Biopsies are currently the only way to definitively diagnose mesothelioma.
Because of their invasiveness, biopsies are often performed after other diagnostic tests.
A biopsy sample is taken to determine the tumor type, malignancy, and stage.
Biopsies can be quite invasive depending on the tumor's size and location.
After a biopsy, the sample will be further analyzed to determine cell types and stage.
Clinical history, exposure to asbestos, and imaging tests can all suggest a diagnosis of mesothelioma; however, definitive diagnosis of mesothelioma requires a biopsy. A biopsy is a procedure in which cells are removed from the body for further investigation and testing.
The biopsy sample is used to:
- Diagnose mesothelioma definitively
- Determine if the mesothelioma is malignant or benign
- Identify the type of mesothelioma
- Categorize the mesothelioma in one of four stages
- Estimate prognosis
In someone with suspected mesothelioma, a biopsy sample can be taken using a surgical approach or non-surgically. Each biopsy procedure has its own pros and cons. Regardless of the biopsy procedure, it is critical that the procedure yield a sufficient amount of material for analysis.
Surgical biopsies are considered the most invasive means of sampling tissue for a mesothelioma diagnosis. Some surgical biopsies are more invasive than others.
- Minimally invasive biopsies, including thoracoscopy, mediastinoscopy, and laparoscopy.
- Open surgical biopsies, including thoracotomy and laparotomy
Minimally invasive biopsies are camera-assisted techniques performed through small “keyhole” incisions. The goal of all surgical biopsies is to obtain a tissue biopsy, which can be submitted for histological analysis.
Camera-assisted Surgical Biopsies (Minimally Invasive)
A thoracoscopy is a procedure in which a small endoscope (also known as a thoracoscope) is passed through an incision in the chest wall to view the contents of the chest cavity. The endoscope is a long tube with a small video camera lens mounted on one end. The surgeon uses the thoracoscope to view the target area and retrieve a tissue samples.
Thoracoscopy can be performed either medically or surgically. Medical thoracoscopy, or pleuroscopy, is usually performed by a pulmonologist (lung specialist) rather than a surgeon. It can be performed under general anesthesia or with local anesthesia and intravenous sedation. Medical thoracoscopy is suited to guide and is diseases of the pleura and the lungs and pleurodesis, if needed.
Surgical thoracoscopy or VATS is usually performed by a thoracic surgeon while the patient is under general anesthesia in an operating theater. Like pleuroscopy, VATS is suitable for extracting a tissue sample for biopsy; however, the thoracic surgeon may also perform a lobectomy or pneumonectomy using the VATS approach. The surgeon can also evaluate the mediastinum (the space between the lungs) and look for abnormal lymph nodes or additional tumors.
Because of its minimally invasive nature and high rate of success in obtaining suitable biopsy samples, thoracoscopy is generally favored over thoracotomy (described below), when feasible.
Laparoscopy is a minimally invasive, camera-assisted procedure used to view the contents of the abdominal cavity. The standard laparoscopic approach is to create one or more ports in the abdominal wall through which instruments can be passed. Laparoscopy is virtually always performed under general anesthesia.
For mesothelioma diagnosis, various laparoscopic instruments are used to retrieve biopsy samples. These instruments may include a small camera (laparoscope or endoscope), grasping steps, and a tissue bag into which tissue samples may be placed. One of the ports may be used to inflate the abdomen with an inert gas, such as nitrogen or carbon dioxide, to improve the surgeon’s field of view. Most of these gases are released at the end of the procedure, and what is not released is absorbed harmlessly by the body.
When possible, it is preferable to use laparoscopic rather than exploratory laparotomy for peritoneal mesothelioma diagnosis. Laparoscopy causes smaller scars, leads to quicker recovery, and tends to produce fewer intra-abdominal adhesions than laparotomy. Another advantage over laparotomy is that a laparoscopy can be performed on an outpatient basis. The procedure itself usually takes about 60 minutes, and post-anesthesia recovery takes approximately 3 hours.
The mediastinum is an important anatomical structure between the lungs that contains the esophagus, trachea, several important nerves, many lymph nodes, and the heart. Because of its proximity to the lungs, malignant pleural mesothelioma may be present within the mediastinum. Any mesothelioma cancer cells found in the mediastinum can greatly affect treatment decisions and prognosis.
