SURGICAL THERAPY OF MESOTHELIOMA

Introduction

With the exception of the use of thoracoscopy for diagnosis, indications for surgery in mesothelioma are controversial. Due to the rarity of disease there are no randomized surgical studies on which to base objective treatment decisions, and most of what constitutes current guidelines has been based on single center retrospective studies or phase I/II trials with limited numbers of patients. This chapter will examine the role of surgery for diagnosis, staging, palliation, and therapy for MPM. In understanding the currensurgical literature for this disease, the reader is reminded that comparisons between reported series are difficult. Factors that highly influence the outcome such as tumor stage and histology are not only often difficult to accurately define in an individual patient but are often variably documented in published reports. Furthermore, indications for selection of patients to undergo a  given procedure are often poorly explained (if at all) and this inevitably leads to bias when comparisons are performed between different series.

Natural History

The natural history of mesothelioma is for the tumor to progress locally causing dyspnea, by either lung entrapment or compression from effusion leading to atelectasis and shunting, and pain from chest wall invasion. Death usually occurs within 6–12 months from initial diagnosis. Though autopsy studies reveal that metastases occur in 50–75% of cases, most are clinically occult and are not the cause of death. The majority

of patients with MPM are diagnosed when the tumor is at an advanced stage. Many untreated patients with early stage disease (American Joint Commission on Cancer (AJCC) Stage I) will probably survive significantly longer than 12 months. Ruffie et al reported median survival of 6.8 months from date of diagnosis until death in 176 untreated patients from 9 Canadian centers from 1969 to 1984. Two more recent trials, however, serve as useful contempoRary benchmarks for outcome in untreated patients. Merritt et al. reported a median survival of 7.1 months in 101 consecutive patients with MPM treated at two tertiary referral centers in Ontario. Symptom management alone was performed. Patients were not clinically staged, and a relatively large proportion  (57%) had non-epithelioid tumors, which are

known to have worse outcome. Another trial performed by the Medical Research Council of Great Britain randomized 409 patients to chemotherapy or active symptom control which included use of steroids, appetite stimulants, bronchodilators, or palliative radiotherapy. Epithelioid tumors occurred in 74% of patientsand 79% were AJCC stage III or IV, proportions that are consistent with most clinical series. Median survival calculated from the date of randomization (median 60 days from date of diagnosis) was 7.6 months, and 1-year survival was 29%. Chemotherapy did not have a survival benefit over active symptom  control; however, pemetrexed, the current standard chemotherapeutic agent was not included in the drug regimen. Two recent prospective randomized trials using modern platinum/antifolate doublet regimens

showed median survival of 11.4 months and 12.1 months, respectively, in non-resectable patients . The median survival for untreated patients is therefore probably between 7 and 10 months from the date of diagnosis and with chemotherapy may extend to 12–13 months, but  will be influenced by initial stage and tumor histology. Though these studies provide a rough benchmark on which to base survival comparisons

with surgical series. One must remember that subjects in most surgical series are usually a highly select group of good performance status patients. The natural history of MPM in such patients is still poorly defined.

Diagnosis

Video-Assisted Thoracoscopy

The benefit of video-assisted thoracoscopic surgery (VATS) for the diagnosis of MPM is that it is a safe, simple, widely available, and highly accurate diagnostic procedure. VATS allows large tissue samples to be obtained from multiple areas of the thoracic cavity, an important consideration since there is considerable

tumor heterogeneity within individual mesothelioma tumors. In fact it has been shown that sarcomatoid elements within a mesothelioma are not uniformly distributed within the tumor and that the greater the number of separate biopsies that are taken, the higher the likelihood of diagnosing biphasic (or mixed) histologic

subtype. As patients with non-epithelioid tumors have significantly worse outcome aftercytoreductive surgery than those with epithelioid tumors do, prior knowledge of cell type can greatly influence subsequent therapy. VATS is generally best performed through a single 1–1.5 cm incision placed on the lateral chest

wall in line of a potential future thoracotomy. The rationale for this is that MPM can occasionally track along thoracostomy incisions, thus limiting the number of incisions that is beneficial and placement in a region that can be completely excised at the time of future cytoreductive surgery facilitates complete resection

without having to perform additional excision of multiple thoracostomy sites. A single 1.5 cm incision will usually allow for placement of a 5 mm angled thoracoscope and an endoscopic biopsy forceps through a soft thoracostomy port. Alternatively, a thoracoscope with a working channel can be used. A single chest drain  an subsequently be placed through the same incisio , though it is useful to close the fascia and  ubcutaneous tissue around the chest drainto limit postoperative leakage of pleural Fluid. VATS can identify whether tumor involves the visceral pleura as well as the parietal pleura (IMIG/AJCC stage IB) but is otherwise fairly limited as a staging modality. VATS lymphadenectomy is to be avoided as a staging

procedure as the interruption of tissue planes may hamper subsequent cytoreductive surgery and it is prone to false positivity due to contamination of specimens from the surrounding tumor. VATS is most easily performed in patients where a large effusive component exists. In this setting, port placement can be easily

determined by correlation with axial imaging. In cases where there is significant parietal tumor bulk, it is often best to locate an underlying pocket of fluid first with an 18 gauge spinal needle. Occasionally, tumor burden is such that VATS is impossible and in these instances a small 2 cm incision (again, placed in line with

a potential thoracotomy incision) can easily access the underlying tumor under direct vision. Another merit of VATS is the ability to perform talc pleurodesis. Instillation of 4–5 g of sterile medical grade talc is generally sufficient. Pleurodesis does not impact the ability to perform extrapleural pneumonectomy (EPP) or

pleurectomy/decortication (PD) at a later stage (indeed it can often facilitate dissection), but can offer significant palliation in patients whoare subsequently found not to be surgical candidates. It must be remembered, however, that talc will cause fluorodeoxyglucose (FDG) activity in the pleural distribution and in mediastinal lymph nodes on subsequent positron emission tomography (PET) imaging. For this

reason it is ideal that PET imaging be performed prior to talc pleurodesis. Despite the obvious benefits of VATS as a diagnostic and therapeutic procedure in mesothelioma, it requires general anesthetic and at

least an overnight hospital stay. CT-guided core needle biopsy is a more convenient method of establishing a tissue diagnosis. It has a high accuracy for diagnosis of mesothelioma but is probably less sensitive for determination of true histologic subtype as generally only a single tumor site is biopsied. The incidence of tumor seeding may be also less than with thoracoscopic biopsy [1]. At the University of Texas

M.D. Anderson Cancer Center CT-guided biopsy is the initial method of diagnosis used for patients with suspected mesothelioma. VATS is reserved for patients in whom there is diagnostic uncertainty or for patients in whom treatment of an associated effusion is indicated. extrapleural plane and potential contamination of the incision with tumor. The worst situation occurs when a thoracotomy is performed and a

partial parietal pleurectomy is undertaken in the mistaken belief that “more is better.” In this setting it is virtually impossible to perform an adequate cytoreductive procedure at a later time.

Staging

The American Joint Commission on Cancer (AJCC)/International Mesothelioma InterestGroup (IMIG) staging system is based primarilyon pathologic data. As such it has significant limitations when applied to clinical staging. Many of the factors that contribute tostage designation such as pericardial invasion,

invasion of the endothoracic fascia, lymph node metastases, and diaphragmatic invasion,to name but a few, are simply not possible to determine accurately with current diagnosticimaging techniques. Though PET can identifyoccult distant metastatic disease in up to 25% ofcases, it is insensitive for determining lymph

node involvement or transdiaphragmatic invasion factors that significantly worsen outcome

and generally contraindicate extrapleural pneumonectomy

Laparoscopy

Transdiaphragmatic invasion is a manifestation of advanced disease (Stage IV) and precludes any form of cytoreductive surgery. Involvement may occur either through direct and contiguous invasion of tumor across the diaphragmatic muscle or by lymphatogenous spread via communicating lymphatics between the pleura and the abdomen. This latter form of metastatic spread may lead to peritoneal carcinomatosis

 and is not necessarily dependent on the degree of tumor bulk within the hemithorax. Because of the inability of axial imaging (MRI, CT or PET) to accurately differentiate transdiaphragmatic from superficial invasion or tumorabutment, Conlon investigated the use of laparoscopyand identified transdiaphragmatic

invasion in 6 of 12 patients with equivocal CTfindings. Importantly, of the remaining six patients, all underwent thoracotomy and noneas found to have transdiaphragmatic invasion. Based on these findings in 1999 we began routinely performing laparoscopy in patients being considered for extrapleural pneumonectomy. Laparoscopy is performed as an outpatient procedure in combination with  ediastinoscopy

(or, more recently, endobronchial ultrasound (EBUS)), usually utilizing a 10 mm periumbilical port and a 5 mm subcostal port on the same side as the mesothelioma. After initial inspection of both diaphragms and the entire peritoneal cavity the abdomen is irrigated with 1,000 cc normal saline. A 0-degree 5 mm laparoscope

is then placed through the subcostal port and advanced beneath the surface of the saline to closely inspect the underside of the ipsilateral diaphragm. The saline helps surrounding organs (liver, spleen, and omentum) be atraumatically displaced away from the diaphragmatic surface while preserving visibility. Suspicious lesions are biopsied, which generally requires placement of an additional 5 mm port. The lavage

fluid is routinely submitted for cytologic analysis. In 109 patients with potentiallyresectable mesothelioma 9 (8.3%) patients werefound to have transdiaphragmatic extension of tumor, and 1 (0.9%) patient had diffuse peritoneal carcinomatosis. CT scans were suspiciousfor diaphragmatic invasion in only 3 (33%) of these patients. In addition, of 78 patients who underwent peritoneal lavage, 2 (2.6%) patientswere found to have peritoneal micrometastaseswithout obvious diaphragmatic invasion. Thus,

12 (11.0%) patients were identified with unsuspectedabdominal involvement and thus wereable to avoid futile cytoreductive surgery. 

