignant mesothelioma.

The molecular pathogenesis of mesothelioma surrounds loss of tumor suppressor gene function, often by deletion.NF2 losses are the most common alterations in malignant mesothelioma, and resultant loss and truncation of merlin(NF2 protein) is seen. Frequent deletion in chromosome 9p21 leads to loss of p16 (cdkn2a) and p14. These twolosses affect two critical tumor suppressor pathways of Rb and p53. Recent data have shown that mutations anddeletions in BAP1 (BRCA-1 associated protein 1), a putative tumor suppressor gene, are also implicated in rareuveal malignant melanoma.

TUMOR SPREAD AND STAGINGPleural mesothelioma is typically a unilateral disease that begins on the parietal pleura. As tumor progresses, itextends to the visceral pleura and into the underlying lung parenchyma. It can also involve the diaphragm. The tumorcan also extend into endothoracic fascia, mediastinal fat, chest wall, and pericardium, all of which are consideredlocally advanced but resectable. However, multifocal involvement of the chest wall, transmural pericardial extension,extension into the abdomen, contralateral involvement, spine involvement, and involvement of major mediastinalstructures are all advanced local disease. Nodal disease can be seen in the bronchopulmonary, hilar, andmediastinal lymph nodes.



The TNM system reflects these features, with T stage increasing with involvement of visceral pleura (T1b),diaphragm and lung (T2), and locally advanced disease that can be resected (T3). Locally advanced disease that isunresectable is designated as T4.

PROGNOSIS AND PREDICTIVE FACTORSThe median survival of pleura malignant mesothelioma is just over one year, with a 5-year survival rate under 10%.Favorable prognostic factors include epithelioid histology, young patient age, favorable patient condition measuredby performance status, and lower stage.

DIFFERENTIALLung carcinomas, especially adenocarcinoma, can involve the pleura in a diffuse fashion, clinically and grosslymimicking mesothelioma. The immunohistochemistry panels are specifically focused on markers that distinguishmesothelioma from adenocarcinoma and can also be extended to squamous carcinoma. This has been referred toas pseudomesotheliomatous carcinoma of the pleura.[4]

The differential diagnoses of biphasic and especially sarcomatoid mesothelioma include melanoma, sarcomatoidcarcinoma, and sarcomas of various types, including synovial sarcoma. Immunohistochemistry panels can help toexclude some of these possibilities, as can molecular testing (eg, KRAS or EGFR mutation in carcinomas, FISHtesting for translocations in synovial sarcoma). Sarcomatoid malignant mesothelioma can often be positive forcytokeratin as the only marker; this makes the distinction from sarcomatoid carcinoma and some sarcomasespecially difficult. The presence of an even focal epithelioid component can be very helpful, as the panels of IHCused to distinguish these entities are more likely to be positive in the epithelioid pattern.[5]

Reactive mesothelial proliferations (mesothelial hyperplasia) can show significant cytologic atypia and therefore canraise concern for malignant mesothelioma. The pattern of growth, linear distribution parallel to the surface andabsence of invasion, can be helpful in this setting.[6]

(see image below)

Immunohistochemistry helps to demonstrate that the atypical mesothelial cells in this reactive proliferation are in fact in oneroughly linear layer, an important criterion supporting a benign process.

Fibrous proliferations can also be quite challenging, and their distinction from sarcomatoid malignant mesotheliomaincludes presence of zonation, absence of necrosis, absence of invasion, and presence of granulation tissuelikecapillaries.[7]

Well-differentiated papillary mesothelioma needs to be distinguished from malignant mesothelioma, epithelioid typewith papillary pattern. Extent of disease, size of tumor masses, nuclear grade, necrosis, and pattern of invasivegrowth can all be used in this setting.

Contributor Information and DisclosuresAuthorAlain C Borczuk, MD Professor of Clinical Pathology, Vice Chairman of Anatomic Pathology, ColumbiaUniversity College of Physicians and Surgeons; Visiting Assistant Professor, Albert Einstein College of Medicine;Attending Pathologist, New York Presbyterian Hospital

Alain C Borczuk, MD is a member of the following medical societies: College of American Pathologists, New YorkPathological Society, Pulmonary Pathology Society, and United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Chief EditorPhilip T Cagle, MD Professor, Department of Pathology, Weill Medical College of Cornell University; Director,Pulmonary Pathology, The Methodist Hospital; Senior Member, The Methodist Hospital Research Institute

Philip T Cagle, MD is a member of the following medical societies: American Association for the Advancement ofScience, American College of Chest Physicians, American Medical Association, American Society forInvestigative Pathology, American Thoracic Society, College of American Pathologists, European Society ofPathology, Federation of American Societies for Experimental Biology, Harris County Medical Society, TexasMedical Association, and United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

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Medscape Reference 2011 WebMD, LLC

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Pathology of Diffuse Malignant Mesothelioma and Other Mesothelial Neoplasms of the Pleura