A mediastinoscopy is similar to a thoracoscopy in that a small tube is inserted through a hole in the chest. In a mediastinoscopy, however, the incision is made centrally just below the patient’s neck and above the sternum (breastbone). Once the surgeon accesses the mediastinum, a small camera on the end of the endoscope (mediastinoscope) is used to see the space. The device can also be used to retrieve samples of tissues that appear to be abnormal and submit them for further analysis by a pathologist.
Mediastinoscopy is considered a minimally invasive procedure, though it is performed under general anesthesia in an operating room. The procedure is usually performed on an outpatient basis, which means patients do not need to spend the night in the hospital. Because of the important structures contained within the mediastinum, a mediastinoscopy carry slightly greater risk than other camera-assisted surgical biopsies used to test for mesothelioma. These risks include serious bleeding or injury to the trachea, esophagus, certain large nerves, or the lung. The overall complication rate associated with mediastinoscopy is small, approximately 1%.
Open Surgery Biopsies
A laparotomy is an open surgical procedure in which a relatively large incision is made in the abdominal wall so that the surgeon can access the abdominal cavity. Laparotomy is to the abdomen what thoracotomy is to the chest. While thoracotomy is procedure used to diagnose pleural mesothelioma, a laparotomy is generally used to retrieve a biopsy sample in the case of peritoneal mesothelioma.
During the laparotomy, a long incision is made in the center of the abdomen in line with the navel (i.e., belly button). The incision is held open with retractors so that the surgeons can view the entire contents of the abdominal cavity looking for visible evidence of cancer. Virtually all areas below the diaphragm and above the pelvis are visible through a laparotomy incision. Because of this wide field of view, this procedure is sometimes called an exploratory laparotomy. In other words, the surgeons are exploring the abdominal cavity for signs of cancer and other disease related to peritoneal mesothelioma.
As with thoracotomy, a biopsy obtained via laparotomy may be combined with tumor resection surgery. This decision may be based on the presence of mesothelioma tumor within the peritoneal space (i.e., abdominal cavity) and any rapid testing that can be done on biopsy samples during the laparotomy itself.
During a thoracotomy, the surgeon will make a large incision (from 5” – 10” long) in the chest. In most cases, the thoracotomy incision will be made under the armpit, about halfway down the chest (axillary thoracotomy). Alternatively, the incision may extend towards the patient’s back (posterolateral thoracotomy) or towards the pectoral region (anterolateral thoracotomy).
In each of these three approaches, the incision is curved to match the contour of the ribs, allowing the thoracic surgeon to gain access to the lungs and chest cavity without cutting through an extensive amount of muscle, bone, or cartilage. If these structures can be left intact as much as possible, patients have an easier recovery from an otherwise highly invasive procedure.
Rarely will the surgeon need to make an incision through the breastbone in the center of the chest (median sternotomy) to perform a thoracotomy for mesothelioma diagnosis. This surgical biopsy technique is only done if other biopsy approaches are not possible.
A biopsy sample retrieved using a thoracotomy is only performed when other types of biopsy are not possible. In most cases, thoracoscopy (described below) can be used instead of thoracotomy. When thoracotomy is required, such as when the pleural space has been obliterated from disease, surgeons generally try to make as small as an incision as possible that still provides an adequate biopsy sample. Conversely, if it is possible to perform a diagnostic biopsy at the same time as a tumor resection surgery (e.g., extrapleural pneumonectomy, pleurectomy with decortication), surgeons may perform a thoracotomy with the intent of first retrieving a biopsy sample, sending it for rapid diagnosis, and continuing to remove all visible areas of mesothelioma from the chest cavity.
Non-surgical biopsies (needle biopsies) use a fine- or large-bore needle to remove cells or bits of tissue from the body for pathological analysis. Needle biopsies are even less invasive than minimally invasive, camera-assisted surgical biopsies since, there is usually no need for an incision.
The obvious advantage of a nonsurgical biopsy is that there is no need for general anesthesia, and recovery from the procedure is very fast. Unfortunately, needle biopsies are not always capable of removing a sufficient sample for analysis. Needle biopsy procedures tend to remove collections of loose cells or cell clusters floating in fluid rather than bits of tissue required for histological study.
Because of these limitations, nonsurgical biopsies are associated with a high rate of false negatives. In fact, a negative needle biopsy cannot be used to rule out a diagnosis of mesothelioma. If the patient’s history strongly suggests mesothelioma (e.g., long-term asbestos exposure, smoking history, chest pain, cough, difficulty breathing, and abnormal radiological imaging), a negative nonsurgical biopsy would need to be followed by a more invasive biopsy procedure to make a definitive diagnosis or rule out mesothelioma.