Mediastinoscopy

The high prevalence of lymph node metastases in MPM (up to 50% of patients undergoing trimodality

therapy) and the poor prognosis that extrapleural nodal involvement confers, are justifications for preoperative assessment of mediastinal nodal metastases. Unfortunately, current radiographic modalities are inaccurate. The sensitivity of CT for detecting mediastinal N2 disease in mesothelioma is only 50–60% asthere is difficulty in differentiating enlarged mediastinal nodes from adjacent areas of tumor

nodularity. Similarly, PET has relatively lowaccuracy at correctly defining N stage. The efficacy of surgical staging of the mediastinumwith cervical mediastinoscopy (CM) is wellestablished for non-small cell lung cancer; however,the utility of the procedure in mesotheliomais less clear. Schouwink and associates

performed CM in 43 patients with MPM andcompared the staging accuracy of CM with thatof CT scanning. Sensitivity, specificity, andaccuracy were 80%, 100%, and 93%, respectively,for CM compared with 60%, 71%, and67% for CT. Mediastinoscopy failed to identify9 (21%) patients who were found to have positiveintrathoracic nodes at thoracotomy, despite the fact that three of these patients had positive

nodes in sites that were potentially accessibleby CM. We routinely perform mediastinal nodalsampling (now with EBUS) at the time of staginglaparoscopy. We reported use of mediastinoscopyin 62 patients with mesothelioma and identified N2 metastases in 10 (16.1%). Ofthese, 46 underwent extrapleural pneumonectomy.Fourteen (30.4%) patients were found tohave extrapleural (N2) nodes at thoracotomy, of

which CM identified only five preoperatively. The sensitivity and accuracy of CM for detecting N2 disease was only 36% and 80%, respectively. One of the reasons for the low sensitivity is that extrapleural nodal metastases in mesothelioma frequently occur in regions that are inaccessible to mediastinoscopy such as the

internal mammary artery chain, the aortopulmonary window, the anterior mediastnal fat and thymic tissue, the intercostal spaces and the retrocrural and anterior diaphragmatic regions. Combined laparoscopy and mediastinoscopy identified 15 of 118 patients (12.7%) in whom either contralateral nodal disease (N3) or

abdominal involvement precluded further surgical therapy. 

Thoracoscopy

More recently, laparoscopy and mediastinoscopy have been combined with bilateral thoracoscopy for surgical staging of patients with mesothelioma. Alvarez et al identified contralateral chest involvement in 3 of 30 (10%) patients and five (20%) were upstaged to stage IV. Additionally, two patients were reclassified rom epithelioid to non-epithelioid histology.  Surgical staging identified 26% of patients who would have received no benefit from trimodality therapy. Though experience with bilateral VATS is yet limited, it may have a role in patients who present with a contralateral effusion or noncalcified pleural plaques. 

Endoscopic Staging

While generally safe, CM requires a cervical incision and is associated with a small risk of recurrent nerve injury, pneumothorax, tracheal injury, hemorrhage, and even death. Endobronchial ultrasound (EBUS) and esophageal ultrasound (EUS)-guided fine needle aspiration (FNA) of mediastinal lymph nodes have been highly effective for staging non-small cell lung cancer (NSCLC). Since 2006 we

have replaced mediastinoscopy with EBUS forassessment of mediastinal nodes in patients beingconsidered for radical resection of MPM. We compared 50 consecutive patients with mesothelioma who underwent CM with 38patients who underwent EBUS. Sensitivity and negative predictive value for mediastinoscopywere 28% and 49%, and 59% and 57% for EBUS. Furthermore, 11 patients had EUS preoperatively, hich revealed infradiaphragmatic nodal metastases in 5 patients (Fig. 7.4). Tournoy

et al performed EUS and FNA in 32 patients with resumed early stage mesothelioma and identified

N2 metastases in 4 (12.5%) [70]. Of the patients who subsequently underwent extrapleural pneumonectomy and mediastinal node dissection (n = 17) there was only one false negative (4.7%). Mediastinoscopy did not identify additional nodal metastases. The data for EBUS and EUS staging in mesothelioma are preliminary,

however, and further studies will be needed to ascertain their benefit. Though these minimally invasive techniques are safe and less traumatic than mediastinoscopy, there is a risk for false positivity because of the danger of mistaking tumor nodules adjacent to the trachea or esophagus as enlarged lymph nodes. Therefore, the procedure should be performed by an operator skilled in endoscopic ultrasound and familiar

with mesothelioma and only well-defined, circumscribednodes should be biopsied. It is also important that there is evidence of lymphoid tissuein any positive aspirate. 

Palliative Surgery

Symptoms in patients with mesothelioma predominately consist of dyspnea, chest pain, cough and constitutional symptoms such asfatigue, fever, and anorexia. Respiratory symptoms are secondary to atelectasis and shunting caused by pleural effusion or lung encasement; or to altered respiratory mechanics secondary tochest wall contraction and impaired movement of the ribs and diaphragm. Surgical palliation is

centered around two issues – treatment and prevention of pleural effusion, and tumor debulkingto allow lung expansion and improved chestwall mechanics.

Pleural Drainage

Treatment of pleural effusion depends on thesize of the effusion, the degree to which it is causing atelectasis and the degree of lung encasement by tumor. Simple thoracentesis israrely effective in providing long-term relief of mesothelioma-related effusion; however, it is areasonable initial procedure to establish a diagnosis

and to evaluate the degree to which thelung will re-expand. In the absence of completere-expansion, pleural symphasis is unlikely tooccur with sclerotherapy. If the lung is trapped because of tumoral involvement of the visceral pleura (as is most often the case except in Stage I disease) placement of an indwelling pleural

catheter such as the PleurX® catherer (CareFusion, San Diego, CA) is preferable. This procedure is most easily performed on an outpatient basis and avoids hospitalization. In addition, complete lung re-expansion is not required to obtain control of the effusion. Tumor progression along the tract of the catheter has

been described but is uncommon. VATS is the preferred method for pleurodesis, particularly in cases where the effusion may be loculated,but will ultimately only be successful in cases where expansion of the majority of thelung can be achieved. In addition to drainage of effusion, VATS provides large quantities of tissuefor diagnosis and histologic subtyping.Limited visceral decortication can occasionally

free entrapped lung, but the case must be taketo limit air leaks as these can lead to the requirement

for prolonged chest tube drainage.

Pleurectomy

Pleurectomy and decortication (PD) have long been used for the control of malignant effusions. The aim of palliative PD is to enable lung re-expansion, ameliorate the contracting effect of tumor on the ribs and intercostal muscles, and to create pleural symphasis. Palliative PD is best accomplished via a posterolateral thoracotomy. Although limited PD can be easily accomplished through a muscle sparing incision, if there is significant tumor burden division of the latissimus dorsi muscle and resection of the seventh rib can greatly facilitate exposure and resection. Dissection is begun by establishing a plane between the involved pleura and the endothoracic fascia. This is most easily accomplished using sharp dissection initially followed by blunt finger dissection. Chest wall bleeding may be controlled using gauze pads for tamponade or use of electrocautery, argon beam coagulation, or radiofrequency such as the highly effective AquaMantys® radiofrequency system (Salient Surgical Technologies, Portsmouth, NH). Once the lung and parietal pleura have been completely mobilized, dissection of the visceral pleura away from the underlying lung parenchyma is performed. The tumor rind is incised on the lateral aspect of the mobilized lung and using sharp dissection a plane is created immediately beneath the visceral pleura. Once established, dissection is continued in all directions using a peanut retractor or using a finger and gauze pad. The pericardium and diaphragmare frequently involved, or at least inseparable from tumor. If palliation is the intent of the procedure rather than cytoreduction, these structures should remain intact, leaving tumor in place where necessary.

7.6 

Cytoreductive Surgery 

The aim of cytoreductive surgery is to provide a removal of all macroscopic tumor from the hemithorax. It is postulated, though unproven, that R0/R1 cytoreduction may prolong survival in patients particularly those with epithelioid tumors who do not have lymph node metastases. Cytoreductive surgery is usually accomplished in the setting of bi- or tri-modality therapy. Local tumor control appears to be improved with R0/R1 cytoreduction and adjuvant radiation therapy. Because of the high rate of distant recurrences (as

high as 50%), systemic therapy is usually also advisable, though the effect of chemotherapy on reducing distal recurrence is unproven. There are two approaches to cytoreduction: extrapleural pneumonectomy and extended pleurectomy/ decortication (or radical pleurectomy/decortication). Each has its merits as well as limitations and will be discussed separately below. 

