Mesothelioma Pathology: What You Need To Know

This pathology outline for mesothelioma is focused on providing you with detailed information about the disease.

Mesothelioma, also known as asbestos cancer, is a rare, aggressive, and deadly form of cancer that develops in the thin layer of the membrane covering internal organs such as the lungs, abdomen, heart, and Tunica vaginalis (testicles).

Mesothelioma of the pleura (pleural mesothelioma) is the most common.

Epidemiology

Since the mid 20th century, mesothelioma incidence has been steadily rising. A WHO recorded mortality database between the years 1994 and 2008 gave an age-adjusted mortality rate of approximately 4.9 per million, male to female ratio of 3.6:1, and a mean age at death of 70 years.

The annual incidence of mesothelioma recorded in the United States is estimated to be approximately 3300 cases per year, although the number is steadily subsiding due to the control of asbestos exposure. Male diagnoses in Australia dominate, and more than 75 percent of the newly diagnosed patients are aged 65 years or older.

Etiology

Asbestos exposure is the primary culprit as it has an etiological fraction that is higher than 80%. Prolonged asbestos exposure has a prolonged latency period. Peritoneal mesothelioma has a significantly shorter latency compared to pleural mesothelioma. Longer latency periods are evident in more recent diagnoses.

The role of the crocidolite (amphibole form of asbestos) is well established. It accounts for approximately 95% of total asbestos used in various applications and is a more potent carcinogen compared to chrysotile of the serpentine form.

Radiation exposure during treatment, Erionite (a highly carcinogenic mineral fiber used in gravel roads), and the SV40 virus (its overall human incidence mesothelioma incidence remains unclear) are also associated with increased risk of mesothelioma.

Smoking is not a risk factor of mesothelioma.

Clinical Features

The distinct types of mesothelioma exhibit different symptoms;

Pleural Mesothelioma Clinical Features:
  • Pleural effusion(build up of fluids in lungs/chest cavity)
  • Shortness of breath(dyspnea)
  • Difficulty breathing
  • Persistent cough
  • Chest pain
  • Unexplained weight loss
  • Fever
Peritoneal Mesothelioma Clinical Features:
  • Peritoneal effusion- build up of fluid in the abdomen
  • Abdominal pain
  • Abdominal swelling
  • Nausea or vomiting
  • A feeling of fullness
  • Diarrhea or constipation
  • Fever or night sweats
  • Unintended/unexplained weight loss
Pericardial Mesothelioma Clinical Features:
  • Arrhythmia (irregular heartbeat or heart palpitations)
  • Difficulty breathing or shortness of breath
  • Heart murmurs
  • Chest pain
  • Fever
  • Cough

Diagnosis

Various tests and procedures are carried out on patients who have experienced mesothelioma symptoms to determine the cause. They include;

Blood Tests such as SOMAmer and MESOMARK.

Imaging Tests such as X-Rays, PET, scans, CT scans, and MRIs.

Biopsies that investigate the presence of cancerous cells in sample tissue.

If diagnosis is made early, a wide range of treatment options are used to extend the life expectancy of the patients.

Laboratory

Laboratory results showing abnormally high levels of SMRP (soluble mesothelin-related peptide) may indicate the presence of mesothelioma.

Radiology Description

Radiographic features such as pleural/peritoneal effusion, pleural wall/omental thickening, tumoral calcification, omental masses, direct invasion of abdominal viscera, including others are strongly suggestive of mesothelioma malignancy.

Prognostic Factors

The epithelioid histology has a better prognosis compared to sarcomatoid and biphasic histologies.

Treatment Options

Various treatment options are available for the different types of mesotheliomas in their consequent stages.

For Stage I-III of pleural, peritoneal, pericardial, and testicular mesothelioma, effective treatment options include chemotherapy, radiation therapy, and surgery. Surgery treatment options include pleurectomy, Extrapleural Pneumonectomy, and Cytoreduction with HIPEC.

Chemotherapy and radiation therapy treatments are used to improve the life quality of the patients and improve their survival rate.

Gross Description

In pleural Mesothelioma, the chest cavity is filled with dense white encircling mass. Parietal pleura is usually more extensively involved. In some cases, lung parenchyma may be involved. Distance metastases have been reported in approximately 50% cases.

In peritoneal mesothelioma, the tumor is characterized by a variable growth pattern which is indistinguishable from extensive carcinomatosis. The tumor is hard or firm in consistency, and cystic and mucoid areas may be present. The liver and the spleen may contain tumor nodules. An intramucosal tumor may be present as multiple polyps.

In pericardial mesothelioma, malignant tumors may encase the heart and large vessels.

Rare tumor presents itself as multiple nodules in testicular mesothelioma.

