10 Things Dependable Trading System Does

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Trading markets profitably is no longer rocket science; in fact you don't have to be a mathematical genius. All it needs is just having one sensible head sitting on your shoulders and ability to follow simple directions given by a well chosen dependable forex trading system. Whether you're trying to take it as a hobby or you want to earn extra cash and be able to quit your daily job. The task is far simpler than you've ever believed using an automated trading system.
A good trading system will:
1. Remove emotions: Handling ones emotion is one of the biggest challenges individual investors have. Inability to cope with losses make investors second guess their decisions and end up losing money. System traders can forget about making emotional and sometimes-reckless decisions by strictly following a pre-developed system. Lowering the rate of human inefficiencies, system traders can boost profits.
2. Save time: Once a reliable system is developed and optimized, next to nothing effort is required by the trader. Automated the signal generation is done by a computer so the trader is freed from spending time on analysis.
3. Remove the brain tasking exercise. The Development, programming and analysis have been done and made ready for instant use as soon as launched by user.
4. Stop bothering about analysis. A good trading system reads information input from the market and makes trade analysis without bothering the user.
5. Start another business: System trading has the potential to free you from your burdensome day-job by supplementing and sometimes replacing your full-time income. This is not to say every trader is billionaire-which would be crazy! What I am saying is that if done properly, and given the 'right' set of tools - there's just NO reason why you can't be successful trading forex.
6. Perfect trading skills. A dependable trading system will provide the trader with an understanding of what goes on -the when and why of every trade.
7. Build confidence and control: Careful observation and imitation of the way the system executes its trade and the results the systems gets helps the trader psychologically to develop confidence and learn to be in control.
8. Helps improve discipline: Since an automated system does not take owner inputs at the point of trading, indiscipline on the part of user can be avoided. Trading with discipline will put more money in your pocket and take less money out. The one constant truth concerning the markets is that discipline = increased profits.
9. Avoid trial and error: With system trading, you can learn the rules and trade profitably WITHOUT the costly and time-consuming act of 'trial and error. You can the basics without biting your finger.
10. Accurate Real-time decisions: Good trading systems use clear and concise rules that give you precise entries and exits - making the right choice ensures 90% of the work is done for you! All you need to do is learn the rules, watch for a setup (the system identifies this for you) and place and manage your trade to target. That's it!
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How to Earn Money With Google Adsense

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Do you want to make money quick? In this article we are going to talk about one of the quickest ways you can make money. Making money quick is not only possible there are people doing it everyday with Google Adsense.

Google AdSense delivers text and image ads that match the content on your website. These are very targeted ads that you can choose the size and color of and they come across to your customer as helpful more than an ad itself.

Google Ads require virtually no maintenance and they help you put advertising on your website without actually having to deal with advertisers yourself. If you can copy and paste a small code you can have targeted advertising on your website in minutes.

Adsense is simple to join and it is free to join. Whether you are an internet newbie or a veteran you can profit quickly by placing Google Adsense ads on your web pages.
Since Google does all of the work by finding the most profitable ads for your pages you can do what you do best....provide good content and lots of it. The more web pages you create the quicker you will be making money. You can learn more here:
https://www.google.com/adsense/
Once you have joined Google Adsense you will want to combine Google search with AdSense to monetize more of your web pages. You can do this by placing a Google search box on your pages. Google AdSense combines Google's search technology with
thousands of keyword advertisers to deliver targeted text-based ads to search result pages. People find these ads useful and click on them, and when they do, Google pays you.

You can see an example of how this works right here on this web page. In fact we combine Google search and Google Adsense on almost every website and web pages we create. We have found it a very easy way to make money quick and to make money over and over. It's great.

The internet offers many ways to make money quick. The nice thing about Google Adsense is you have the largest search engine in the world doing your advertising for you. This truely allows you to make money quickly and you can do it over and over with as many products as you want.
About the Author
Kaushik Das is a full-time Internet Marketer. Learn about a new keyword generation and analysis tool that all of the gurus are secretly using to quadruple their Adwords and Adsense earnings... http://manomanju.com/keyword-elite
Article Source: www.Ezine-Article.com

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Mesothelioma

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Mesotheliomas form a spectrum of tumors that usually arise in the pleura or in the abdominal cavity. The malignant tumors arising within the pleura are strongly associated with prior asbestos exposure in up to 90% of cases. The time period from initial exposure to development of the cancer may range from 25-45 years and the lifetime risk of developing mesothelioma following heavy exposure ranges from 7-10%. It diffusely spreads through the pleural space, directly invading other thoracic structures and associated with pleural effusion. The underlying lung is usually encased within the tumor.