Extrapleural Pneumonectomy (EPP)

Technique

Extrapleural pneumonectomy involves the enbloc resection of the parietal and visceral pleura, lung, ipsilateral pericardium and diaphragm. Preoperative placement of defibrillator EKG leads is performed in the  vent of an  Intraoperative rapid supraventricular arrhythmia that requires synchronized cardioversion. Because of the potential risk of injury to the superior vena cava during dissection of rightsided tumors, large bore femoral venous access is obtained. A nasogastric tube is placed, which posterior dissection. A generous posterolateral thoracotomy incision is performed, extending the incision anteriorly in line with the underlying ribs. The latissimus dorsi muscle is divided but the serratus anterior muscle should be spared. In the event of a postoperative bronchopleura  fistula, an intact serratus muscle is useful for repair. The anterior most attachments of the muscle should be elevated off the underlying chest wall and retracted superiorly. Removal of the seventh rib provides optimal access to the extrapleural plane, which should initially be developed sharply . Once the correct plane is identified it may be extended in all directions using blunt dissection. It is useful to place gauze packs in areas thathave been dissected to tamponade oozing from the chest wall. We have found the preoperative intravenous administration of tranexamic acid to be useful to control chest wall oozing. The Aquamantys® radiofrequency system (Salient Surgical Technologies, Portsmouth, NH) or an argon beam coagulator is useful for direct control of chest wall bleeding. Once the extrapleuralplane has been dissected to the level of thehilum anteriorly and posteriorly, an incision ismade in the pericardium anterior to the phrenic nerve, and the pericardium attached to the overling pleura and tumor is resected en-bloc with the specimen. Finally, the diaphragm is resected along with the associated overlying lung and tumor. Generally, the diaphragmatic fibers can be bluntly avulsed from their peripheral attachments followed by sharp or cautery dissection of intervening fibers. Once the peripheral attachments are taken down, blunt dissection with sponge forceps allows the muscle to be separated from the underlying peritoneum. It can be difficult to keep the peritoneum entirely intact, especially in the region of the central tendon; however, lacerations inthe peritoneum can be easily repaired with a fine absorbable suture. The unproven rationale for maintaining the integrity of the peritoneumis that it preserves the integrity of the abdominal cavity from potential contamination with tumor from the chest. In the region of the esophageal hiatus, it is ideal to preserve some of the crural fibers to mitigate against herniation of the stomach into the post-pneumonectomy space. Once the entire specimen has been mobilized the hilarstructures can be divided. The pulmonary artery and veins should be divided first. The main bronchus is freed of surrounding tissue to the level of the carina. A firing of the stapling device (generally a TA-30 3.0 mm) is placed on

the distal bronchus first. This allows the anesthesiologist to retract the end of the left-sided double lumen  ndotracheal tube back into the  rachea while preventing ventilation of the left lung for left-sided tumors.  additionally, it prevents migration of bronchial secretions into the chest cavity after division of the main bronchus. The stapling device is then placed across the main stem bronchus at the level of the carina and two separate rows of staples fired before division of the bronchus. Application of the stapler under direct bronchoscopic examination can be useful to ensure that the bronchial stump is flush with the carina and that there is no redundant bronchus left that will retain secretions. Once the specimen is removed from the

chest cavity, hemostasis is secured and the cavity irrigated with at least 3 L of weak betadine solution. The anterior and inferior margins of resection are marked with numerous titanium clips to aid in planning of adjuvant radiotherapy. Though postoperative care is similar to that of any pneumonectomy, certain point  are worthy of mention. Early mobilization should be encouraged to lessen the risk of contralateral atelectasis and pneumonia. Transient gastroparesis can occur following EPP, especially where one or both vagus nerves have been injured or sacrificed during dissection, therefore nasogastric drainage should be continued during the first 24 h and great care taken when advancing diet. Because of the greater degree of chest wall oozing and drainage after EPP compared to standard pneumonectomy, it is advisable to leave the chest drain in place for at least 48 h. Earlier withdrawal may allow excessive amounts of fluid to accumulate early in the pneumonectomy space which may cause contralateral mediastinal shift and cardiopulmonary dysfunction. Additionally, excellent control of postoperative pain is required not only for patient comfort but also for optimal respiratory function. Epidural analgesia generally provides better control of pain than intravenous narcotics, and because of the extended thoracotomy incision epidural analgesia should be continued for at least 4–5 days after surgery.

 Adjuvant Therapy 

Extrapleural pneumonectomy generally provides a more complete cytoreduction compared to radical P/D since the entire lung is removed, limiting the area at risk for local recurrence to the chest wall and mediastinum contiguous with the resected tumor. As the lung is resected, adjuvant radiation may be administered to the postpneumonectomy space. Hemithoracic radiation following P/D is problematic because it is technically difficult to deliver adequate tumoricidal doses of radiation to the entire at-risk area without causing severe toxicity to the underlying lung. Furthermore, conventional photon/electron

beam radiotherapy has not been shown to decrease local recurrence after P/D. EPP is associated with significantly higher postoperative morbidity than P/D, and in most series mortality is also higher (3–8% in experienced centers, . Extrapleural pneumonectomy is usually performed as part of a multimodality therapeutic regimen (Table 7.2). In the absence of adjuvant therapy local recurrence rates range between 30% and 50%. Two recent studies have demonstrated the efficacy of hemithoracic radiation in reducing local recurrence after EPP. In a phase II multicenter study from Memorial Sloan Kettering Cancer Center (MSKCC), Rusch et al delivered 54 Gy of irradiation to 54 patients who had undergone EPP. Radiotherapy was performed using anteroposterior photon beams, placing specially designed blocks over radiation sensitive structures after threshold doses for thoseorgans had been achieved. The corresponding underdosed areas of the chest wall were then treated with matched electron beams. Local recurrences occurred in only 13% and were mainly in the posteroinferior paravertebral sulcus, areas difficult to adequately treat with this radiotherapy technique. Patients with stages I and II had a median survival of 33.8 months  whereas the median survival of patients with stage III or IV was only 10 months. A retros ective study, from the M.D. Anderson Cancer Center (MDACC), evaluated 63 patients treated with intensity modulated radiation therapy (IMRT) (median dose 45 Gy) after EPP [52]. IMRT has advantages over conventional radiation because the entire hemithorax can be more accurately targeted while limiting radiation toxicity to surrounding structures. In-field recurrences occurred in only 5% and overall locoregional recurrence was 13%. It should be kept in mind that the patients treated in both these studies were of advanced stage − 69% stage III/IV in the MSKCC study; 87% stage III/IV in the MDACC study. Despite excellent local control, however, distant metastases occurred in 63% and 54% of patients in each study, respectively, suggesting the need for systemic treatment in addition to local therapy. Pleurectomy/Decortication (P/D) The term “pleurectomy/decortication” can mea  different things to different surgeons. It can refer to a partial debulking of tumor from the parietal and visceral pleural surfaces leaving large amounts gross tumor behind, it can be a subtotal resection of the parietal and visceral pleura leaving behind only minimal amounts of macroscopic tumor, or it can include complete removal of all macroscopic tumor, which usually entails resection and reconstruction of the diaphragm and pericardium in addition to total pleurectomy . In terms of cytoreductiv  surgery, the latter procedure is optimal and is frequently termed “extended” or “radical” pleurectomy/decortication to distinguish it from lesser debulking procedures.

Technique

Radical P/D begins with a complete extrapleural mobilization of the lung to the level of the hilar structures similar to that performed during the initial dissection for EPP. If the pleura/ tumor is inseparable from the pericardium or diaphragm (as it most often is) these structures are resected and reconstructed in a manner similar to that of EPP. Once the lung and overlying pleura have been completely mobilized, an incision is made in the parietal pleura and taken through the tumor and visceral pleura down to the level of the lung parenchyma. Using sharp dissection a plane is created immediately underneath the visceral pleura. This plane is then further elaborated using blunt dissection with a peanut sponge or a gauzed finger. Paradoxically, this is often more easily accomplished in patients who have a significant tumor rind as it can be difficult to completely remove minimally involved pleura. Although the lung parenchyma often bleeds it will usually abate quickly. In this way the entire visceral pleura and overlying tumor and parietal pleura can be resected down to the hilar structures. The pleura is traced all the way into the fissures, and the pulmonary artery and veins will usually be encountered and should be completely freed of any overlying pleura or tumor. Occasionally, lung parenchyma that has been atelectatic for lengthy periods from overlying tumor will seldom expand, and these areas are often best resected with a linear stapler. Similarly, portions of lung that have been devitalized during dissection or those with significant lacerations are often best removed. Though usually all tumor can be resected from the underlying lung, occasionally and in particular in early stage disease, there can be a multitude of tiny subpleural tumor deposits that remain adherent to the lung after visceral pleurectomy. These may be directly removed using sharp dissection or may be ablated using thermal energy (argon beam , electrocautery, radiofrequency ablation, or cryoablation (personal observation). Typically, there are three large-bore chest drains : one over the diaphragm coursing posteriorly to drain the costovertebral recess, one in the posterior sulcus,

and one anteriorly. 

Postoperative Care 

Because the chest wall can continue to slowly ooze blood and maximum expansion of the lung is ideal postoperatively, it can be helpful to keep patients intubated overnight following pleurectomy/ decortications. This ensures maximal expansion of atelectatic lung and the inflated lung aids in tamponading diffuse chest wall

oozing. Air leaks are prominent, particularly on positive pressure ventilation, but will usually subside within a week. Chest drains are placed at the lowest amount of suction that is sufficient to maintain complete expansion of the lung, usually negative 10–20 cm H20. 

