The most common cause of dyspnea in patients with diffuse malignant pleural mesothelioma is a large pleural effusion [2]. Pleural effusion in diffuse malignant pleural mesothelioma is usually unilateral, present at the site of disease. The effusion might cause atelectasis and/or pneumonia of the underlying lung and might restrict the movement of the ipsilateral hemidiaphragm. In advanced disease, malignant mesothelioma usually encases the lung resulting in restrictive lung function and/or pneumonia [3].

Patients might present with pneumothorax or hydropneumothorax which usually also results in dyspnea (Fig. 3.1). Once thought to be rare, pneumothorax or hydropneumothorax as initial presentation is now understood to occur in up to 10 % of cases. In a series of 91 patients who underwent pleurectomy for spontaneous pneumothorax, five patients (4.3 %) were diagnosed with malignant mesothelioma [4]. Alkhuja et al. described four patients who presented with spontaneous pneumothorax and were ultimately diagnosed with malignant mesothelioma [5]. Two of the four patients were diagnosed with malignant mesothelioma 12 and 22 months after the initial pneumothorax. Pneumothorax might be under-recognized in this patient population given a recent radiologic study of 92 patients who were diagnosed with malignant pleural mesothelioma between 1997 and 2006 [6]. Nine (of 92) patients (10 %) were found to have pneumothorax on computed tomography (CT) imaging studies.

Dyspnea due to mesothelioma might be compounded by other lung diseases that are often present in this patient population such as chronic obstructive pulmonary disease, asbestosis, or ischemic heart disease [3].

Chest pain in malignant pleural mesothelioma is most often of nonpleuritic quality, although pleuritic chest pain can also occur. In contrast to the nonpleuritic chest pain, pleuritic pain is typically characterized by a sudden, intense, and sometimes stabbing or shooting chest pain that is usually most severe when the lungs move during breathing, coughing, sneezing, or even talking. In a study by Adams et al., 62 patients (69 %) presented with chest pain; in 56 patients the chest pain was of nonpleuritic quality and only six patients had pleuritic chest pain [7].

Chest pain is generally caused by significant chest wall invasion by the malignant mesothelioma [2]. The pain might radiate to the upper abdomen, shoulder, or arm because of entrapment of intercostal thoracic, autonomic, or brachial plexus nerves. Involvement of the phrenic nerve by the mesothelioma might lead to hemidiaphragmatic paralysis. Occasionally, persistent chest wall pain precedes the development of either pleural masses or effusion by months and an initial chest X-ray might even be negative.

Cough may occur but is usually not a prominent symptom. Cough is more frequent in patients presenting with a pleural effusion [8].

The local expansion of the malignant mesothelioma sometimes leads to chest wall masses which, when invading into mediastinal structures, might impinge on large vessels, nerves, the esophagus, or the trachea or airways resulting in rare symptoms such as superior vena cava syndrome, hoarseness, Horner’s syndrome, or dysphagia [3]. Invasion of the pericardium and the heart might lead to pericardial tamponade and arrhythmias.

Diffuse malignant pleural mesothelioma typically encases the lungs as a thick rind and grows along the fissures, while relatively sparing lung parenchyma; however, a few cases of malignant mesothelioma have been reported that clinically and radiologically mimic interstitial lung disease [9−13]. Larsen et al. described five cases of diffuse intrapulmonary malignant mesothelioma [9]. In those cases, the tumor had a preferential intraparenchymal growth pattern without significant pleural involvement. All five patients were men with a median age of 56 years. Patients presented with chronic dyspnea, cough, and acute dyspnea with bilateral pneumothorax, and were initially diagnosed as interstitial lung disease based on clinical and radiologic findings. Microscopic pleural involvement was identified in four cases. The median survival of three of the five patients treated with chemotherapy was 28 months [9]. Two patients received no therapy and survived 3 and 4 weeks, respectively.

Diffuse malignant pleural mesothelioma might spread to the abdomen and patients might present with ascites , constipation, or even bowel obstruction. Mesothelioma can also spread to the contralateral hemithorax resulting in bilateral pleural effusion [3].

In rare cases, malignant mesothelioma has been diagnosed at a prior incision site. Guenday et al. reported a 37-year-old woman who underwent pericardiocentesis for pericardial effusion with negative cytologic examination [14]. Seven months later, she presented with a skin lesion at the prior incision site which was found to be malignant mesothelioma. She was also diagnosed with pericardial malignant mesothelioma.