The abdominal peritoneal variant is also related to asbestos exposure and 50% of these patients may have pulmonary fibrosis. Although 50% of these cases may be limited to the abdominal cavity, intestinal obstruction is common frequently leading to death.
The classic histopathology of the mesothelioma is a biphasic tumor with both an epithelioid and sarcomatoid or spindle cell component. From this description, it can be readily appreciated how the diagnosis may be very difficult to confirm. The table below lists the major histologic variants of the tumor. The task of the pathologist is to separate the mesothelioma from its many mimics including adenocarcinoma from the lung (in pleural cases) and soft tissue sarcomas such as malignant fibrous histiocytoma (in peritoneal cases). Immunoperoxidase studies and electron microscopy may aid in this distinction.
Unfortunately, the disease has a progressively downhill course. The importance in making the correct diagnosis is more of a medicolegal issue, because of the association of asbestos exposure, rather than a therapeutic one.
OUTLINE
Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy		  
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY  
Malignant Peritoneal Mesothelioma in Women

A Study of 75 Cases With Emphasis on Their Morphologic Spectrum and Differential Diagnosis
Patricia M. Baker, MD, etal.
Am J Clin Pathol 2005;123:724-737 Abstract quote

Seventy-five malignant mesotheliomas of the peritoneum in women were reviewed to highlight their morphologic spectrum. The patients ranged from 17 to 92 (mean, 47.4) years of age. The clinical presentation was usually abdominal or pelvic pain, abdominal swelling (sometimes due to ascites), or a pelvic mass.

On microscopic examination, the majority of the tumors had only an epithelial morphology, but 4 were biphasic and 1 was sarcomatoid. The most common epithelial patterns were tubular and papillary (which often coexisted), but 5 tumors were purely diffuse; 2 had cells with abundant glassy eosinophilic cytoplasm (so-called deciduoid mesothelioma). The cells in the tubular and papillary patterns were generally cuboidal with scant to moderate amounts of eosinophilic cytoplasm. Nuclear atypia was usually only mild, although a minority of cases had moderate or even, occasionally, severe atypia. Many tumors had foci that, viewed in isolation, resembled so-called well-differentiated papillary mesothelioma, and accordingly that diagnosis should be made cautiously.

Unusual features were lymphoid follicles (13 cases), striking myxoid stroma (5 cases), prominent foamy histiocytes (5 cases), and a striking vascular proliferation (1 case). The varied morphology of peritoneal malignant mesotheliomas may raise a broad differential diagnosis, but in most cases the resemblance to other tumors is limited.

Histochemistry, immunohistochemistry, and electron microscopy may provide important aid, particularly when tissue is limited, but should be needed only occasionally.

PATHOGENESIS CHARACTERIZATION
ASBESTOSIS  

Current controversies regarding the role of asbestos exposure in the causation of malignant mesothelioma: The need for an evidence-based approach to develop medicolegal guidelines.

Marchevsky AM, Wick MR.

Ann Diagn Pathol. 2003 Oct;7(5):321-32. Abstract quote  
Asbestos is a group of fibrous silicate minerals that includes two mineralogic groups: amphiboles and serpentines. While the carcinogenic role of amphiboles (eg, crocidolite and amosite) is well established, medical "experts" that tend to strongly advocate their views currently argue in medicolegal cases multiple specific issues regarding the carcinogenicity of asbestos fibers.
For example, it is controversial whether chrysotile causes malignant mesothelioma (MM); what are the specific carcinogenic thresholds for amphiboles and chrysotile; what occupations are truly at risk to develop MM as a result of asbestos exposure; what is the role of chrysotile in the development of peritoneal MM; how to assign causation in individuals exposed to multiple industrial products containing variable concentrations of various asbestos fibers; and, what criteria should be used to accept causation in household exposure cases and others. The causation criteria currently acceptable in U.S. courts are surprisingly flexible and subject to variable interpretation by medical "experts." At a time where thousands of individuals are claiming causation of MM by asbestos exposure, there is a need to develop more specific causation guidelines based on scientific evidence. Evidence-based medicine has been proposed as a new approach to the study, teaching, and the practice of medicine and has been used as a process of systematically reviewing the relevant studies in the literature to assess their scientific validity and development of guidelines.
This article summarizes some of the current controversies regarding the role of asbestos exposure in the causation of MM and suggests the need for future evidence-based medicine-type studies to develop causation guidelines that could be used consistently during litigation.
c-KIT  