Adjuvant Therapy 

Because the lung is left in situ, P/D offers less complete cytoreduction than EPP but impacts pulmonary function significantly less. This is reflected in the lower perioperative mortality reported in most series compared to EPP , and also in the higher incidence of local recurrence, which generally ranges from 50% to 100% . Unlike EPP, the intact lung that remains limits the ability to administer effective radiation postoperatively. Gupta et al reported 123 patients who received hemithoracic radiation therapy (median 43 Gy) similar to the regimen used at MSKCC for EPP. Despite a preponderance of patients with stage I and II (59%) median survival was only 14 months, and local recurrence occurred in 56% of patients. Similarly, Lee and colleagues performed P/D on 26 patients using intraoperative radiation followed by postoperative 3-dimensional conformal radiation or IMRT. 69% of patients had stage I disease and so it is not surprising that the median survival was reasonably good (18 months). Fifty percent of patients had recurred or died by 1 year however, and although the exact frequency of local recurrences was not reported, the author  stated that most patients died from progressive disease, and that the “site of f ilure was mostly locoregional.”

Intrapleural Therapies

The relatively high local recurrence rate following cytoreductive surgery alone has prompted use intrapleural therapies after PD or EPP. These have primarily involved intrapleural administration of platinum-based chemotherapy or intracavitary photodynamic therapy (PDT) with preoperatively administered photosensitizers. The concept behind intrapleural therapy is straightforward – extrapleural dissection

of mesothelioma cannot reliably achieve an R0 resection and microscopic tumor deposits are frequently left behind. This is evident in local recurrence rates of up to 30–50% following EPP alone. Because of the even greater propensity for microscopic, and even macroscopic tumor remnants following pleurectomy/decortication, local recurrence rates can be as high as 70–100% with this procedure. Intrapleural chemotherapy is theoretically able to treat the entire at-risk area of the hemithorax and has been shown to permeate up to 5 mm into tissue. Most trials of ip chemotherapy however have been small phase I and II studies with limited numbers of patients. Rates of local recurrence have varied between 17% and 100% . Earlier studies tended to rely on the instillation of chemotherapeutic agent into the chest cavity via chest drains in the postoperative period. More recently, capitalizing on the tumoricidal effect of hyperthermia, investigators have evaluated intraoperative intrapleural perfusion of cytotoxics heated to 42°C. The largest study of this nature was recently reported by Tilleman and colleagues from the Brigham and Women’s Hospital. Ninety-two patients were enrolled on a phase II study which included EPP and intraoperative heated chemoperfusion with cisplatin. Renal function was maintained by the concomitant administration of sodium thiosulfate and amifostine. Though recurrence within the ipsilateral chest was low (17%) and operative mortality 4%, median survival was only 13 months. Admittedly, nearly half of the patients had stage III disease and 42% had non-epithelioid histology. Thirty-two percent recurred in the contralateral chest and 26% in the abdomen, highlighting the need for more effective systemic therapies. The same group previously published their experience using a similar regimen in 44 patients who were ineligible for EPP and who underwent PD instead. Local recurrence was 57% and treatment related mortality was 11%, probably at least somewhat related to the fact that this was an older, higher risk group.

Extrapleural Pneumonectomy Versus Pleurectomy/Decortication There is considerable controversy over the selection of which operation is the most appropriate. Some surgeons perform only EPP, others only P/D, and many tailor selection of operation to the patient and the degree of tumor load. As previously mentioned, in addition to the oncologic pros and cons of either operation, selection must also take into account the application of adjuvant therapies as well as patient and tumorrelated factors. Clearly, an elderly patient or one with poor cardiopulmonary function is unlikely to tolerate EPP and would be better served with P/D. Patients with non-epithelioid histology (especially sarcomatoid) have poor outcome after EPP and these patients should also probably undergo P/D if surgery is even contemplated at all. The controversy exists mainly around good performance status patients with epithelioid tumors in whom either operation would be technically feasible. There have been no randomized prospective comparisons of these procedures in carefully staged and stratified patients. The largest retrospective comparison of EPP and P/D that exists was performed by Flores and colleagues who reported a combined series from three separate institutions that included 663 patients. Overall median survival was 14 months and was slightly longer for the 278 patients who underwent P/D than for the 385 patients who had EPP (16 vs 12 months, p<0.001). However, it should be recognized that significantly more patients in the P/D/ group had early stage tumors (35% vs 25% (p < 0.001)). In addition, the institutions involved in this study performed P/D not only for patients who would not medically tolerate EPP, but also for fit patients when there was “minimal visceral involvement” [23] and for patients with low tumor volume [46]. This bias toward performing P/D on patients with biologically more favorable tumors makes it difficult to draw firm conclusions from the data. Furthermore, a previous analysis from one of the institutions revealed no difference in survival among 222 patients with EPP and 126 patients with P/D  

PATHOHISTOLOGICAL DIAGNOSISAND DIFFERENTIAL DIAGNOSIS

Introduction

Malignant mesothelioma is a malignant tumour originating from mesothelial cells. Most frequently, it arises in the pleura (70–95%). Primary peritoneal mesothelioma is less frequent (6–10%). Rarely, the primary site of malignant mesothelioma is the pericardium or the tunica vaginalis of the testis [34]. The most frequent pleural and peritoneal tumour is metastatic carcinoma; therefore morphological diagnosis by the surgical pathologist has to take into account clinical history and radiology. Asbestos exposure is the highest risk factor ofpleural and peritoneal malignant mesothelioma and reported in approximately 54–90% of the patients. The mean latency period between exposure and tumour diagnosis ranges from 35 to  0 years. In peritoneal mesothelioma, an increased pulmonal asbestos exposure of the lung can be observed in 85% of the patients. Further, patients with peritoneal mesotheliomas have a higher pulmonal  asbestos exposure than those with pleural mesotheliomas. The incidence of malignant pleural  esothelioma shows marked variation in different countries. The highest incidence rates are reported from Great Britain, Belgium and Australia with annual incidences from about 30 cases per million.

In women, occupational asbestos exposure plays a minor role than in men. It has been found in approximately 23%. No occupational asbestos exposure has been found in young patients with malignant peritoneal mesothelioma. In women, malignant peritoneal mesothelioma occurs in younger age and is associated with better prognosis. Two percent to 5% arise in the first 2 decades of life. Other possible risk factors for malignant mesothelioma are radiation, recurrent peritonitis and simian virus 40 (SV 40). The association between Simian virus 40 (SV 40) and risk of mesothelioma development remains a controversial

discussion. Exposure to erionite (zeolith mineral fibre similar in appearance with amphibole asbestos) leads to higher incidences of mesothelioma and plays an important role in environmental exposure (Turkey). Prognosis is dependent on histological type. Longest survival can be seen in patients with epithelioid malignant mesothelioma. Patients with sarcomatoid malignant mesothelioma have the

worst prognosis and prognosis of biphasic malignant mesothelioma lies in between. Grading has not been proven to correlate with prognosis. For differential diagnosis between metastasis, primary malignant mesothelioma or reactive mesothelial proliferation, not only histology but also a panel of immunohistological markers is essential. 

Malignant Mesothelioma of the Pleura

The most common primary tumour of the pleura is diffuse malignant mesothelioma (WHO nomenclature), but often this tumour is designated as malignant mesothelioma or simply as mesothelioma 

Morphology

Macroscopy and Tumour Spread Early malignant mesothelioma begins as multiple nodules, usually in the parietal pleura and less frequently in the visceral pleura. Later, nodules become confluent and diffuse tumour

growth leads to pleural mass, pleural thickening (more than 1 cm to several cm) and effusion. Parietal and visceral pleura are both involved and cannot be separated. The tumour has a firm, sometimes gelatinous consistency, and spreads throughout the pleura, grows along interlobular spaces and encloses the lung. Hyaline pleural plaques are often present – up to 40% 

Histological Patterns

 Malignant mesothelioma has the capability to reveal either epithelial or mesenchymal differentiation or both. Depending on the histological growth pattern, epithelioid, sarcomatoid, biphasic and desmoplastic malignant mesothelioma are distinguished according to the WHOclassification

Epithelioid Mesothelioma

The most frequent one is epithelioid malignant mesothelioma. It shows different growth patterns,

mostly tubular or tubulopapillar. Tubules are small and papillary structures have vasculated stroma cores . Papillary areas may show psammoma bodies. Sheet-like or microglandular (also revered to as adenomatoid) growth pattern can also be seen and are admixed with tubulopapillar areas . Sometimes pseudo-signet ring cells are demonstrable (negative for mucine) or clear cell differentiation 

Sarcomatoid Mesothelioma

Sarcomatoid malignant mesothelioma shows spindle cells, which are arranged in a haphazard  pattern, or giant cells with anaplasia. Tumour growth resembles fibrosarcoma or malignant fibrous histiocytoma. Focal areas of osteosarcomatous or chondrosarcomatous differentiation can be found. In sarcomatoid malignant mesothelioma, greater atypia, mitotic activity and more necrosis can be found compared to epithelial mesothelioma

Biphasic Mesothelioma 

Biphasic malignant mesothelioma comprises both the aforementioned components, showing an epithelioid and sarcomatoid differentiation. At least 10% of the tumour should be represented by one of the components to be called biphasic. About 30% of all mesotheliomas are biphasic [23, 53], but the more tumour tissue sampled, the higher percentage of biphasic differentiation can be detected. Spindle cell differentiation of tumour cells must not be confused with pronounced stroma reaction in epithelioid

mesothelioma. Focal osseous differentiation is possible. 