Micro Description

This refers to the description of the tissue sample examined under a microscope to help with mesothelioma diagnosis. The main histopathological features include;

Epithelioid which is characterized by small, clear, uniform, deciduiod, and tubulopapillary cell types.

Sarcomatoid cells which are spindle-shaped.

Biphasic which includes a combination of epithelial and sarcomatoid cells.


Pathology mesothelioma
By Nephron (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons

The image shows the features of mesothelioma:

• Nuclear membrane irregularies.
• 3-D clusters of more than 10 cells with “knobby” borders.
• Large NC ratio (focal).
• Occasional gigantic cells.
• Macronucleoli.
• Multiple nucleoli.

Cytology Description

Cytology is often used due to its effectiveness in the diagnosis of an epithelioid variant. Serious effusions are presented as some of the features of malignant mesothelioma cells.

The cytologic features of malignant mesothelioma include intercellular spaces, optically dense cytoplasm with lacy peripheral vacuoles, frequent multinucleation, and scalloped borders of cell clusters.

The main disadvantage of cytology is that it does not have the ability to assess invasion.

Positive Stains

Histochemistry and immunochemistry play a crucial role in the diagnosis of mesothelioma.

In histochemical studies, mesothelioma vacuoles produce hyaluronic acid which is easily identified by staining with Alcian blue with or without hyaluronidase. The vacuoles are reported negative for PASD.

In immunochemistry, a panel of antibodies are used to help establish mesothelioma diagnosis. A combination of carcinogenic antigen (CEA), Ber-EP4, Leu-M1, B72.3, and MOC31 to monoclonal antibodies is used to distinguish approximately 90% of pulmonary adenocarcinomas from pleural mesothelioma.

Cytokeratin CAM5.2 and pancytokeratin marker AE1/AE3 are used to differentiate cancerous sarcomatous mesothelioma from sarcoma.

Among all positive mesothelioma markers, calretinin, pancytokeratin, and WT1 (Wilms’Tumor-1) are often highly recommended. Roughly 70-95 percent of all mesothelioma cancers show nuclear positivity for WT-1. Also, all mesotheliomas are positive for cytoplasmic staining and calretinin.

For the D2-40, approximately 90-100 percent of all mesotheliomas are positive with cell membrane positivity.

Negative Stains

Negative markers including B72.3, MOC31, TTF1, BerEP4, and NapsinA are used to differentiate mesothelioma from lung cancer where they are all negative for mesothelioma.

Molecular/Cytogenetics Description

Mesothelioma usually results from the accumulation of various acquired genetic events such as deletions, losses, rearrangements of chromosomes or gain of chromosomes. Chromosomal deletions are especially known to lead to the inactivation of multiple onco-suppresor genes.

Asbestos fibers have been found to induce DNA as well as chromosomal damage with most mesothelioma cases showing multiple chromosomal abnormalities. Chromosomal losses are much more common compared to gains.

One of the most common cytogenic abnormality in mesotheliomas is the deletion of 9p21 which is the locus of CDKN2A and a tumor suppressor gene (TSG). The loss of TSGCDKN2A/p15 (ARF) is fairly common in malignant mesothelioma. Loss of mutations in NF2 occurs in roughly half of the total cases. Mutations of the LATS2 gene at 13q21 are also identified.

BRCA Associated Protein 1(BAP1) germline mutations may identify those with a high risk of developing mesothelioma.

Differential Diagnosis

When making a pathological diagnosis of mesothelioma, many diseases must be differentiated and the tissue to be differentiated usually varies in terms of the histological type.

Those of epithelioid nature must be differentiated from lung adenocarcinoma for mesothelioma of the pleura and peritoneal serous carcinoma or ovarian serous papillary adenocarcinoma for peritoneal mesothelioma. Sarcomatoid carcinoma, also known as pleomorphic carcinoma/spindle cell carcinoma is usually difficult to differentiate from sarcomatoid pleural mesothelioma.

For the biphasic type, pulmonary or carcinosarcoma blastoma of the lung, carcinosarcoma of the female genital organs, and biphasic synovial sarcoma of pleural mesothelioma must be differentiated from their peritoneal mesothelioma counterpart.

The differential diagnosis for desmoplastic mesothelioma can be difficult to differentiate as it has a similar histology to fibrous pleuritis especially if only a small biopsy specimen is available. Also, reactive mesothelial hyperplasia which is associated with pleuritis or other pleural or lung disease must as well be differentiated from early-stage epithelioid mesothelioma.

References;

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741803/
  • http://www.pathologyoutlines.com/topic/pleuramesothelioma.html
  • https://www.asbestos.com/mesothelioma/histology/
  • https://www.ncbi.nlm.nih.gov/pubmed/15894403
  • https://www.ncbi.nlm.nih.gov/pubmed/16965949