Michele Carbone, MD, PhD; Hedy Lee Kindler, MD; Valerie Rusch, MD. (Transcribed
from MARF Executive Director Chris Hahn's notes of a presentation
made at ASCO, May 19, 2002.)
* * * * * * * * * * * *
Pathology and Genetics of Mesothelioma. Michele Carbone, MD, PhD
Dr. Carbone first described the diagnosis of mesothelioma:
Diagnosis of mesothelioma should normally be accomplished with a thoracoscopy.
In reaching the diagnosis, it is essential to consider the whole patient,
including all of the following factors: the pathology slides, immunostains,
x-ray, patient history, and tumor appearance at surgery. For example,
despite all of the other factors indicating mesothelioma, if the patient
is 6 years old Dr. Carbone would probably not diagnose mesothelioma where
he would if the patient were 60 years old.
Mesothelioma cell types are usually categorized as epithelial, fibrous
or sarcomatoid, biphasic, or poorly differentiated. However, in virtually
100% of the cases if you cut enough from the tumor, you will see some
of both epithelial and sarcomatoid. Thus, if the analysis is deep enough,
the tumor usually proves to be biphasic.
In 2002, with advances in immunostaining and histology, mesothelioma can
be clearly distinguished from adenocarcinoma. This is true even of epithelial
mesothelioma, which appears more similar to adenocarcinoma than does sarcomatoid.
The spindle-cell, sarcomatoid mesothelioma is more often diagnosed incorrectly.
In mesothelioma, keratin, calretinin and WT-1 are usually positive. CEA,
BerEp4, and PASD are usually negative. Epithelial mesothelioma has long
branching microvilli. Where all of these factors are present, diagnosis
is easy. Problems arise when the results are more mixed. In these situations,
molecular pathology using an electroscope, rather than histology alone,
can be used to make a definitive diagnosis.
It is important to follow up carefully on the conclusions stated in the
pathologist's report. For example, the report may state that the immunostain
is calretinin positive. But many types of tumors are calretinin positive.
Are only 2% of the cells calretinin positive? If so, it is not mesothelioma,
whereas if 100% are then the mesothelioma diagnosis may be appropriate.
This is especially important with sarcomatoid mesothelioma. By its appearance,
sarcomatoid mesothelioma could be virtually anything. Therefore, careful
histology is essential. Again, if just 2% of the cells are positive for
keratin, it is not mesothelioma; whereas if 100% are positive it may be.
An example of why careful pathology is so important arises with synovial
sarcoma. This is often confused with sarcomatoid mesothelioma, because
the histology of both tumors is very similar. However, synovial sarcoma
is much more responsive to chemotherapy than is sarcomatoid mesothelioma.
If synovial sarcoma is inaccurately diagnosed as sarcomatoid mesothelioma,
treatment which would in fact likely be beneficial may not be administered.
Similarly, "fantastic cures" of mesothelioma often are more
benign or treatable tumors misdiagnosed.
The poorly differentiated mesothelioma cell type is the most difficult
to diagnosis and frequently causes problems. This is to be expected, given
that "poorly differentiated" basically means that it does not
look like a mesothelioma. Poorly differentiated mesothelioma is usually
an exclusion diagnosis, i.e. all other possible diseases are ruled out
until mesothelioma is the only possibility left. This is a very difficult
diagnosis to make.
Dr. Carbone also described his work in mesothelioma genetics:
In the Cappodecia region of Turkey, there are three villages known as the
mesothelioma villages, where it is said that 50% of the residents die
of mesothelioma. This is supposedly from exposure to the mineral, erionite,
which is common in the area. Indeed, the villages' houses are made
from erionite. Investigators went looking in these villages for asbestos,
did not find any, but found erionite in the lungs of those who had died
from mesothelioma. They put the erionite in hamsters and the hamsters
developed mesothelioma, so it was concluded that erionite was causing
the mesothelioma in Cappodecia.
However, in some houses, 100% of the occupants develop mesothelioma (these
are known as the houses of death), whereas in other houses, none of the
occupants develop mesothelioma. Moreover, in the next village over, where
erionite is just as prevalent, nobody develops mesothelioma.
With mesothelioma developing in only 5% of crocidolite asbestos workers,
how does one explain the incidence of up to 50% in some families in Cappodecia?
Dr. Carbone and his colleagues concluded that the connection is in the
families themselves, not in their houses. In Cappodecia, the predisposition
to mesothelioma is genetic, as an autosomal dominant trait, and erionite
exposure may be a co-factor.
Dr. Carbone and his colleagues are very interested in cases of multiple
family members developing mesothelioma here in the U.S.
Chemotherapy for in Mesothelioma
Hedy Lee Kindler, MD
Dr. Kindler briefly ran through the general results of the various chemotherapies,
showing the basis for a new, cautious optimism:
Most of the various chemotherapies have been evaluated in mesothelioma,
but few have shown response rates better than 20%. This has led to therapeutic
nihilism. However, recent results provide the basis for a new, cautious optimism.
Among the "cytotoxic" chemotherapies, doxorubicin showed response
rates of 14% and was the gold standard. Its analog, epirubicin was similar.