Rare Forms of Mesothelioma

In desmoplastic malignant mesothelioma, dense eosinophilic stroma of desmoplastic type predominates throughout at least 50% of the tumour. Atypical spindle cells are distributed in a patternless manner. Particularly in small biopsies, desmoplastic malignant mesothelioma may be confused with reactive sclerosing pleuritis as there might not be overt infiltration of fat or muscle

tissue or sarcomatoid differentiation to prove malignancy. Desmoplastic mesothelioma can be regarded as a subtype of sarcomatoid malignant mesothelioma.

Differential Diagnosis of Malignant

Mesothelioma and Pleural Metastases

Although diffuse malignant mesothelioma is the most common primary neoplasm arising in the pleura, metastatic carcinoma by far is the most frequent pleural tumour overall [4, 32]. In daily routine pleural biopsy diagnostic, one has to deal with the question, if mesothelial proliferation is reactive or neoplastic, primary mesothelioma or metastatic. Histology is the gold standard of diagnostic, but morphology alone cannot solve

the problem and needs to be accomplished by additional immunohistochemical analyses

Morphological Differences

Epithelioid malignant mesothelioma needs to be distinguished from metastatic carcinoma, particularly of the lung, breast, gastrointestinal tract and prostate. To separate malignant mesothelioma from metastases, immunohistochemistry is essential, but some morphological characteristics narrow the possible differential diagnosis . Clear cell differentiation of mesothelioma can be misdiagnosed for metastatic renal cell

carcinoma, clear cell adenocarcinoma of the lung or malignant melanoma. Sarcomatoid malignant mesothelioma raises the possible differential diagnosis of spindle cell carcinoma, different types of sarcoma (leiomysarcoma, synovial sarcoma, angiosarcoma, pleomorphicsarcoma and others) and again sarcomatoid

renal cell carcinoma or malignant melanoma. Macroscopic appearance of the tumour is important, since malignant mesothelioma usually shows diffuse growth and metastases of the above-mentioned tumours are mainly circumscribed. Thymoma and solitary fibrous tumour, respectively, has to be taken into consideration as well. Reactive changes like sclerosing pleuritis or papillary mesothelial hyperplasia need to be ruled out Pleomorphic malignant mesothelioma can mimic pleural metastasis of pleomorphic carcinoma, mostly of the lung, or pleomorphic sarcoma (malignant fibrous histiocytoma). Psammoma bodies can be seen in metastasis of serous ovarian cancer, primary peritoneal carcinoma,

papillary lung or renal carcinoma as well as in papillary or tubulo-papillary malignant mesothelioma. They do not prove the metastatic origin of the tumour

Immunohistochemistry

Immunohistochemistry is essential for diagnosis of epithelioid malignant mesothelioma, for delineating reactive from neoplastic mesothelial proliferation and for excluding or ascertaining pleural metastases, mainly adenocarcinoma. With the exception of TTF-1, there is no other single immunohistochemical marker which is able to prove or exclude malignant mesothelioma, yet. A panel of different immunohistochemical markers

has to be applied 

Important Markers for Differential Diagnosis

Pancytokeratin

Epithelioid mesothelioma is strongly positive for pancytokeratin. More than 70% of sarcomatoid mesotheliomas are positive with the broad spectrum cytokeratin in the cytoplasm. 

CK 5/6

64–100% of epithelioid malignant mesotheliomas express CK5/6 [55, 56] and it also helps to highlight tumour cells in desmoplastic malignant mesothelioma. The marker serves to distinguish mesothelioma from lung adenocarcinomas. This marker usually characterises squamous cell differentiation but can also be found in adenocarcinoma of the lung in 2–19%

Calretinin

Calretinin is one of the best known and most specific positive mesothelioma markers. It is positive in almost all epithelioid mesotheliomas with a nuclear and cytoplasmatic staining pattern. Nevertheless, specificity is not 100%, because focal cytoplasmatic  expression can be found 0–38% of lung carcinomas, whereas positive nuclear otaining is only found in mesothelioma .

WT-1

WT-1 is negative in adenocarcinoma of the lung, and cells of malignant mesothelioma show positive reaction in 75–90% . In recent studies none of the lung adenocarcinomas were found to express WT-1 . It is one of the best markers to distinguish malignant mesothelioma from adenocarcinoma of the lung. Serous adenocarcinoma of the ovary also shows positive WT-1 reaction.

D2-40

Malignant mesothelioma shows membrane positivity of D2-40 (podoplanin) in more than 96% (Fig. 5.9), adenocarcinoma of the lung focally in up to 7% . D2-40 is a marker that stains a protein which is expressed in lymphatic endothelial cells . It can be a very useful marker in histological specimens to diagnose malignant mesothelioma  but not in serous effusion cytological smears, because it

does not distinguish mesothelioma cells from metastatic cells of serous adenocarcinoma, seminoma or malignant peripheral nerve sheath tumour, which are also positive 

TTF-1

To our knowledge, TTF-1 has never been proven to be expressed in malignant mesothelioma but is positive in about 85% of lung adenocarcinoma (nuclear expression), but not in squamous cell carcinoma. Reversely, it does not prove the pulmonary origin of pleural metastases because thyroid carcinoma is

also positive and some other primary tumours rarely show TTF-1 expression, one among them being adenocarcinoma of the colon in 10%

BerEP4

Adenocarcinoma of the lung is positive for BerEP4 (also known as HEA) in more than 5%. Malignant mesothelioma focally expresses BerEP4 in up to 20% [38, 55, 56]. Fifty-five percent to 90% of pulmonary adenocarcinomas are positive for CEA and malignant mesothelioma expresses this marker in less than 5%

MOC-31

MOC-31 is another useful immunohistochemical marker to separate malignant mesothelioma from pulmonary adenocarcinoma. This antibody reacts with most carcinomas and only patchily with epithelioid mesothelioma. It is positive in more than 95% of adenocarcinoma and in up to 10% of malignant mesothelioma

BG8

Analogous expression is achieved with BG8 [38, 55, 56], which shows diffuse strong positivity in 98–100% of adenocarcinoma. Only weak and focally staining in 3–7% of malignant mesothelioma have been described . BG 8 could be useful in differentiating epithelioid mesothelioma from lung adenocarcinoma

and serous carcinomas.

Claudin

Claudin 4 is a marker, which is expressed in pleural metastasis of adenocarcinoma of the lung, breast, gastrointestinal tract and ovary in 100% [29]. The majority of epithelioid and sarcomatoid malignant mesotheliomas are negative, but positivity may be found in a minority of cases 

Conclusions Immunohistochemistry

Immunohistochemical markers expressed in malignant epithelioid mesothelioma or in metastasis of adenocarcinoma (modified according to the International Consensus Statement of Pathologic Diagnosis of Malignant Mesothelioma . Sensitivity of the markers is 80% or more. At least two mesothelioma/ carcinoma markers should be applied the International Consensus Statement of Pathologic Diagnosis of Malignant Mesothelioma . Sensitivity of each marker should be at

least 80%. When there are discordant findings, additional markers should be performed. Positivity of calretinin, especially nuclear expression, and/or another of the mesothelioma markers in combination with expression of CK5/6 is very suggestive of malignant mesothelioma. Expression of CK5/6 together with negativemesothelioma markers and positive carcinoma  markers is found in metastasis of squamous cell

carcinoma and in a minority of adenocarcinoma or adenosquamous carcinoma of the lung 

Reactive Versus Neoplastic

Mesothelial Proliferation

In small, superficial pleural biopsies, differentiation between reactive or neoplastic mesothelial proliferations can be difficult. Macroscopic appearance in important and need to includes into the diagnosis [20] and has to take into account if the lesion is diffuse or circumscribed, inflammation, pneumonia of the lung, bilateralism, involvement of parietal or visceral pleura. Papillary mesothelial proliferation occurs in

reactive hyperplasia and malignant epithelioid mesothelioma. Cytological atypia can be more pronounced in reactive hyperplasia, whereas malignant mesothelioma cells usually are uniform and bland. Proliferation, for example, Ki67, in malignant mesothelioma is higher than in reactive changes . Fibrovascular cores in papillary lesions are a clue for malignancy; papillary proliferations in reactive

changes mainly consist of epithelial cells .

Reactive mesothelial proliferations tend to express desmin and are negative for EMA whereas neoplastic mesothelial cells show a contrarious pattern. It is very important, which EMA-clone is applied for immunohistochemistry: clone E29 should be

used and is positive in 75% of malignant mesothelioma and negative in reactive mesothelial proliferation. Clone Mc5 is not specific and positive in 70% of malignant mesothelioma and 60% of reactive changes

Primary Pleural Tumours Other than

Malignant Mesothelioma

Several other tumours arise in the pleura, benign and malignant. Adenomatoid tumour is a benign mesothelial tumour mostly seen in the tunica vaginalis of the genital tract but it can develop in the pleura also. It is a circumscribed, solitary tumour with epithelioid morphology, tubular structures and fibrous stroma. Pseudo-signet ring cells can be found and may be mistaken for metastasis of signet ring cell carcinoma.