Lymphatic and hematogenous dissemination occurs late in the course of malignant pleural mesothelioma, and is identified fairly commonly in autopsy series. All organs can be involved. Metastatic disease has been described in liver, lung, heart, brain, meninges, thyroid, adrenal glands, kidneys, pancreas, bone, soft tissue, skin, and lymph nodes [15, 16]. Systemic lymphadenopathy is an exceedingly rare initial presentation of malignant mesothelioma with only a few cases being reported. In some of these case reports, the malignant mesothelioma was initially diagnosed in a lymph node, most commonly cervical, supraclavicular, or axillary, which initiated a search for the primary tumor, with peritoneal, pleural, or pericardial mesothelioma subsequently identified. [17−21]. In one case of metastatic disease to the neck, the malignant pleural mesothelioma was not identified until 8 months after the initial diagnosis in the lymph node [22].

Other rare presentations include aphonia and dysphagia, abdominal distension , pressure sensation in the abdominal right upper quadrant, nausea, bad taste in the mouth, perceived tachycardia, headache, paraneoplastic syndrome , chest wall lump, lymphadenopathy, and hemoptysis [7, 23].

The average time interval between onset of symptoms and diagnosis is usually 2–3 months [3], but insidious and nonspecific symptoms may delay diagnosis up to 3–6 months or more [2, 24]. However, symptoms may present for an even longer time until a diagnosis is established, leading in some cases to long latency periods [5].

Diffuse malignant pleural mesothelioma is slightly more common in the right pleura, and bilateral involvement at initial diagnosis is uncommon. A study by Adams found that the tumor was right sided in 55 % of patients, left sided in 41 %, and bilateral in 3 % [7]. Similarly, in the radiologic study by Seely, the right hemithorax was more commonly involved than the left (61 vs. 36 %, respectively), and 3 % of patients had bilateral involvement [6]. Tanrikulu et al. studied 363 patients with pleural mesothelioma and also showed that the majority of mesotheliomas were right sided (61 %), with only 7 % bilateral [24]. In a study of 272 patients with malignant mesothelioma in southeast England, right-sided disease were 1.6 times more common than left-sided disease based on clinical, radiologic, and autopsy data [25].

Abdominal distension and/or increasing abdominal girth is the most frequent initial symptom, occurring in 30–80 % of patients with peritoneal malignant mesothelioma [26−28]. It is usually due to ascites or may be due to tumor mass expansion within the abdominal cavity. Ascites is the most common sign, occurring in 90 % of the patients [29]. In contrast to patients with abdominal distension due to excess caloric intake or benign ascites associated with nonmalignant conditions (e.g., cirrhosis) where patients can gain weight, patients with mesothelioma often exhibit weight loss .

Pain is the second most common symptom in patients with diffuse malignant peritoneal mesothelioma, although in some studies, it was more common than abdominal distension [30, 31] (Fig. 3.2). In most cases, the pain is diffuse and nonspecific, although rarely, patients can present with an acute abdomen secondary to perforation or bowel obstruction [32].

Early satiety, dysphagia, and shortness of breath are other nonspecific symptoms that may occur in patients with peritoneal mesothelioma. These symptoms are likely due to ascites or an enlarging abdominal mass and they can contribute to weight loss, impaired performance status, and fatigue. Abdominal distension may manifest as a new or worsening abdominal wall hernia.

Gastrointestinal complications such as bowel obstruction are usually a manifestation of advanced disease and occur late in the course of the disease [26, 33]. A palpable abdominal mass, deep vein thrombosis, and arterial occlusion may also occur [26, 27].

Malignant peritoneal mesotheliomas of the abdominal cavity can occasionally clinically mimic ovarian tumors, especially in young women. Although malignant peritoneal mesothelioma can secondarily involve the ovaries, patients with malignant peritoneal mesothelioma characteristically present with abdominal disease rather than with ovarian masses. Mani et al. described seven cases of peritoneal mesothelioma in which the initial manifestation was an ovarian mass [34]. The patients, ranging from 22 to 52 years old, underwent surgery with a primary diagnosis of ovarian cancer, exhibiting masses measuring 3.8–9 cm. Four of the seven cases were predominantly cystic and three were solid tumors. Histologically, the cystic tumors were multicystic mesotheliomas, and the three solid tumors were diffuse malignant mesotheliomas .

Occasionally, malignant mesothelioma is an incidental finding during infertility surgery or other gynecologic surgery [30]. In a study of 75 women with malignant peritoneal mesothelioma, 13 (17 %) were incidental surgical findings [35].

