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Malignant Mesothelioma of the Pleural Space

Malignant Mesothelioma of the Pleural Space

ABSTRACT: Malignant pleural mesothelioma is an aggressive tumor associated with exposure to asbestos. Although this disease is rare, with an annual incidence in the United States of 2,000 to 3,000 cases, a steady rise in cases has been reported. Malignant pleural mesothelioma has a variable clinical presentation and may be difficult to diagnose. Pathologically, the disease is subdivided into three microscopic subtypes: epithelial, sarcomatous, and mixed histologies. Although there is no widely accepted staging system for mesothelioma, the Butchart, TNM, and Brigham staging systems have been used most commonly. Diffuse malignant pleural mesothelioma is resistant to standard modes of therapy and, if untreated, results in death 4 to 12 months from the time of diagnosis. For selected patients, an aggressive approach combining radical surgery with chemotherapy and radiotherapy has demonstrated a long-term survival advantage. New and innovative therapeutic modalities are presently being investigated in an attempt to provide viable alternatives for patients with early and advanced disease. [ONCOLOGY 13(7):919-926, 1999]

Introduction

Diffuse malignant pleural mesothelioma is an
uncommon tumor characterized by local aggressiveness and historically
poor patient prognosis. The relationship between asbestos and
mesothelioma is a classic epidemiologic model of exposure leading to
disease. At present, the evaluation of a patient with suspected
mesothelioma can be challenging due to difficulties in securing a
pathologic diagnosis and determining the appropriate management.
Limited knowledge of the biology of this tumor and its poor response
to conventional therapy has resulted in a variety of therapeutic approaches.

Clinical Presentation and Diagnostic Work-Up

The latency period between exposure to asbestos and the appearance of
mesothelioma can be more than 15 years (median, 32 years).[1] The
majority of patients seen are over 55 years of age at
presentation.[2] The disease is more common in men (male-female
ratio, 3:1).[3] Mesothelioma can occur in children but is thought to
be unassociated with asbestos exposure.[4]

The initial clinical presentation of mesothelioma may be variable.
Most series report a 2- to 3-month median time from the appearance of
symptoms to diagnosis.[5]

Patients may present with nonspecific complaints, such as night
sweats, weight loss, malaise, cough, and fever. Alternatively, 60% to
90% of patients may have specific complaints of dyspnea or chest pain.

Typically, dyspnea is first caused by a pleural effusion.[6] As the
disease progresses, the effusion becomes loculated and the pleural
space is replaced by tumor. In patients with progressive disease,
dyspnea is caused by constriction over the underlying lung parenchyma.

Usually, the chest pain is initially reported as poorly localized or
dull; however, as the disease progresses, the pain becomes localized
due to entrapment of the intercostal nerves. Historically, the right
chest has been more commonly affected than the left (60% vs 40% of cases).[7]

In advanced stages, chest and abdominal wall deformity, ascites, and
cachexia are commonly observed due to uncontrollable tumor growth.[5]
Metastases are infrequent; however, they have been observed in cases
of advanced disease or in long-term survivors of multimodality therapy.

The physical findings of mesothelioma vary according to the stage of
the disease. Decreased breath sounds on the ipsilateral side
secondary to pleural effusion may be the only early finding. Once the
disease is advanced, a chest or abdominal mass may be palpable. The
presence of an abdominal mass is an ominous sign indicating
transdiaphragmatic involvement and an unresectable tumor. Symptoms of
bowel obstruction indicate very advanced disease.

Although laboratory evaluation of the mesothelioma patient is
typically unremarkable, nonspecific findings, such as anemia of
chronic disease, eosinophilia, and hypergammaglobulinemia, may be
present.[7] Occasionally, thrombocytosis (> 400 × 109/L)
may be observed; it is thought to signal a worse prognosis.[8]

Radiologic Evaluation

The radiographic presentation of mesothelioma can be extremely
variable, depending on the stage of the disease. Chest x-rays, as
well as computed tomography (CT) and magnetic resonance imaging (MRI)
of the chest, play a major role in the evaluation of this disease.
Chest x-rays are helpful in showing pleural plaques, pleural
thickening, pleural effusion, and parenchymal fibrosis—all of
which are commonly present in mesothelioma patients. Scans of the
chest improve visualization of these abnormalities and permit a
better evaluation of tumor infiltration into fissures and mediastinal
structures, as well as mediastinal adenopathy.