The platinums were also in the low teens.
The antifolates appear active in mesothelioma. Edatrexate showed a 25%
response rate, but had high toxicity. The toxicity was treatable, but
treating it also lowered the drug effectiveness. Methotrexate has shown
a good response rates, but is difficult to give where there is a pleural
effusion. Pemetrexed has been evaluated with cisplatin in a phase III
clinical trial, the results of which were announced by Dr. Vogelzang at
ASCO. In a phase II, the results of pemetrexed alone were squarely in
the mid-range of chemotherapies generally, but did include some dramatic
Most studies of gemcitabine alone show no activity in mesothelioma. However,
gemcitabine in combination with cisplatin is the current gold standard.
This is based primarily on one study which showed a 48% response rate.
However, later studies showed response rates of 26%, 16% and 9% for this
Vinorelbine showed a response rate of 24% in one study.) were observed
and 16 (55%) had stable disease. The median survival from start of treatment
was 10.6 months.
The taxanes, which are natural products, have shown only minimal activity
in mesothelioma. Paclitaxel and docetaxel have been evaluated.
Similarly, the camptothecins (e.g. topotecan and irinotecan) have not shown
significant responses as single agents. However, in combination with other
drugs good results have been reported.
Onconase is a novel antineoplastic ribonuclease derived from leopard frog
eggs. A previous phase III clinical trial of onconase versus doxorubicin
was flawed in that there were more poor-prognosis patients in the onconase
arm than in the doxorubicin arm. When only those most likely to benefit
from chemotherapy were considered, the median survival was 11.6 months
for onconase and 9.6 months for doxorubicin. A second phase III trial
is now open comparing onconase to onconase plus doxorubicin to doxorubicin alone.
A problem in evaluating the results from all of these studies is that chemotherapy
often improves symptoms even when there is no measurable tumor response.
For this reason, the UK is conducting a huge mesothelioma clinical trial,
involving 840 patients, using quality of life as the measure.
The "noncytotoxic" drug therapies are starting to receive increased
attention. Vascular endothelial growth factor (VEGF) is an autocrine growth
factor for mesothelioma. VEGF is present in higher levels in patients
with mesothelioma than patients with any other solid tumor. In mesothelioma
VEGF expression correlates with microvessel density, and high microvessel
density is associated with poor survival. in mesothelioma patients. Drugs
which inhibit VEGF, angiogenesis inhibitors, include SU5416, bevacizumab,
thalidomide, and PTK 787.
A phase II study of SU5416 at the University of Chicago [partially funded
through a grant from MARF] showed "pretty good" results, with
partial responses in 11% of the patients and minor responses in another
11%. Additionally, animal models show a striking symbiotic effect when
angiogenesis inhibitors are combined with cytoxic drugs. Therefore, the
University of Chicago is continuing its study using a more advanced angiogenesis
inhibitor, bevacizumab, plus gemcitabine and cisplatin, versus gemcitabine
and cisplatin alone. Thalidomide also is in phase II trials.
Epidermal growth factor receptor (EGFR) is also overexpressed in mesothelioma.
EGFR has been shown to be overexpressed in 11 of 13 epithelioid tumors,
two of four biphasic tumors, and one of seven sarcomatoid tumors. The
Cancer and Leukemia Group B (CALGB) is studying ZD1839, or Iressa, an
inhibitor of EGFR.
Another growth factor, PDGF (Platelet-derived growth factor) is, like VEGF,
also thought to be an autocrine growth factor for mesothelioma. CALGB
is studying the drug PTK 787, which inhibits both VEGF and PDGF. The drug
Gleevec, STI-571, has had suprisingly successful results in leukemia,
where it inhibits c-kit. However, Gleevec also inhibits PDGF, and therefore
the University of Chicago will be studying Gleevec in a phase II mesothelioma trial.
In summary, these newer drugs are offering modest, but real responses.
We need to further understand the biology of the mesothelioma tumor, in
order to continue to develop these targeted therapies.
Diagnosis, Staging And Locoregional Therapy Of Mesothelioma
Valerie W. Rusch, MD
Dr. Rusch provided a very current overview on the status of diagnosis,
staging and locoregional therapy of malignant mesothelioma:
The typical mm patient is male (from occupational exposure to asbestos)
with a latency of a minimum of 20 years between exposure and development
of disease. Most patients present with pleural effusion and accompanying
dyspnea (shortness of breath), and/or with chest pain. This reflects the
stage at diagnosis, as pleural effusion reflects very early stage disease.
This is a common misconception among primary care and pulmonary physicians
who believe pleural effusion is late stage. In fact, it is in early stage
that a large effusion is able to form while there is still free pleural
space and minimal pleural tumor.
As the tumor progresses, the pleural space fuses and the tumor invades
or encases the chest wall, causing chest pain which becomes intractable.
At presentation, distant metastasis is rare. The usual natural history
of the disease is local progression, then developing metastatic disease
late. This late metastasis can be widely disseminated to virtually all
organs, but metastases to the other lung or to the peritoneum are most
common. At autopsy, half of all patients have obvious metastatic disease.