c-Kit is not expressed in malignant mesothelioma.
Horvai AE, Li L, Xu Z, Kramer MJ, Jablons DM, Treseler PA.
Department of Pathology, University of California, San Francisco, California 94143, USA.
 Mod Pathol. 2003 Aug;16(8):818-22. Abstract quote Overexpression of KIT protein (CD117), the product of the c-kit gene, has been shown to have important prognostic and therapeutic implications for a number of malignant neoplasms. Previous studies have shown conflicting results regarding the expression of c-kit in malignant mesothelioma.

To determine whether malignant mesothelioma expresses KIT, immunohistochemistry and RT-PCR were used to analyze archived tissue from 37 cases of mesothelioma. Although a subset of mesotheliomas demonstrated specific staining with the DAKO anti-KIT antibody, in each case staining was nuclear. We could not detect c-kit mRNA by a sensitive RT-PCR assay, even in cases with strong nuclear staining. Furthermore, a second anti-KIT antibody (Cell-Marque) only demonstrated staining in a single mesothelioma case and in none of the cases that demonstrated nuclear staining.

We conclude that immunoreactivity for KIT in mesothelioma does not represent expression of the c-kit gene and may represent antibody cross-reaction with nuclear proteins. Our results raise doubt about previously reported expression of KIT in mesothelioma and consequently, the applicability of therapeutic agents that target the kinase activity of KIT.
GAMMA GCS  

Overexpression of gamma-glutamylcysteine synthetase in human malignant mesothelioma.
Jarvinen K, Soini Y, Kahlos K, Kinnula VL.
Department of Internal Medicine, University of Oulu, Helsinki, Finland.
 Hum Pathol 2002 Jul;33(7):748-55 Abstract quote Mesothelioma is a fatal tumor resistant to all treatment modalities for reasons that are still unresolved. Glutathione (GSH)-associated pathways are induced by oxidants and cytotoxic drugs, and they are also involved in the progression and resistance of some tumor cells in vitro. The rate-limiting enzyme in GSH biosynthesis is gamma-glutamylcysteine synthetase (gamma GCS). However, the expression of this enzyme has not been systematically investigated in malignant tumors, and there are no studies of gamma GCS in biopsy specimens of malignant mesothelioma.
We investigated the immunohistochemical distribution and expression of both subunits of gamma GCS in healthy pleural mesothelium, pleural mesothelioma tumor biopsy samples (34 cases), and mesothelioma cells in culture (7 cell lines). Nonmalignant mesothelium showed no immunoreactivity for either subunit in any of the cases. The heavy (catalytic) subunit of gamma GCS was highly immunostained in 29 and weakly positive in 5 cases. High-moderate and weak immunoreactivity of the light (regulatory) subunit of gamma GCS was found in 15 and 7 tumors, respectively, whereas 12 cases showed no reactivity. There was no correlation with either catalytic or regulatory subunit expression and patient survival. There was, however, a significant correlation between the heavy chain and multidrug resistance protein (MRP) 2 (P =.048), whereas no correlation was observed between the light chain and MRP1 or MRP2. Treatment of cultured mesothelioma cells with buthionine sulfoximine (BSO), to inhibit gamma GCS, significantly potentiated cisplatin-induced cytotoxicity mainly by nonapoptotic mechanism when assessed by counting the living cells, TUNEL (terminal deoxytransferase-mediated dUTP nick-end labeling) assay, and caspase-3 cleavage.
In conclusion, gamma GCS is highly positive in most cases of malignant mesothelioma and may play an important role in the primary drug resistance of this tumor in vivo.
NO ASBESTOS  

Mesothelioma in patients with nonoccupational asbestos exposure An evidence-based approach to causation assessment. Marchevsky AM, Harber P, Crawford L, Wick MR. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Ann Diagn Pathol. 2006 Aug;10(4):241-50. Abstract quote  

The specific parameters of nonoccupational asbestos exposures (NOAE) that can distinguish an idiopathic from an asbestos-caused malignant mesothelioma (MM) are controversial. A systematic literature review yielded 1028 cases with this putative association. Only 287 of those reports had a defined single exposure to a household, building occupant, or neighborhood/community asbestos source. The available "evidence" was used to develop semiarbitrary evidence-based causation guideline rules for the assessment of putative associations between MM and NOAE.