Cytology usually is uniform. Well-differentiated papillary mesothelioma rarely develops in the pleura. It is mainly seenin the peritoneum and is described below. Synovial sarcoma is a biphasic tumour and is

very rarely seen in the pleura . Differential diagnosis is biphasic malignant mesothelioma. Most synovial sarcomas are pleural metastases and only a minority is primary to the pleura. Patients usually are younger than patients with malignant mesothelioma; the average age is 33 years . They are localised compared to the diffuse growth of malignant mesothelioma. Epithelioid component can be difficult to detect, tumour growth is more compact with long spindle cell fascicles compared to malignant mesothelioma, which tends to have smaller, less cellular fascicles with greater pleomorphism. It is important to know that synovial sarcoma can be positive for calretinin and malignant mesothelioma for CD99. Demonstration

of Syt-translocation t(X;18) provides the diagnosis 

Peritoneal Mesothelioma

Pathohistological Diagnosis

Malignant peritoneal mesothelioma is characterised by a peritoneal tumour mass with unspecific clinical symptoms like abdominal pain, abdominal swelling, anorexia, weight loss, and/ or ascites. Radiological features are non-specific. Therefore, the histological examination is essential to yield correct diagnosis. Examination of ascites or fine-needle aspiration can be useful but is of low diagnostic potential because of the small numbers of malignant cells in the fluid and their cytological resemblance to normal mesothelial

cells. The use of immunocytology can be useful in some cases. But in general, sampling of tumour biopsy has a higher diagnostic significance whereas immunohistochemical examination is indispensable in distinguishing MPM from other lesions and neoplasias. 

Macroscopy

Malignant peritoneal mesothelioma consists of multiple or innumerable nodules approximately 1.5 cm in diameter. The tumour mass is undistinguishable from peritoneal metastases or primary peritoneal carcinoma. The cut surface is frequently heterogeneous with solid regions and embedded cystic or mucoid areas into the tumour mass. The localised subtype forms a typically circumscribed

mass invading adjacent organs without a diffuse growth through the abdominal cavity. In contrast, the diffuse type shows a widespread expansion and involvement of the abdominal organs along parietal and visceral peritoneum. Infiltrating per continuitatem into the stomach from serosa to the mucosa is seen in every fourth case. Involvement of liver, abdominal wall, pancreas, bladder, retroperitoneum or diaphragm with invasion into the pleural cavity are less common. In 7% of the cases, abdominal, thoracic or inguinal lymph node metastases are found. Haematogenous metastases are seen in the liver,

lung, pleura, pericard, kidney, pancreas or in bones.

Microscopy

Analogue to pleural mesotheliomas, malignant peritoneal mesothelioma is divided into three different major histological types: epithelioid mesothelioma, sarcomatoid mesothelioma and the mixed or biphasic type. There are further rare subtypes like the undifferentiated type (poor differentiated) or lymphohistiocytoid and

desmoplastic mesothelioma (that belongs to the sarcomatoid subtype). The most common type of malignant peritoneal mesothelioma is the epithelioid subtype in more than 50%. In approximately 25% of MPM, a sarcomatoid component can be found, but pure sarcomatoid mesothelioma is very infrequent in the peritoneum and more commonly seen in the pleura.

In women, a deciduoid subtype has been described, that can be mistaken for an extensive ectopic decidual reaction. This subtype can be found in women during pregnancy as well as in women of advanced age. Patients with this subtype have a worse prognosis with a median survival rate of 7 months. Asbestos exposure can be found in 35–80% . 75% of malignant peritoneal mesotheliomas

are epithelioid mesotheliomas resembling normal mesothelial cells. They are composed of trabecular, papillary or tubulo-papillary formed tumour nests. Microglandular or signet-ring cell patterns are also found. The tumour cells invade submesothelial connective tissue, fatty tissue and muscle which help to distinguish malignant mesothelioma from reactive mesothelial hyperplasia.

Malignant Mesothelioma of Tunica Vaginalis Testis 

Malignant mesothelioma of tunica vaginalis testis is a rare  tumour that belongs to malignant peritoneal mesothelioma because during embryonal period, tunica vaginalis testis evolves from invagination of the abdominal peritoneal membrane and is covered by mesothelial cells. Less than 5% of malignant peritoneal mesotheliomas are localised primarily in the tunica vaginalis testis . Several studies evaluated that mesotheliomas of tunica vaginalis testis are asbestos related in case

of significant asbestos burden

 Well-Differentiated Papillary Mesothelioma

Well-differentiated papillary mesothelioma is a rare subtype of epithelioid mesothelioma with low malignant potential in contrast to malignant peritoneal mesothelioma. It occurs more frequently in the peritoneum than in the pleura and it is typically most common in young woman without asbestos exposure, but its relation

to asbestos exposure remains still unclear. One study group reported an occupationally asbestos exposure in 42% of all examined patients. Macroscopically, the tumour size ranges from 1 cm to more than 3 cm, but more than half of the cases of well-differentiated papillary mesotheliomas are smaller than 1 cm.

Furthermore, it can occur as solitary type or multifocal type. The latter shows more aggressive behaviour. In some cases, patients with initial well-differentiated papillary mesothelioma die from diffuse malignant mesothelioma during the course of disease

Prognosis and Predictive Factors

The diffuse type of malignant mesothelioma is a highly aggressive tumour, whereas no characteristic features were found to distinguish favourable or less favourable groups. Women have a better outcome but the reason still remains unclear [78]. Well-differentiated papillary mesothelioma is associated with better prognosis. Distinction between histological subtypes is an important predictive value because epithelioid

mesothelioma has a better prognosis than the sarcomatoid or biphasic subtype. Several studies investigated on the value of potential prognostic factors. Male gender, age <53 years, loss of weight, tumour volume, sarcomatoid or biphasic histological subtype, mitotic count and nuclear size were identified as

negative prognostic factors, but further studies are needed to evaluate these features 

5Pathohistological Diagnosis and Differential Diagnosis 

Differential Diagnosis

Several neoplastic and non-neoplastic processes1 have to be excluded due to the infrequent incidence of malignant peritoneal mesothelioma and certain histomorphological similarities to other benign lesions and malignancies whereas malignant peritoneal mesotheliomas remains still a differential diagnosis.

Non-neoplastic lesions include inflammatory processes like reactive mesothelial proliferations related to peritonitis, tuberculosis, sarcoidosis or foreign body reaction and adhesions that develop after surgical intervention. In women, endometriosis and endosalpingiosis or decidual knots formed during pregnancy

caused by decidual transformation of the serosal membrane can impress as tumourous process. Neoplastic lesions have to be distinguished from peritoneal metastases, primary peritoneal   carcinoma, lymphoma, sarcoma and benign lesions/tumours like benign multicystic mesothelioma, adenomatoid tumour, leiomyomatosis peritonealis disseminata and gliomatosis peritonei 

Benign Lesions

Benign Multicystic Peritoneal Mesothelioma Benign multicystic peritoneal mesothelioma arises in pelvic serosa and forms a mulitcystic tumour mass occurring predominantly in young and middle-aged women. In less than 20%, benign multicystic peritoneal mesothelioma can be found in males . In contrast to malignant peritoneal mesothelioma, asbestos exposure is not found. The tumour comprises a multicystic tumour mass that is either solitary or in most cases diffuse or multilocated. The tumour cysts are translucent, filled with serous fluid and confluent and delimited by a fibrous band. The cysts measures less than 1 cm up to 20 cm in diameter. The multicystic mesothelioma has a benign or indolent course and is inclined to recur in one-half of the cases between 1 and 27 years. In rare cases, multiple recurrence and malignant transformation to malignant mesotheliomas have been observed 

Adenomatoid Tumour

Adenomatoid tumour – also designated as benign mesothelioma – is a very rare benign mesothelial tumour that forms gland-like tumour nests with adenoid, angiomatous or cystic structures with smooth muscle proliferations embedded in a fibromatous stroma. It occurs most frequently in the tunica vaginalis testis. Macroscopically, the Malignant Lesions

Peritoneal Metastases

Peitoneal metastases are secondary tumours of the peritoneum and the most common tumours of the peritoneum. Ovarian carcinoma, colorectal cancer and gastric cancer just as carcinomas of the pancreas, gallbladder, uterus and lung are the most frequent tumours that show peritoneal involvement. Peritoneal metastases represent advanced tumour stage and are associated with a poor prognosis. In patients with  olorectal carcinoma, peritoneal metastases occur in 10–15%. Primary ovarian carcinomas show peritoneal metastases in 65–70%, pancreatic carcinomas in 35% and gastric cancer in 25–30%. Peritoneal metastases

caused by separation of individual tumor cells from the primary tumour. The invasion of these dissociated tumour cells depends on the location of the primary tumour. Invasion in blood and lymphatic vessel is characteristic for carcinomas of the gastrointestinal tract. Tumours that are adherent to the peritoneum, like ovarian carcinomas, show direct peritoneal involvement. Frequently, peritoneal metastases show

similar histological pattern like their primary tumour; most of peritoneal metastases are adenocarcinomas. Tumour heterogeneity, like differences of tumour grading, causes diagnostic problems. Peritoneal metastases of a primary low-grade adenocarcinoma can show a highgrade pattern, for example. Loss of original

histological pattern can occur in tumours after chemotherapy. In such cases, clinical informations about pretreatment or knowledge of primary tumour site is helpful to confirm the correct diagnosis. Particularly, in case of mixed carcinomas like adenocarcinoma with partial endocrine type or adenosquamous carcinoma,

peritoneal metastases can consist of only one of the histological pattern. A correct diagnosis on the basis of conventional histology is difficultin most cases and additional immunohistochemistry is required.