Similar to diffuse malignant pleural mesothelioma, the mean time interval between the onset of symptoms and the establishment of the diagnosis is typically 2–3 months. Manzini et al. found that the median diagnosis time (first symptoms to diagnosis) was 2 months (range, 0–29 months) [36]. Acherman et al. reported a mean diagnosis time of 10 months [30]. However, in a few patients, the time between symptoms and diagnosis has been reported in years, reflecting the lack of specific symptoms, the rarity of the disease, and the difficulty in distinguishing between diffuse malignant peritoneal mesothelioma and other primary or metastatic peritoneal tumors [26, 29]. In a study of 75 women with malignant peritoneal mesothelioma, Baker et al. identified four cases with delayed diagnosis between 2 months and 3 years [35]. In these four cases, a diagnosis of florid reactive or atypical mesothelial hyperplasia was made at initial surgery; however, later laparotomy for persistent symptoms showed malignant mesothelioma .

Malignant mesothelioma can be associated with various paraneoplastic syndromes, including thrombocytosis [36], migratory thrombophlebitis, disseminated intravascular coagulation, venous thrombosis [37, 38], thrombotic thrombocytopenic purpura (TTP) [39], Coombs-positive hemolytic anemia, hypoglycemia [27], fever, paraneoplastic hepatopathy [27], sensory–motor polyneuropathy [40], Anti-Ma2 antibody-associated paraneoplastic syndrome (presenting with opsoclonus and diffuse cerebellar signs) [41], anti-Yo-related paraneoplastic cerebellar degeneration [42], renal disease, and hypercalcemia. These paraneoplastic syndromes are of course not unique to malignant mesothelioma and also have been described in other malignancies. Paraneoplastic syndromes are generally seen in the context of advanced disease; however, in some cases, malignant mesothelioma is diagnosed during the workup of the paraneoplastic syndrome. Archer et al. reported a sarcomatoid mesothelioma patient with opsoclonus and diffuse cerebellar signs who had an anti-Ma2 antibody-associated paraneoplastic syndrome [41]. Socola et al. reported a patient who presented with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura associated with severe abdominal pain culminating in an acute abdomen who was found to have diffuse malignant peritoneal mesothelioma with tumor located in the left side of the pelvis encasing the distal sigmoid colon [39]. Banayan et al. reported a case of a 45-year-old woman with recurrent jugular vein thrombosis associated with weight loss, weakness, and anemia; who on workup was found to have peritoneal mesothelioma [38].

Some patients develop a paraneoplastic syndrome after mesothelioma diagnosis . Tanriverdi et al. reported a 51-year-old woman who was diagnosed with malignant pleural mesothelioma and underwent chemotherapy [42]. Two weeks after completion of the chemotherapy, the patient developed anti-Yo-related paraneoplastic cerebellar degeneration. Bech and Sorensen described a 57-year-old man with malignant pleural mesothelioma who developed sensory–motor polyneuropathy 18 days after diagnosis of the mesothelioma [40]. Extensive workup could not identify a specific cause for those symptoms and therefore a paraneoplastic syndrome was suspected. The patient was treated with immunoglobulin and prednisolone with improvement of the symptoms .

Malignant mesothelioma patients might present with constitutional symptoms such as fatigue, hyperhidrosis, weight loss, tiredness, or sweating. They may also exhibit dry cough, fever, or night sweats [2]. These symptoms are usually found at advanced stage of the disease. In a study of malignant peritoneal mesotheliomas, vomiting was associated with worse survival [36].

Men comprise 60–84 % of all cases of malignant pleural mesothelioma [6, 7, 23, 24]. The mean age for men with malignant pleural mesothelioma has been reported between 54 and 59 years with an age range from 20 to 77 years [7, 23]. The mean age for women is very similar and described between 55 and 60 years, ranging from 24 to 80 years [7, 23]. In studies that did not report age by gender, the mean age for malignant pleural mesothelioma was between 51 and 68 years with reported age ranges from 19 to 88 years [6, 24, 30]. However, although rare, malignant pleural mesotheliomas have also been described in children [47, 48].

Similar to diffuse malignant pleural mesotheliomas , peritoneal mesotheliomas are more commonly reported in men than women. In a study of 81 patients with malignant peritoneal mesotheliomas, 57 men (70.4 %) and 24 women were included [35]. Acherman et al. [29] reported that out of 51 patients with malignant peritoneal mesothelioma, 34 were men (66.7 %).

In a study of 75 malignant peritoneal mesotheliomas in women, the mean age was 47.4 years with an age range from 17 to 92 years [34]. In other studies, the mean age for men was between 51.2 and 63.0 years and for women between 48.7 and 68.0 years [29, 35].

Malignant peritoneal mesotheliomas have rarely been described in children [48, 49].