The rules are classified into class A (tissue burden analysis shows asbestos body counts or fiber counts in lung tissues comparable to MM caused by occupational exposure to asbestos) and classes B to D based on whether certain combinations of NOAE features and MM (evidence) have been described in over 15% (class B), 5% to 15% (class C), and less than 5% (class D) of the patients reviewed. The proposed 4 classes of evidence-based causation guidelines provide a semiarbitrary framework to evaluate the causation of individual MM patients by NOAE based on decreasing levels of currently available evidence. The neoplasms in classes A to C patients are probably caused by NOAE, with decreasing weight of evidence in the 3 groups. There is minimal evidence to support the causation of MM by NOAE in class D patients.

There is no evidence or only anecdotal evidence to support a causal association between MM and NOAE in individuals who cannot be classified into any of the 4 classes. Future studies are needed to provide more comprehensive data regarding the association between MM and NOAE.

CLINICAL VARIANTS CHARACTERIZATION
GENERAL Adapted from Am J Clin Pathol 2000;113:619-622
BENIGN Adenomatoid tumor
HYPERPLASTIC VS. BORDERLINE NEOPLASTIC Multicystic mesothelioma
Localized or diffuse "well-differentiated papillary mesothelioma"
OVERTLY MALIGNANT  
Localized or diffuse epithelioid mesothelioma
 Large polygonal-cell tube
Tubulopapillary type
Mucin-containing polyhedral-cell type
Small cell type
Clear cell type
Oncocytoid or granular-cell types
Localized or diffuse sarcomatoid types
 Fibrosarcoma or malignant fibrous histiocytoma-like
With divergent differentiation (eg osteochondroid, myogenous)
Lymphohistiocytoid (lymphoma-like)
Desmoplastic
Localized or diffuse biphasic mesothelioma
  
INFLAMMATORY PROCESS  

Malignant mesothelioma of the peritoneum presenting as an inflammatory lesion: a report of four cases.
Kerrigan SA, Cagle P, Churg A.
 Am J Surg Pathol 2003 Feb;27(2):248-53 Abstract quote Most cases of malignant mesothelioma present with obvious diffuse tumor, and the presence of grossly visible diffuse tumor is usually cited as an important criterion for making the diagnosis.
We report four cases of unsuspected malignant mesothelioma of the peritoneum presenting as localized acute inflammatory lesions. The clinical diagnoses were acute appendicitis in two cases, acute cholecystitis in the third case, and incarcerated umbilical hernia in the fourth case. In all cases tumor was not evident at initial surgical exploration or on gross pathologic examination, and the diagnosis was only made on microscopic examination of the resected specimens. All cases showed a tubulopapillary form of epithelial mesothelioma with obvious tissue invasion, but the foci of tumor were too small to be seen grossly or were present deep in fibrous tissue.
On follow-up all patients developed grossly evident tumor, and one of these patients is alive without evidence of disease 5 years after presentation.
We conclude that peritoneal mesotheliomas may occasionally present as inflammatory processes without grossly evident tumor and can be diagnosed by microscopic findings alone.
LOCALIZED  

Localized malignant mesothelioma.

Allen TC, Cagle PT, Churg AM, Colby TV, Gibbs AR, Hammar SP, Corson JM, Grimes MM, Ordonez NG, Roggli V, Travis WD, Wick MR.

Department of Pathology, Baylor College of Medicine, Houston, TX, USA.

Am J Surg Pathol. 2005 Jul;29(7):866-73. Abstract quote  

Localized malignant mesotheliomas are uncommon sharply circumscribed tumors of the serosal membranes with the microscopic appearance of diffuse malignant mesothelioma but without any evidence of diffuse spread. Little is known about their behavior.

