Mesothelioma and its Differential Diagnosis and Mesothelioma Treatments

Clinical Features of Mesothelioma

• Males >> females
• Age: 7^th and 8^th decades (with broad range)
• Signs and symptoms – shortness of breath, chest pain, recurrent effusions, Bloody pleural effusion,Dyspnoea
• Sites:  Pleura >> peritoneal >> other sites
• Majority associated with asbestos exposure
• Treatment: None proven; recent interest in extrapleural pneumonectomy and chemo/radiotherapy
• Prognosis:  Survival 6 to 18 months (epithelioid greater tha
• sarcomatoid/desmoplastic)
• Survival over five years is rare, but well documented.

Patterns of Presentation of Mesothelioma

• Diffuse process of pleura, peritoneum, or pericardium – by far the most common
• Localized pleural, mediastinal, or intraabdominal mass (all rare)-see below
• Metastatic disease, usually as lymphadenopathy (also rare)

 Differential Diagnosis

• When confronted with a potential mesothelioma, one needs to know as much clinical and radiologic information as is available.  The gross findings at the time of surgery or autopsy are extremely useful and these can often be inferred from radiologic studies.  If these features do not fit with the diagnosis that is being considered, then the pathologist should go back and re-assess the problem.
• The differential diagnosis of malignant mesothelioma depends on whether one is dealing with:
• An epithelial/epithelioid proliferation
• A spindle cell/fibroblastic proliferation and the approach to these two settings is entirely different. 
• The basic questions are whether the process is reactive or neoplastic, and if neoplastic is it mesothelioma or some other neoplasm mimicking a mesothelioma?  The diagnostic approach, criteria of malignancy, and ancillary tests, particularly immunostains, for these two groups are entirely different:

            Epithelioid proliferations:

Reactive mesothelial hyperplasia vs. neoplasm

If neoplastic, mesothelioma vs. carcinoma (or melanoma, etc.)

For spindled/fibroblastic proliferations:

Fibrous pleurisy vs. neoplasm

If neoplastic, desmoplastic/sarcomatoid mesothelioma vs. other (sarcoma, melanoma, sarcomatoid carcinoma, etc.)

1.         The distinction of benign mesothelial proliferations from mesothelioma is covered by Churg and recommendations summarized below:

2.         The distinction between mesothelioma and metastatic carcinoma involving the pleura is the most common problem and the one that has engendered the largest number of papers in the literature and the situation in which immunohistochemical staining is most useful.  The following are some of the features that I personally have found helpful over the years in distinguishing mesothelioma from carcinoma:

• Fibrous stroma produced by the proliferation?  This favors a neoplasm.
• Stromal invasion?  This favors a neoplasm; beware of entrapment of mesothelial cells particularly in the pericardium.
• Complex cellular proliferation or cohesive sheet-like proliferation?  Favors neoplasm.
• Are papillae present?  Favors a neoplasm.
• Is necrosis present?  Favors a neoplasm.
• Cytologic features?  Cytologically bland, cells can be seen in reactive mesothelial proliferations and mesothelioma; marked nuclear atypia usually favors carcinoma.
• Nuclear molding?  Favors carcinoma.
• Columnar cell shape?  Favors carcinoma.
• Mucous production?  Faint mucicarmine positivity not uncommon in mesothelioma; intracellular droplet positivity with PASd favors carcinoma (but rarely reported in mesothelioma).
• Cytokeratin stain:  Good to confirm the cells actually stain; strong diffuse positivity characteristic of mesothelioma (as well as, obviously, some carcinomas); CK may highlight stromal invasion
• Electron microscopy?  Rarely helpful (to me!); cases that are diagnostic ultrastructurally tend to be easy light microscopy diagnoses (my bias).

The issue of carcinoma versus mesothelioma remains the most common problem and the vast majority of these cases are recognized with clinical history, knowledge of gross/radiologic findings, knowledge of prior neoplasms, and careful attention to routine histology. Carcinomas look like carcinomas and mesotheliomas look like mesotheliomas!  Immunohistochemistry is usually confirmatory.

Nevertheless, immunohistochemistry is considered by most to be the mainstay in this differential diagnostic problem and the horizon is ever changing as new antibodies are added and older ones are cast aside. The recommendation of an international mesothelioma working group is that one use at least two positive markers for mesothelioma and at least two positive markers for carcinoma in making this distinction. 

Practically speaking most experts do at least 6 antibodies for the carcinoma vs mesothelioma differential. In addition, sex and site of the biopsy are issues in selecting antibody panels; ER/PR stains may be indicated in women and the differential for carcinomas in the abdomen is different for that in the chest. I like a pancytokeratin, not for its discriminatory value, but to highlight the architecture of the proliferation, help highlight invasion, etc.