Carcinoma of Unknown Primary (CUP)

Carcinoma of unknown primary (CUP) is seen in 3–5% of all tumour diseases. In 5–10% the peritoneum is involved (Muir 1995). On the other hand, 2–4% of primary peritoneal tumours represent the origin of CUP . Histologically, most peritoneal metastases are adenocarcinomas in 40–60%, undifferentiated carcinomas in 15–30%, squamous carcinomas in 15–20% and in 3–5% small cell carcinomas or endocrine

tumours are observed. Therefore, immunohistochemistry is necessary to classify tumour infiltration but in some cases the assignment to the localisation of the primary tumour site is not possible

Primary Peritoneal Carcinoma

Primary peritoneal carcinoma (PPC) is an extraovarian neoplasia that resembles surface epithelial tumours of ovarian origin. It occurs xclusively in middle-aged women between 53 and 62 years. Fifteen percent of ‘typical ovarian cancers’ are primary peritoneal carcinomas. It consists of confluent tumour masses

transforming omentum and mesenteriums to tumour bulks and involving the surface of the liver, anterior abdominal wall and the peritoneal side of the diaphragm. The most common histological subtype is serous adenocarcinoma whereas, like in surface carcinoma of the ovary, transitional cell, clear cell, mucinous or squamous cell carcinomas have been reported. Histologically and immunohistologically, PPC is undistinguishable from ovarian carcinoma. To separate these two tumour entities, certain criteria have

been developed

Primary Peritoneal Borderline Tumour

Primary peritoneal borderline tumour is a rare neoplasia of the peritoneum that only arises in women mostly between 16 and 67years of age. Median age is 32 years. Characteristically, this tumour shows morphological similarities to serous borderline tumour of the ovary but arises from the peritoneum without or with minimal involvement of the ovarian surface . Macroscopically, the tumour nodules appear

like non-invasive implants of ovarian borderline tumour with smaller knots or adhesions. Only in rare cases, tumour mass is found. Like ovarian borderline tumour, most tumours are of serous types with psammoma bodies

Immunohistochemistry

Malignant peritoneal mesothelioma shows the same immunohistochemical staining pattern like the pleural counterpart expressing calretinin, WT1 (Wilm’s tumour antigen 1), EMA, Cytokeratin 5/6, D2-40. Characteristically, they are negative for CEA, TTF-1, BerEp-4 (HEA), B72.3, MOC- 31, BG8 and Claudin-4 . A marker panel including antibodies that are frequently positive in mesotheliomas should be used. EMA and desmin help to distinguish benign mesothelial lesions from MPM in most cases.

Up to 80% of malignant mesotheliomas show positive immunostaining of EMA and up to 85% of benign mesothelial lesions express desmin. But both, EMA and desmin, have a low sensitivity and specificity of 70–75% differentiating benign from malignant mesothelial lesions, because weak membrane positivity of

EMA can be found in reactive mesothelial proliferation. On the other hand, some cases of malignant mesothelioma are EMA negative. To separate mesotheliomas from sarcomas, lymphomas or melanomas, the use of cytokeratin is helpful. 

Primary Peritoneal Carcinoma/Metastases

of Serous Ovarian Cancer Versus Malignant

Peritoneal Mesothelioma

Epithelioid type of malignant peritoneal mesothelioma shows close overlapping histomorphological similarities to primary peritoneal carcinoma/metastases of serous ovarian cancer; therefore, distinction of these tumour entities is very important for further therapy, because MPM is a radio- and chemotherapy-resistant malignancy with poor prognosis. Several studies evaluated expression of immunohistochemical markers

to differentiate malignant mesotheliomas from primary peritoneal carcinoma/metastases of serous ovarian carcinoma. A high sensitivity of h-Caldesmon, Calretinin and D2-40 as well as a high specificity of calretinin and D2-40 (95%) has been reported in mesotheliomas. In primary peritoneal carcinomas/metastases of serous ovarian carcinoma, estrogen receptor and BerEp4 show a high sensitivity, and non-mesothelioma markers (like estrogen receptor, progesterone receptor, B72.3, CA19-9, CD15 and to a lesser extent

BerEp-4) are characterised by a high specificity . In case of D2-40, some studies reported a limited use because D2-40 is expressed in 13–65% of primary peritoneal carcinomas/metastases of serous ovarian carcinoma. Estrogen receptor, BerEp-4, MOC-31 and BG8 are expressed in primary peritoneal carcinomas/metastases of serous ovarian carcinoma to a high extent but are negative or infrequently detectable in malignant mesotheliomas . In general, to differentiate malignant peritoneal

mesothelioma from primary peritoneal carcinomas/ metastases of serous ovarian carcinoma, a panel including antibodies that are frequently positive in mesotheliomas (like Calretinin and WT-1) on the one hand and non-mesothelial markers (like estrogene receptor, BerEP-4, MOC-1 and BG8) on the other hand should be used

BIOPSY TECHNIQUES FOR THE DIAGNOSIS OF MESOTHELIOMA

Introduction

The incidence of mesothelioma continues to increase; it has a poor prognosis and definitive diagnosis is often difficult to obtain . In Europe, 5,000 people die annually from mesothelioma and in Britain the incidence is rojected to peak in 2011–2015 at 1,950–2,450 deaths per year. The prognosis is poor with a study in the USA showing a 1-year survival of 64% from onset of symptoms and median survival of 10 months. A British study  found a median survival of 14 months from the onset of symptoms.

Clinical Presentation

The most common clinical presentation forpatients is progressive dyspnoea and/or chest wall pain. Dyspnoea at presentation is usually caused by a pleural effusion but as the disease progresses this can be caused by pleural restriction. At presentation 90% patients have a pleural effusion with 10% patients having little or no fluid [30]. The effusion is usually unilateral (95%). The chest wall pain is usually caused by significant chest wall invasion. Other symptoms include a dry cough, weight loss, fever, fatigue or night sweats. The patient may also present after abnormalities are found on a routine chest radiograph [2] or present with minimal non-specific symptoms with the diagnosis only becoming apparent with time.

A detailed occupational history is important, although sometimes difficult because of the time that has elapsed since the exposure. Common prior occupational exposures include laggers, pipefitters, plumbers, heavy construction or shipbuilding industry workers and those working aboard ships, especially in the boiler room. 4.3 Investigation of Pleural Effusion Mesothelioma may be suspected on presentation because of the history, including exposure and symptoms, and abnormalities on the chest radiograph. If a pleural effusion is present then the initial investigations should be a diagnostic/therapeutic pleural aspiration and contrast-enhanced computed tomography (CT). The contrast allows differentiation between thickened pleura,

pleural effusion and underlying collapsed or aerated lung, allowing a detailed look at the pleura including whether the pleural thickening is irregular, circumferential and involves the mediastinal border. It also aids decisions regarding the next, most appropriate, investigation. Pleural aspiration is a simple investigation that can be performed, under ultrasound guidance, in clinic at the initial review and should be sent for cytology with immunocytochemistry if appropriate

 Cytology 

The diagnostic sensitivity of pleural cytology with malignancy has been reported at about 60%; however, the reported sensitivity for mesothelioma has been reported as much lower than this at 20–32% . This number included those that were suspicious but not diagnostic for mesothelioma. If only the positive results were included and the suspicious results excluded, the sensitivity decreased to 16%. However, it is worth noting that if cytology is positive then the median time to diagnosis is reduced. In one study, this time was reduced from an average of 12 to 4 weeks. It often proves difficult to differentiate between reactive mesothelial cells secondary to an inflammatory response and malignant cells; therefore, pleural tissue is often required to confirm the diagnosis. Immunocytochemistry can help to differentiate between mesothelioma and adenocarcinoma. Sending a second sample if the first was negative has been shown to increase the yield for malignancy by a further 27%; however, in the case of mesothelioma it is unlikely to be this successful and likely to delay diagnosis further. Repeated thoracocenthesis has also been shown to increase the number of pleural loculations which could have an impact on later investigations such as thoracoscopy. 

The European Respiratory Society (ERS) and European Society of Thoracic Surgeons (ESTS) guidelines on the management of mesothelioma state that it is not recommended to make a diagnosis of mesothelioma based on cytology alone because of the high risk of diagnostic error. 