We report 23 new cases. The mean age at presentation was 63 years, and the sex ratio was approximately 2:1 (male/female). Twenty-one tumors were pleural and 2 were peritoneal. Sixteen tumors reproduced microscopic patterns of diffuse epithelial mesotheliomas, 6 had mixed epithelial and sarcomatous patterns, and 1 was purely sarcomatous. After surgical excision of the tumor, 10 of 21 patients with follow-up data were alive without evidence of disease from 18 months to 11 years after diagnosis. Patients who died had developed local recurrences and metastases, but none had diffuse pleural spread.

Localized malignant mesotheliomas should be separated from diffuse malignant mesotheliomas because of their localized presentation, quite different biologic behavior, and far better prognosis.
MILIARY LUNG METASTASIS  

Miliary pulmonary metastases from a clinically occult pleural mesothelioma.
Livasy CA, Tishko DJ, Maygarden SJ.
 Ann Diagn Pathol. 2003 Aug;7(4):249-53. Abstract quote Mesothelioma is a rare neoplasm of the serosal membranes. Signs and symptoms of a pleural effusion typically herald discovery of the tumor.

We report a case of miliary metastatic mesothelioma involving both lungs in a 54-year-old man who presented with right-sided chest discomfort, numerous pulmonary nodules detected by computed tomography of the chest, and absent pleural effusion.

Immunohistochemical and electron microscopy studies performed on wedge biopsies of parenchymal pulmonary nodules led to the diagnosis of metastatic mesothelioma. Subsequent pleural evaluation and biopsy of pleural thickening noted at a site of prior chest wall trauma identified the primary neoplasm and confirmed the diagnosis as malignant epithelioid mesothelioma. The histologic appearance of discohesive epithelioid cells in a distinctly myxoid background was the clue in this case leading to the consideration of metastatic mesothelioma and a thorough immunohistochemical evaluation of the tumor.

This case shows that mesothelioma may metastasize throughout the lungs in a miliary pattern and the metastases may be clinically detected before the primary pleural tumor. Metastatic mesothelioma is a consideration for metastatic pulmonary tumors of unknown origin.
PARATESTICULAR  

Paratesticular papillary mesothelioma: a case with borderline features.

Cabay RJ, Siddiqui NH, Alam S.

Department of Pathology, College of Medicine, University of Illinois, Chicago, IL 60612-7335, USA.

Arch Pathol Lab Med. 2006 Jan;130(1):90-2. Abstract quote  

Most often, mesotheliomas involve the serosal (serous) membranes of the pleura and peritoneum. Sometimes, mesothelial proliferations are identified in other locations. On very rare occasions, a mesothelioma is found within the tunica vaginalis of the paratesticular region.

We report a case of papillary mesothelioma of the tunica vaginalis in a 52-year-old man. Although this lesion had papillary structures lined by a single layer of mesothelial cells with predominantly bland nuclear and cytologic features, there was evidence of a minimal presence of mesothelial cells in the underlying stroma. This combination of benign and semimalignant characteristics can make the diagnosis of such a lesion problematic.

We think that a diagnosis of "borderline papillary mesothelioma" can be considered for similar mesothelial proliferations to allow for a possible increase in diagnostic accuracy and provide an enhanced informational platform from which patients and clinicians can benefit.
SKIN METASTASIS  

Widespread cutaneous and perioral metastases of mesothelioma.

Cassarino DS, Xue W, Shannon KJ.

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, and Greenbelt, MD, USA.
J Cutan Pathol. 2003 Oct;30(9):582-5 Abstract quote.  

BACKGROUND: Cutaneous involvement by mesothelioma represents a rare occurrence from an uncommon neoplasm. Most cases have resulted from local extension of an underlying body cavity mesothelioma or from surgical site contamination. We could only find six previously reported cases of distant cutaneous metastases of mesothelioma.

METHODS: We describe a case of metastatic mesothelioma involving multiple skin sites and the lip in a 64-year-old man with an underlying primary pleural mesothelioma.

RESULTS: A 64-year-old man presented with a lip lesion clinically diagnosed as keratoacanthoma vs. squamous cell carcinoma. Evaluation of the lip biopsy revealed tubulo-glandular and acinar-like arrangements of plump epithelioid cells with a hobnailed appearance, vesicular nuclei, and prominent nucleoli. The initial impression of metastatic carcinoma was revised to probable mesothelioma upon discovery of a previous history of pleural mesothelioma. Positive immunohistochemical stains for anti-cytokeratin, anti-calretinin, and HBME-1 and negative stains for anti-CEA, Leu-M1, B72.3, and Ber-Ep4 confirmed the diagnosis.