All cases

  Pankeratin to assess positivity and pattern

Markers favoring mesothelioma:

• Cytokeratin 5/6*
• Calretinin*
• WT-1*
• Thrombomodulin
• HBME1
• Membrane pattern with EM
• D2-40 (new, and many are excited about this one)
• Podoplanin (new, and many are excited about this one)

Markers favoring carcinoma:

• CEA*
• CD15*
• B72.3*
• MOC 31*
• TTF-1 (for lung ca)*
• BerEp4
• BG8
• EMA with cytoplastic pattern
• Surfactant (for lung ca)
• Others (e.g. ER/PR, CDX-2, PSA, etc. depending on situation)

None of these antibodies is perfect and occasional mesotheliomas stain positively (usually only a few cells focally) with carcinoma markers and carcinomas may stain with mesothelioma markers.  Squamous carcinoma, transitional carcinoma, and some others are frequently positive with cytokeratin 5/6 and adenocarcinomas of the lung not uncommonly stains with calretinin.  It is said that cytoplasmic and nuclear staining with calretinin is a good marker for mesothelioma.  The greater number of antibodies that one uses the greater the likelihood for discrepant staining and then one has to take a step back and try to prioritize the findings and keep a mental tally sheet of the positive and negative features that favor one diagnosis over the other.  In a small minority a confident diagnosis is not possible.

There have been a number of studies suggesting specific panels to use in the differential diagnosis of mesothelioma and adenocarcinoma.  Again, no panel is perfect and the antibodies suggested vary from study to study since some labs have their own favorite antibodies.  In the study by Yaziji, et al. a three antibody panel, including calretinin, BG8, and MOC 31 provided 96% sensitivity and specificity for distinguishing epithelioid mesothelioma from adenocarcinoma.  In clinical practice, the senior author (Dr. Gown) said that he would rarely follow this recommendation and usually did at least six antibodies as mentioned above. 

Ordonez has reviewed immunohistochemistry and electron microscopy in the distinction of peritoneal mesothelioma and serous carcinoma and concluded that BerEp-4 and MOC 31 are the best negative mesothelioma markers in this situation and that the best positive markers are D2-40, podoplanin, and calretinin.

3.         Desmoplastic mesothelioma versus fibrous pleuritis.  As defined above, a desmoplastic mesothelioma is a sarcomatoid mesothelioma that has greater than 50% dense collagenized stroma sometimes with a vague storiform appearance.  These regions are not overtly sarcomatous.  Since desmoplastic mesotheliomas may over grow hyaline pleural plaques it is sometimes difficult, if not impossible, to separate the pre-existing benign fibrotic reaction of the pleura from a desmoplastic mesothelioma since the latter may produce regions that are nearly indistinguishable from hyaline pleural plaque.  Abrupt transitions in cellularity are one of the most useful clues that the process is neoplastic.  The separation of desmoplastic mesothelioma from fibrous pleurisy is summarized as follows (from Churg):

The series by Mangano et al. nicely showed that desmoplastic mesothelioma could be separated from fibrous pleurisy on the basis of the presence of a diffuse storiform proliferation of the pleura and one or more of the following features:

• Invasion of the chest wall or lung
• Foci of bland necrosis
• Frankly sarcomatoid foci
• Distant metastases

Immunostaining in the setting of desmoplastic mesothelioma vs. fibrous pleurisy is helpful in highlighting invasion of cytokeratin positive cells into structures adjacent to the pleura such as lung or chest wall.  Doing carcinoma markers in this setting is inappropriate.

While rarely a problem, desmoid tumors may present as pleural masses and could mimic a desmoplastic mesothelioma.  In general these are more localized and have a more extensive soft tissue component.  These have recently been reviewed by Andino, et al.

4.         Sarcomatoid mesothelioma versus other sarcoma.  Distinguishing sarcomatoid mesotheliomas from other sarcomas involving the pleura is such an uncommon scenario that it is rarely encountered by the surgical pathologist.  In such cases careful attention to any prior history of sarcoma, the pattern of growth in the pleural space (sarcomas tend to be multiple nodules rather than more diffuse growth) and selected immunostains based on the histology of the process should allow resolution of most cases.  The only sarcomas seen in the pleura with any frequency, and ones which not uncommonly closely mimic a mesothelioma, are malignant vascular tumors.  When synovial sarcoma is in the differential, molecular studies for the X:18 translocation are useful.

Localized Malignant Mesotheliomas

The US & Canadian Mesothelioma Panel has put together a series of 22 cases that included both pleural and peritoneal locations.

• 15 men, 7 women; age 37-83 years; mean 62.4
• 20 pleural, 2 peritoneal
• Mean size: 6.1 cm
• 15 epithelial, 6 biphasic, 1 sarcomatous
• Immunohistochemistry and ultrastructural studies as for diffuse mesothelioma
• Follow-up in 11 cases; 7 dead of disease at 7 months to 6 years, 1 dead of unrelated causes, 3 (27%) alive at 6-18 months.  Those who died tended to die of metastatic disease as opposed to local spread.
• Based on these studies, localized malignant mesothelioma is now recognized as an unusual variant of malignant mesothelioma.  These appear as localized masses that are usually pleural based.  In the peritoneum they may involve adjacent structures and simulate primary tumors of the colon, stomach, liver, etc.

ASBESTOS AND MESOTHELIOMAS

While the vast majority of mesotheliomas are associated with asbestos exposure (the exact percent varies with the series) one essentially never encounters asbestos bodies in routine histologic sections of the pleura and the tumors that arise therein.  The search for asbestos bodies should be in lung tissue if it is included with the pleural biopsy.  The identification of asbestos bodies (even a single body) in routine histologic material of the lung suggests significant prior exposure and can be used to support an asbestos-associated mesothelioma.  An attribution of cause or association between a mesothelioma and asbestos exposure can also be made if there is sufficient documentation of exposure in the clinical history.

Mesothilioma Treatment

1. Palliative compensation
2. Seek specialist Advice