Chest wall involvement, as evidenced by distortion of the intercostal
spaces and infiltration of extrapleural soft tissue or encasement of
the hemidiaphragm (suggesting diaphragmatic involvement), may be more
difficult to determine with CT. MRI may be more useful in detecting
these abnormalities because of its ability to define the disease
extent by signal alteration in T1- and T2-weighted images.[9]

The use of both CT and MRI has been demonstrated to be effective in
determining resectability.[10] The radiologic signs of
unresectability include the following: mediastinal organ invasion and full-thickness
transdiaphragmatic involvement.

Recently, fluorodeoxyglucose positron emission tomography (PET) has
been shown to be a sensitive method for diagnosing and determining
the invasiveness of diffuse malignant pleural mesothelioma.[11] In
addition to the aforementioned imaging modalities, two-dimensional
echocardiography is utilized in the preoperative imaging work-up to
rule out pericardial involvement and assess cardiac function.

Thoracocentesis, Pleuroscopy, and Thoracoscopy

Thoracocentesis is a valuable tool in the initial evaluation of a
patient who presents with a pleural effusion. The fluid sample
retrieved can be evaluated for macroscopic characteristics, as well
as cytology and the chemistry profile. In mesothelioma, the fluid is
typically clear yellow and rarely yields a diagnosis (30% to 35%) due
to the difficulty in distinguishing between tumor cells and reactive
mesothelial cells.[12] Recently, however, with the development of
histochemical and immunohisto-chemical staining techniques, as well
as electron microscopic analysis, diagnostic accuracy has improved.[13]

Closed pleural needle biopsy has also been used to rule out diffuse
malignant pleural mesothelioma. The results of this technique should
be interpreted with caution due to its high false-negative rate;
however, with the availability of more accurate histopathologic
tests, diagnostic accuracy is improving.[14]

With the evolution of minimally invasive technology, the evaluation
of patients via pleuroscopy or thoracoscopy has been
encouraged.[15,16] These techniques allow for better visualization of
the tumor, which, in turn, improves the adequacy of tissue sample
biopsies. In cases that are not amenable to pleuroscopy, open biopsy
is also encouraged. It is important to place biopsy sites or
incisions strategically so that they can be resected should the
patient be a candidate for surgical therapy.

Mesothelioma is well known to be locally aggressive and recur at
these sites.[17] If the patient is not a candidate for surgery,
pleuroscopy with biopsy is still the procedure of choice at Brigham
and Women’s Hospital to confirm the diagnosis of mesothelioma.

Pathology

Microscopically, the cells of origin are pluripotential cells that
can differentiate into mesenchymal or epithelial cells. Three
different histologic types have been described: epithelial,
sarcomatous, and mixed. The histologic classification also has
prognostic significance. The sarcomatous and mixed types have been
shown to correlate with a poorer patient prognosis than the
epithelial type.[18]

The definitive diagnosis of diffuse malignant pleural mesothelioma
may be elusive. It is particularly difficult to distinguish diffuse
malignant pleural mesothelioma from adenocarcinoma. Table
1
[19,20] displays useful parameters to differentiate between
those two pathologies.

In terms of gross pathology, the pleural surfaces of patients with
mesothelioma are seeded by malignant cells. These cells grow into
small nodularities that coalesce to create tumor masses. Over time,
the pleural space is replaced by tumor, creating mechanical
constriction of the normal lung parenchyma and pericardium. The
uncontrollable tumor growth may invade the mediastinum, chest wall,
or subdiaphragmatic structures. The patient usually succumbs to
conditions secondary to local tumor invasion, as opposed to
metastatic disease.

Staging Systems

Currently, no widely accepted staging system for diffuse malignant
pleural mesothelioma exists. The first staging system, proposed by
Butchart et al in 1976 and based on 29 patients,[21] is widely used.
This system has two main weaknesses: (1) nodes are classified as
extrathoracic or intrathoracic based on their location, rather than
on tumor burden; and (2) there is no correlation between stage and survival.

In 1990, the International Union Against Cancer developed a
system[22] based on tumor, nodal status, and metastases. This TNM
system also had limitations and was revised in 1995 by the
International Mesothelioma Interest Group (Table
2
).[23] It has to be validated in a prospective, multicenter,
randomized trial.

Sugarbaker and colleagues proposed the Brigham Staging System based
on tumor, resectability, and nodal status[24]; this system was
revised in 1998 (Table 3)[25] based
on survival data from 183 patients (Figure
1
).[25] For stage I disease, median patient survival was 25
months, as compared with median survival times of 20 and 16 months
for patients with stage II and III disease, respectively.

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