Investigation of Pleural Thickening with No Effusion 

Benign causes of pleural thickening commonly include previous pleural infection or haemothorax and benign asbestos-related pleural thickening. When seen at the lung apices it is generally due to prior infection from tuberculosis or fungi. It is uncommon for asbestos to cause apical pleural thickening. CT changes suggesting malignancy as opposed to benign pleural thickening are (1)circumferential thickening, (2) nodular pleuralthickening, (3) parietal pleural thickening >1 cm and (4) mediastinal pleural involvement. Whilst these changes were specific (100%, 94%, 94% and 88%, respectively), they were not overly sensitive (41%, 51%, 36% and 56%, respectively), and did not allow differentiation of mesothelioma from other cancers. If there is evidence suggesting malignancy, these patients will require a pleural biopsy. The thoracic CT scan is helpful in deciding which method would be most suitable 

Percutaneous Pleural Biopsy Techniques

Abrams Needle

The use of a blind closed needle biopsy (BCNB) was first described by Abrams in 1958 . It provided an alternative to an open pleural biopsy, which requires a general anaesthetic . Compared to other pleural biopsy techniques it  is inexpensive and can be carried out under local anaesthetic. Chakrabarti et al. found no difference in the diagnostic sensitivity between respiratory registrars and their more junior counterparts . Although low yields were reported when diagnosing mesothelioma, it was hoped that this might be improved with the advent of improved histopathological tests. Radiologically Guided Percutaneous Pleural Biopsy Pleural thickening, whether benign or malignant, is frequently not uniform, and imageguided

biopsy facilitates selection of the most appropriate biopsy site. It also enables safe biopsies in the absence of a pleural effusion. Percutaneous pleural biopsy has been described with both transthoracic ultrasound (US) and CT as image guidance modalities. CT-guided biopsy permits access to areas not easily accessible to ultrasound such as pleural lesions near or behind ribs or along the paravertebral surfaces [50]. Higher sensitivities have been reported with C than with US-guided biopsies although there have been no trials

directly comparing them [49]. Metintas et al. looked at 30 patients with mesothelioma who underwent CT-guided closed needle biopsy. This was diagnostic in 25 (83.3%) . Adams et al. reviewed 21 cases of mesothelioma that had received an image-guided biopsy in their work up (6 US and 15 CT). Their diagnostic sensitivity was 86%. It is also worth noting that of these, four patients had a pleural thickness of

less than 5 mm and all of these biopsies were successful. Cutting needle biopsy has been shown to be more sensitive than fine needle aspiration in the diagnosis of malignancy and the difference is even more marked with mesothelioma  with a sensitivity of 93 versus 50% in favour of using a cutting needle. The overall sensitivity can be increased with a combination of both techniques. Complications occur in less than 5% patients using image-guided pleural biopsy techniques  and include pneumothorax, intrapleural bleeding, subcutaneous haematoma and damage to the diaphragm and abdominal viscera. 

Positron Emission Tomography (PET) CT 

PET scans are increasingly being used in the evaluation of patients with mesothelioma [58]. F-fluoro-2-deoxy-d-glucose (FDG)–PET has been shown to accurately differentiate benign pleural disease from mesothelioma. In one study of 98 patients with 63 pleural malignancies, FDG-PET had a sensitivity for detecting malignancy of 96.8% and a specificity of 88.5% and appeared to confirm malignant pleural disease that cannot be identified at CT . Neither of the two malignancies that did not show FDG were mesothelioma. Another study of nine patients with mesothelioma  showed that all the primary tumours were FDG positive. Although no trials have looked at PET-CT being used to increase the diagnostic yield of CT-guided biopsies, there may be a role for this in the future, particularly in those patients who clinically appear to have mesothelioma but have already had negative biopsies and are not suitable for thoracoscopic/surgical biopsies. 

Thoracoscopy

Thoracoscopy was first described in 1910 . It provides a means of diagnosis for effusions of unknown cause and is particularly important in the diagnosis and management of malignant pleural mesothelioma . It is now recommended by the European Respiratory Society and the European Society of Thoracic Surgeons

 and the British Thoracic Society  early in the diagnostic pathway of patients with a symptomatic exudative pleural effusion of unknown cause. Thoracoscopy can be performed by surgeons under general anaesthetic – Video-Assisted Thoracoscopic Surgery (VATS) but increasingly is being performed by physicians under local anaesthetic – Local Anaesthetic Thoracoscopy (LAT). In the UK the number of

centres offering LAT has increased from 11 in 1999 to 37 in 2009 . Thoracoscopy allows direct visual assessment of the pleura and subsequent biopsy of the abnormal areas as well the option of a therapeutic

talc poudrage at the same time. Success rates for pleurodesis via thoracoscopy are generally very good and can be as high as 86%  at 1 month. 

Local Anaesthetic Thoracoscopy

This allows direct visualisation of the pleura and the option of a therapeutic procedure without the need for a general anaesthetic. This is an important advantage over VATS as many patients requiring thoracoscopy have comorbidities  and a reduced performance status leading to significant risk from a general anaesthetic.

It should, however, be noted that across Europe many physicians carrying out thoracoscopy choose to perform this in the presence of an anaesthetist (and often a GA). Boutin et al. reviewed 188 cases of mesothelioma that had undergone thoracoscopy . 185/188 (98.4%) were diagnosed after thoracoscopy with a 100% specificity. These results have been mirrored in a number of recent studies with the sensitivity for the diagnosis of mesothelioma ranging from 88% to 100% with a specificity of 100% . The thoracoscope can be flexible, semirigid or rigid. One study comparing the use of rigid with flexible thoracoscope  looked at 30 consecutive patients with pleural effusion of unknown cause. The first 10 underwent rigid thoracoscopy whilst the following 20 underwent thoracoscopy with both rigid and flexible thoracoscope. Of those with a final diagnosis of mesothelioma 13/15 (87%) were diagnosed at thoracoscopy. Three biopsies were more informative with the flexible thoracoscope whilst

eight were more informative with the rigid thoracoscope. Two biopsies from the flexible thoracoscope were upgraded from reactive pleurisy to mesothelioma by the rigid thoracoscope biopsies. Overall, it was felt that the rigid instrument  as superior because it was easier to manipulate and obtain larger biopsies. Munavvar et al. trialled the use of a semirigid thoracoscope, hoping to combine the advantages of the flexible

and rigid instruments. They correctly diagnosed 15/15 patients with mesothelioma and did not appear to experience the difficulties previously described with the flexible thoracoscope.  

Video-Assisted Thoracoscopic Surgery

VATS usually requires general anaesthesia and the placement of a dual lumen tube. VATS is therefore more expensive and time consuming than LAT . There have been no trials directly comparing it to LAT; however, the diagnosticefficacy of the two methods appears comparable. Harris et al. performed VATS on 182 patients. Of the 98 patients with malignancy 29 sensitivity for malignancy was 95% with a specificity

of 100% though they did not state what malignancies the 5 false negatives were. Grossebner et al. reported on 25 patients referred with suspected mesothelioma . Of these 23 had mesothelioma and all were diagnosed from VATS biopsy. Comparing complications and length of stay in hospital is difficult because more extensive procedures are often carried out in the VATS groups and there are no recent trials looking

purely at diagnosis with or without pleurodesis. Studies looking at complications from VATS often include patients with conditions such as empyema that require the extensive breaking down of adhesions, which is more difficult with LAT. However, complications do seem higher with VATS; de Groot et al. reported that nine (26%) of their patients had a major complication  whilst Harris et al. reported one death (due

to pulmonary laceration), major complications in 15% (haemorrhage, prolonged air leak, empyema, pneumonia, wound infection, congestive cardiac failure, entering peritoneum, biopsy pneumothorax, myocardial infarction, post operative seizure) and minor complications in 8% (subcutaneous emphysema, fever, hypotension, intercostal neuritis). However, Viskum et al. reported no deaths in their series of 566 examinations with air embolism and cardiac dysrhythmias occurring in less than 1%.

Open Biopsy

 Prior to thoracoscopy, this was the next stage in the diagnostic pathway if closed needle biopsy failed. It is now required only if there is obliteration of the pleural space and CT-guided biopsy is not possible or has failed to reach a diagnosis. Its main complication is intractable chest wall pain. Of all the pleural  Biopsy techniques, this technique has the highest rate of tract seeding 

Prophylactic Radiotherapy

Mesothelioma seeding along pleural intervention tracts is well recognised and present as subcutaneous nodules of varying size. O’Rourke et al. recorded the characteristics of 12 patients that had subcutaneous nodules. 75% reported mild pain, 17% slight pain and 8.3% moderate pain with ulceration in 1 patient. A review of the literature on tract seeding of mesothelioma [34] found that this ranged from 0% to 48% with the risks highest after thoracotomy (24%) and thoracoscopy (9–16%) and lower for smaller incisions such as needle biopsy (0–22%). A recent study of 212 patients who did not receive prophylactic radiotherapy

showed that there was an overall rate of tract seeding of 13.2% . Seeding was more common after thoracotomy (25.8%) versus thoracoscopy and closed needle biopsy or CT-guided biopsy (11.0%). 157 patients received chemotherapy and 26 received multi-modal therapy which may explain why the recurrence rate was lower than the 40% reported by Boutin et al.  in the control arm of their trial of prophylactic

radiotherapy. Boutin showed no tumour seedling in the intervention arm (21 Gy in three fractions) and this trial result led to national guidelines promoting the practise of giving prophylactic radiotherapy after pleural interventions in patients with mesothelioma . Recent trials, however, have failed to support its

use. Bydder et al. randomised 43 patients (58 sites) to receive a single dose of radiotherapy (10 Gy) or no radiotherapy [12] whilst O’Rourke et al. recruited 61 patients (60 sites) to have three fractions of 7 Gy or no radiotherapy. Both studies showed no difference in tumour seeding between their control and treatment groups (10% control vs 7% radiotherapy and 10% control vs 13% radiotherapy, respectively).

Important differences between the trials were that all of the patients in Boutin’s original trial underwent a thoracoscopy (with a large chest wall incision) whilst only 23–39% in the two more recent trials did. There was also a difference in the radiotherapy regime in Bydder trial. All of these trials are underpowered and there is therefore still the