Fine-needle aspiration is the least invasive way of obtaining cells for mesothelioma diagnosis. In this procedure, the healthcare provider uses an imaging device such as a CT scanner, ultrasound, or fluoroscope to guide the placement of a needle through the chest wall into an area of abnormal cells, tissue, or fluid.
This procedure is performed under local anesthesia or, in some cases, no anesthesia. The patient is awake during the process. Fine-needle aspiration usually takes place in the interventional radiology department or similar location within a hospital or clinic.
Because of the needle’s small diameter, only clusters of cells, small bits of tissue, and fluid can usually be removed. Fine-needle aspiration causes patients little to no discomfort; however, the chance of obtaining enough tissue for a diagnosis is moderate to low. Thus, fine-needle aspiration may be a useful first diagnostic procedure for mesothelioma, but patients undergoing this procedure should anticipate the need for additional diagnostic testing. Fine-needle aspiration is more likely to be successful if the physician can obtain fluid from an affected lymph node, but that technically challenging. The chances for obtaining a sufficient tissue sample are also increased by when a core biopsy is taken using a larger, cutting needle rather than a fine needle. A core biopsy sample can extract tissue, rather than cells, which means it can be sent for histology, rather than cytology.
Thoracentesis is a procedure in which a needle is used to extract fluid from the chest cavity. Thoracentesis may be used for diagnostic, therapeutic, or palliative purposes. When used for diagnosing mesothelioma, the fluid is drained from the chest cavity is sent to a pathologist for examination. The main difference between a fine-needle aspiration and a diagnostic thoracentesis is that in thoracentesis, a the needle is larger and more fluid is removed.
Thoracentesis can be done at the patient’s bedside using local anesthesia. The patient is fully awake and, in fact, usually sits upright during the procedure. A portable X-ray or other imaging device is used to identify abnormal fluid collections within the chest cavity. The physician then sterilizes and numbs a region on the patient’s back halfway between the patient’s spine and flank (mid-scapular line). A large-bore needle is then inserted between two of the patient’s ribs through the chest wall and into the pleural space. Fluid is drawn off through gravity or under gentle suction and sent for analysis. A follow-up chest X-ray is necessary to make sure a sufficient amount of fluid was removed and that no complications have occurred, such as pneumothorax (collapsed lung).
As with fine-needle aspiration, the pleural fluid removed during thoracentesis may not contain enough cells to make a definitive diagnosis of mesothelioma. Moreover, it may be difficult from the cells removed during thoracentesis to differentiate mesothelioma from adenocarcinoma or to distinguish between different subtypes of mesothelioma.
Paracentesis is performed in much the same way as a thoracentesis, except that in a paracentesis, a large-bore needle is introduced in the left lower quadrant of the abdomen. An ultrasound or fluoroscope may be used to guide the needle as it is inserted.
In most cases, the procedure can be done at the patient’s bedside. Since the area has been sterilized and numbed with local anesthetic, the patient should not feel pain, only pressure, during the procedure.
The accuracy of a diagnostic paracentesis depends on extracting cancerous cells, if they exist. Importantly, patients may still have mesothelioma even if a diagnostic paracentesis is negative.19 Moreover, paracentesis alone may not be able to provide the pathologist with enough information to determine if the mesothelioma is benign or malignant.20
The pericardium is a fibrous sheath that covers the heart. Under normal circumstances, there is only a thin layer of fluid between this sheath and the heart itself. In certain diseases, such as primary pericardial mesothelioma or pleural mesothelioma, fluid may accumulate in the pericardial space.
In preparation for a pericardiocentesis, patients will undergo echocardiography (ultrasound imaging of the heart) to characterize the anatomy of the heart and the abnormal fluid collection. The echocardiogram may be performed with the probe against the patient’s chest (transthoracic echocardiogram, TTE) or with the probe inserted into the patient’s esophagus (transesophageal echocardiogram, TEE).
Pericardiocentesis is a procedure in which a needle is placed into this space to remove that fluid. An area on the chest, usually just below the sternum or bottom edge of the rib cage, is sterilized and numbed with local anesthetic, prior to placing the pericardiocentesis needle. Traditionally, a fluoroscope or portable X-ray device was used to guide needle placement into the pericardial space.