Effusions in malignant mesothelioma are of exudative quality as established by Light criteria [50] that include one or more of the following: (1) pleural fluid/serum (PF/S) protein ratio greater than 0.5; (2) PF/S lactate dehydrogenase (LDH) greater than 0.6; and (3) pleural fluid LDH level greater than two-thirds of the serum upper limit of normal [51]. Gottherer et al. characterized the pleural fluids of 26 patients with diffuse malignant pleural mesothelioma [52]. (Table 3.3). All pleural fluids were determined to be exudative by protein and LDH levels. The pleural fluid of nine (of 17) patients had a low pH (< 7.30, range 6.92–7.26); in eight patients, the pleural fluid had a pH of ≥ 7.30. The study showed that patients with lower pleural fluid pH and PF/S glucose ratio had a shorter survival. In a study by Tanrikulu et al., a pleural fluid glucose level of ≤ 40 mg/dL and a serum LDH level of ≤ 500 U/L was associated with poor survival [24].

Research has focused on the identification of serological and fluid markers for diagnosis, response to treatment, and prognosis of malignant mesothelioma . Although some promising candidate markers have been studied, currently, there are no serologic or fluid markers to aid in establishing a diagnosis of malignant mesothelioma because low sensitivity and specificity do not allow for their use in routine clinical practice. However, evidence suggests that some markers might be useful in the follow up of patients after treatment to identify possible recurrence and/or progression of disease. Other markers might have some prognostic value. Some of the more recently studied biomarkers include fibulin-3, mesothelin, and osteopontin.

Fibulin-3 is an extracellular glycoprotein that is encoded by the epidermal growth factor-containing fibulin-like extracellular matrix protein (EFEMP1) gene. Recently, Pass et al. showed that plasma and effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma than in asbestos-exposed people without mesothelioma [53]. These studies concluded that in conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels might be able to differentiate mesothelioma effusions from other malignant and benign effusions. However, additional studies will be required to determine the role of fibulin-3 as a biomarker for diagnosis and monitoring patients after initial treatment .

Mesothelin, a glycoprotein that is expressed on the surface of benign mesothelial cells, was found to be overexpressed in some malignant mesothelioma. Soluble mesothelin-related peptides (SMRPs) are thought to be a splice-variant of mesothelin that can be found in serum and pleural fluid [54]. Elevated levels of SMRP have been identified in epithelioid but not sarcomatoid mesotheliomas. However, mesothelin can also be increased in other tumors such as ovarian carcinoma, pancreatic carcinoma, and lung cancers or in renal insufficiency. Furthermore, the sensitivity and specificity appear to depend on the detection method and cutoff values used and therefore, further studies are necessary to establish the diagnostic and prognostic importance of that biomarker .

Osteopontin is a glycoprotein that mediates cell–matrix interactions and is overexpressed in several types of cancers. Pass et al. showed that serum osteopontin levels were significantly higher in patients with malignant pleural mesothelioma than in patients with exposure to asbestos [55]. Furthermore, tumor cells stained for osteopontin in 36 of 38 cases of pleural mesothelioma. However, further studies are necessary to confirm those data .

Carcinoembryonic antigen (CEA) has also been studied for its use in malignant mesothelioma. A meta-analysis of 11 studies that identified the value of CEA to distinguish between malignant mesothelioma and metastatic lung cancer showed that the sensitivity of CEA for malignant pleural mesothelioma ranged from 0.73 to 1.00 (mean 0.97, 95 % CI: 0.93–0.99) when the CEA assay was negative [56]. Interestingly, in 8 of 11 studies the sensitivities were 1.00 and only one study showed a relative low sensitivity (0.73). Therefore, a high pleural fluid CEA might assist in ruling out malignant mesothelioma, and the pleural fluid CEA assay might be useful in helping distinguish malignant pleural mesothelioma from metastatic lung cancer .

Hyaluronic acid (HA) has been proposed as a putative diagnostic marker because its level is increased in approximately 60 % of pleural effusions from patients with malignant mesothelioma [57]. On the other hand, Fuhrman et al. did not show a significant difference in HA of pleural fluid between benign pleural effusion and effusion associated with malignant pleural mesothelioma; however, HA was significantly higher in mesothelioma than in nonmesothelioma malignancies [58]. In the serum, elevated HA levels have been described only in advanced stage mesothelioma [59]; and a significant percentage of malignant mesothelioma may not secrete HA [58, 60].

Studies suggest that a combination of biomarkers might be superior to the use of any single marker. Creaney et al. showed that a combination of effusion HA, and serum and effusion mesothelin had a greater diagnostic accuracy than effusion mesothelin alone [61]. Furthermore, SMRP might improve CYFRA-21–1 and CEA accuracy in pleural effusion in the differential diagnosis of malignant pleural mesothelioma [62]. Further studies are necessary to identify a combination of biomarkers that might be helpful in the diagnosis, prognosis, and disease progression of malignant mesothelioma .