For pathological diagnosis, the interaction between the pulmonary medicine
physician, the thoracic surgeon and the pathologist is extremely important.
With an experienced pathologist and good immunostains, it is sometimes
possible now to make a definitive diagnosis merely from pleural fluid
cytology or the cell block from a thoracentesis. More frequently Video
Assisted Thoracoscopy (VATS) is required, or where the pleural space has
fused, an open pleural biopsy with a
A thoracotomy is
never necessary, and thoracic surgeons should be discouraged from performing
exploratory thoracotomy for diagnosis. The VATS pleurectomy, which is
also currently popular, should also be discouraged. It deprives the patient
the opportunity of any form of definitive surgical therapy.
One of the major advances in the last decade is that the staging system
proposed by the International Mesothelioma Interest Group (IMIG) has now
been formally adopted by both the International Union Against Cancer (UICC)
and the American Joint Committee on Cancer (AJCC). The development and
international acceptance of this staging system will greatly facilitate
the design and performance of clinical trials in mm.
The staging system is based on TNM (Tumor, Nodes, Metastasis), and recent
evidence establishes that staging status under this system correlates
with survival. T, extent of tumor, has four stages:
T1a = very early disease, involving the parietal pleura only
T1b = involvement of the parietal pleura and the visceral pleura, with
free pleural space and pleural studding
T2 = confluent pleural disease with invasion of the diaphragm muscle or lung.
T3 = locally advanced, resectable
T4 = locally advanced, unresectable.
The N component is currently identical to the lung cancer staging system.
M0 or M1 is used to indicate whether metastasis exists.
In terms of the methods used for staging, the CT scan is still the standard
for imaging. However, it does not define well the presence or absence
of chest wall or diaphragm invasion. MRI is occasionally better for this
purpose, but not so as to justify the cost of uniform MRI pre-surgery.
PET is not good for T or N status, but sometimes, i.e. in 5 to 10% of
patients, is useful for unsuspected metastases. PET is also starting to
be used to measure response to induction therapy. To diagnose trans-diaphragm
or peritoneal involvement, the laparoscopy is the gold standard.
Surgical procedures can be categorized as having either palliative intent
or curative intent. For palliative intent, the talc pleuradesis through
a chest tube or VATS is an excellent option for patients who are elderly,
have co-morbidities (other health conditions) or are otherwise not candidates
for curative surgery. Also, the parietal pleurectomy is reasonable for
patients with a partially trapped lung, to extend the lung and control
the effusion, for palliation only.
The curative intent surgical procedures are either the EPP, extrapleural
pneumonectomy, or the P/D, pleurectomy decortication. EPP is removal of
the pleura and lung en blanc, usually with resection of the diaphragm,
and sometimes the pericardium. P/D is the same operation, except leaving
the lung in place.
Dr. Rusch's input on the long-running debate between EPP and P/D was
as follows: The drawback of EPP is its higher mortality rate, between
5 and 8 percent, compared to 2 to 3 percent for P/D. However, those who
have developed expertise with EPP have now reduced the mortality rate
down to an acceptable 5 percent. With EPP, the tumor is completely resectable
more often with P/D. With P/D, the tumor is completely resectable only
in highly selected cases. Finally, EPP facilitates post operative adjuvant
radiation therapy, since in effect there is "an empty box."
Following P/D, radiation therapy is hampered by concern for the lung.
Pre-operative evaluation at Memorial Sloan Kettering includes CT scan of
the chest and upper abdomen, PET scan, detailed cardiopulmonary function,
and histology. Histology is evaluated because sarcomatoid or mixed cell
type has a much worse prognosis than epithelial. Typically, surgeons are
not keen to operate where cell type is sarcomatoid.
Adjuvant therapies include photodynamic therapy (PDT), chemotherapy and
radiation therapy. PDT is applied following surgery to eradicate minimal
gross residual tumor. In phase I and II trials, PDT has been shown to
be usually safe; however, occasionally there are significant complications,
so it has not become widely accepted. Its ability to accomplish long-term
local control is undefined.
Chemotherapy following either type of surgery can be intrapleural or systemic.
Intrapleural chemo is usually cisplatin-based. It is feasible, but offers
poor long term local control. The value of hyperthermic perfusion is being
studied but is still undefined. Systemic chemotherapy is also usually
cisplatin-based. Its impact on outcome is also undefined.
Prophylactic radiation to the chest wall after thoracoscopy prevents incisional
implants. Thus, for palliation, VATS and pleuradesis can be performed,
followed by three days of radiation to prevent incisional implants.
The value of hemithoracic radiation following P/D is questionable, because
of the difficulty of protecting the lung. 70-80% of patients experience
local recurrence. A clinical trial at MSK has shown hemithoracic high
dose radiation to be effective after EPP. It was safe, had very low complications,
and dramatically reduced local recurrence to only 10%. Median survival
of Stage I or II patients in this clinical trial with surgery and radiation
only was 33.8 months. For Stage III and IV patients with more locally
advanced disease the median survival was 10 months. These patients tended
to have relapses in distant sites. So MSK's protocol for locally advanced
disease patients (i.e. T3 or N2) is induction therapy first, then EPP
followed by hemithoracic radiation therapy.