Up to 20% of MPM patients have no prior asbestos exposure, and the majority of individuals with exposure do not develop disease. This suggests that asbestos exposure is not necessary or sufficient to cause mesothelioma. These observations have led to a growing interest in identifying whether genetic mutations result in disease susceptibility and whether they can serve as potential therapeutic targets.
Mutations in the BAP1 tumor suppressor gene have been associated with a variety of malignancies, and BAP1 is frequently mutated in MPM. In recent small case series, somatic BAP1 mutations have been reported in 57%–63% of MPM tumor samples.7,8
Germline BAP1 mutations coupled with somatic loss of the second BAP1 allele were discovered in mesothelioma tumor samples from affected families, in which up to 50% of family members developed MPM despite modest levels of environmental asbestos exposure.9
Germline and somatic BAP1 mutations resulting in a loss of heterozygosity have been associated with a novel tumor predisposition syndrome associated with various other malignancies. Uveal melanoma, cutaneous melanoma, renal cell carcinoma, cholangiocarcinoma, and basal cell carcinoma are most frequently described, but a variety of other tumors have also been associated with the syndrome. The prevalence of germline BAP1 mutations was 6% in a large asbestos-exposed cohort with both mesothelioma and a family history of cancer. Two-thirds of this group had two or more primary cancers. These patients were also noted to have a significantly lower age of onset with a higher occurrence of peritoneal involvement.10 In addition, somatic loss of the NF2 and CDKN2A/ARF tumor suppressor genes has also been associated with MPM but appears to be less prevalent than BAP1 mutations.8
Approximately 2% of mesothelioma patients are young (<40 years) and comprise a subgroup with unique clinical characteristics, such as improved overall survival and balanced sex distribution.11 It is unclear if genetic susceptibility is the driver of the pathogenesis in these younger patients.
Patients with MPM present with the triad of pleural effusion, dyspnea, and chest wall pain in 60% of cases. Dyspnea may be a result of pleural fluid accumulation or lung encasement by tumor, which results in decreased chest wall expansion predisposing patients to pneumonia. MPM is typically extensive at presentation, and complications of local invasion are common. This includes superior vena cava obstruction, cardiac tamponade, spinal cord compression, phrenic nerve or recurrent laryngeal nerve paralysis, diaphragmatic dysfunction, Horner’s syndrome, dysphagia, subcutaneous involvement, and direct extension through the chest wall. Spread to the contralateral pleural cavity and across the diaphragm is seen in 10%–20% of cases. Peritoneal involvement may manifest as ascites or bowel obstruction and results in significant morbidity. Onset of local symptoms typically leads to diagnostic evaluation. Late features of MPM include constitutional symptoms and hematogenous metastases to virtually any organ.5,12–15
Accurate diagnosis of MPM can be challenging, since it is uncommon and often difficult to distinguish from benign conditions. The diagnosis of MPM is based on an adequate tissue sample in the context of appropriate clinical, radiographic, and surgical findings. A definitive morphologic diagnosis is typically confirmed with immunohistochemistry.
The three primary histologic subtypes of MPM include epithelioid (50%–70%), sarcomatoid (10%–20%), and mixed (biphasic) categories. The epithelioid histology is the most common and has a better prognosis than the other histologies.1,16 Under the heading of sarcomatoid mesothelioma are two additional rare subtypes, the desmoplastic and lymphohistiocytic variants, which account for <5% of all MPM diagnoses. Differentiating MPM from benign conditions and other malignancies is a frequent diagnostic problem. Histologic features and immunohistochemical (IHC) panels can be used to make these distinctions in both scenarios. In distinguishing MPM from carcinoma, the International Mesothelioma Interest Group (IMIG) recommends the use of at least two mesothelioma IHC markers and two carcinoma markers to confirm the diagnosis. If there are discordant findings, additional markers should be used. Common malignant mesothelioma IHC markers include Wilm’s tumor 1, calretinin, cytokeratin 5/6, and D2-40 (podoplanin), and frequently utilized IHC markers for carcinoma are MOC-31, BG8 (Lewisy), and Ber-EP4.17 In addition, it is recommended that the pathologist should not consider the presence or absence of a history of asbestos exposure when making a diagnosis of MPM. While the prior standards suggested that tissue biopsy for histology was required to render a diagnosis of MPM, more recent guidelines from the IMIG have established highly effective diagnostic criteria for MPM based on cytology alone. While the sensitivity of cytology may be lower, the accuracy is excellent (with positive predictive values approaching 100%) when these criteria and appropriate ancillary techniques are applied.18–21