Echocardiography is currently a popular imaging method for pericardiocentesis and provides excellent results. A transthoracic echocardiogram does not expose the patient or staff to radiation and provides the physician with suitable images of the fluid around the heart. After fluid has been removed and sent for analysis, the needle is removed and replaced with a catheter, which is left in place to continue draining fluid from the pericardial space.
What Happens After a Biopsy?
Biopsy samples are sent to a clinical laboratory for analysis by a pathologist. The sample is subjected to a number of tests to learn more about the nature of the tissue, discover whether cancer cells are present, and provide information about cancer staging. If the patient had a surgical biopsy or other procedure in which a portion of tissue was removed, the sample is sent to histology. On the other hand, if the patient had a nonsurgical biopsy, such as a fine-needle aspiration, the fluid retrieved is sent to cytology.
In most cases, histological analysis of a tissue sample can provide allows the pathologist make a definitive diagnosis and determine the cancer’s histological stage. When a surgical biopsy to obtain a tissue sample is not possible, a nonsurgical biopsy and cytological analysis may be enough to make a mesothelioma diagnosis and estimate the stage, especially if imaging studies show that the cancer has invaded surrounding tissues.
Histology is the scientific study of cells and tissues that make up biological structures. When discussing the diagnosis of mesothelioma, histology refers to the microscopic examination of tissue samples to identify and characterize disease. Pathologists apply special stains and antibodies to the tissue samples to aid in diagnosis.
The three goals of histological analysis in patients with suspected mesothelioma are to
- Make a definitive diagnosis of mesothelioma or rule out mesothelioma.
- If mesothelioma is present, determine what type of cell is involved.
- Determine the histological stage of the mesothelioma.
There is no single histological test that can identify or rule out mesothelioma 100% of the time. Individual tests are about 80% accurate (sensitivity and specificity). However, by subjecting the tissue sample to several of these tests, the diagnosis becomes more certain.
Each clinical laboratory has its own set of histochemical and immunohistochemical tests that it uses to identify mesothelioma. Some tests should be positive, while others should be negative in order to be consistent with mesothelioma. For example, one set of tests used to distinguish between reactions of the mesothelioma and actual mesothelioma includes:
- Desmin (negative)
- EMA (positive)
- p53 (positive)
- GLUT1 (positive)
- IMP3 (positive)
Epithelioid mesothelioma can look like many other cancers under a microscope, especially lung adenocarcinoma. Therefore, many immunohistochemical tests are used to distinguish epithelioid mesothelioma from other cancers. Once a diagnosis of mesothelioma has been made, determining the cell type is relatively straightforward.
While 20 mesothelioma cell types have been identified, only three types of mesothelioma are important for prognosis: epithelioid, sarcomatoid, and biphasic. A fourth type, desmoplastic, may also influence prognosis and may be noted on the pathology report. Desmoplastic mesothelioma is a particularly aggressive form of sarcomatoid mesothelioma and is quite rare.
Separating benign from malignant mesothelioma is one of the most challenging aspects of mesothelioma diagnosis. A mesothelioma is malignant when cancer cells have invaded the stroma, but this is not always easy to identify under a microscope. Pathologists who are unsure of the malignant nature of the mesothelioma consult the help of specialists and follow consensus guidelines.
Cytology is the science of examining cells to characterize and diagnose disease. A pathologist will study samples obtained from nonsurgical biopsies such as fine-needle aspiration and thoracentesis. The cells collected during these biopsy procedures can be stained or treated in various ways to help the pathologist identify and characterize the retrieved cells. Based on the results of these studies, the pathologist can provide an assessment of the biopsy.
While cytology can be very helpful in diagnosing certain cancers, such as cervical cancer, the process has limited usefulness in the diagnosis and staging of mesothelioma. The main limitations of cytology in the diagnosis and characterization of mesothelioma are:
- Nonsurgical biopsy methods may not provide a sample sufficient for diagnostic purposes (especially sarcomatoid mesothelioma, which typically does not shed cells into a pleural effusion)
- Cytology does not allow for formal histological subtyping (e.g., epithelioid versus sarcomatoid mesothelioma)
- Cytology cannot reveal whether mesothelioma invades surrounding tissues
In certain circumstances, oncologists may find cytology is sufficient for both diagnosis and management of mesothelioma. However, such circumstances are more the exception than the rule. The International Mesothelioma Interest Group suggests that cytology results from mesothelioma diagnosis be followed by formal histology, which almost certainly requires an additional biopsy procedure.