CONCLUSION: We report a rare example of multiple cutaneous metastases of mesothelioma. We also demonstrate the usefulness of relatively new and specific immunomarkers for mesothelioma vs. adenocarcinoma. Metastatic mesothelioma to the skin or lip is a very rare occurrence but should be considered in the differential diagnosis of malignant epithelioid neoplasms.

HISTOLOGICAL TYPES CHARACTERIZATION
HISTOLOGICAL VARIANTS  
BENIGN CYSTIC MESOTHELIOMA  

Benign cystic mesothelioma of the peritoneum: A clinicopathologic study of 17 cases and immunohistochemical analysis of estrogen and progesterone receptor status.
Sawh RN, Malpica A, Deavers MT, Liu J, Silva EG.
Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX.		 Hum Pathol 2003 Apr;34(4):369-74 Abstract quote Benign cystic mesothelioma (BCM) is an uncommon lesion of the peritoneum occurring predominantly in women of reproductive age. Although most patients are managed by surgical resection, a reported high incidence of cyst recurrence has led to the use of hormonal therapy in isolated cases in an attempt to control cyst size and relieve local symptoms.

To date, the estrogen receptor (ER) and progesterone receptor (PR) status of BCM has not been evaluated. Here we present our experience with 17 cases (13 women, 4 men) of BCM seen over a 19-year period, including an immunohistochemical analysis of ER and PR status in 14 cases. All lesions showed typical morphological features of BCM, and calretinin immunostaining was positive in 14 of 14 cases. Five patients experienced either 1 or 2 tumor recurrences, and no patients died of disease. One case was diffusely positive for ER only, 1 case was focally positive for PR only, and 1 case was focally positive for both ER and PR.

Although immunohistochemical detection of female sex hormone receptors in BCM is uncommon, the focal presence of ER and/or PR in some lesions does provide weak biologic support for the use of hormonal manipulation as a therapeutic option.
CLEAR CELL  

Mesothelioma with clear cell features: An ultrastructural and immunohistochemical study of 20 cases.

Ordonez NG.

Hum Pathol. 2005 May;36(5):465-73. Abstract quote  

Summary Mesotheliomas with clear cell morphology are rare and only a few individual case reports have been documented in the literature.

The author reports a series of 20 epithelioid mesotheliomas with clear features, 17 of which originated in the pleura and 3 in the peritoneum. Eighteen of the patients were men and 2 were women. Twelve patients had a history of asbestos exposure. Electron microscopy and special histochemical stains demonstrated that the cytoplasmic clearing seen in hematoxylin and eosin-stained sections resulted from multiple factors that can occur either singly or in combination.

The most frequent cause of the cytoplasmic clearing was the accumulation of large amounts of intracytoplasmic glycogen. Another but somewhat less common factor was the accumulation of large amounts of lipid, which occurred alone or with glycogen. Other less common causes were marked mitochondrial swelling, the presence of numerous intracytoplasmic vesicles, and a large number of intracytoplasmic lumens. The value of immunohistochemistry in helping to distinguish epithelioid mesotheliomas from some carcinomas with clear cell morphology is emphasized.

In addition, it was determined that because electron microscopy was decisive in establishing the cause of the cytoplasmic clearing in most of the cases, tissue for electron microscopy should routinely be procured for ultrastructural studies.
DECIDUOID FEATURES  

Malignant deciduoid mesothelioma: a diagnostic challenge.

Mourra N, de Chaisemartin C, Goubin-Versini I, Parc R, Flejou JF.

Department of Pathology, Hopital St-Antoine, Paris, France.

Arch Pathol Lab Med. 2005 Mar;129(3):403-6. Abstract quote  

Malignant deciduoid mesothelioma, a rare phenotype of epithelioid mesothelioma, arises more commonly from the peritoneum of young women, but it is also reported in the pleura of elderly people.

We report a case of malignant deciduoid mesothelioma that occurred in a 41-year-old woman after cesarean section and was initially misdiagnosed as pseudotumoral deciduosis. Microscopically, the tumor was entirely composed of deciduoid areas, and only scattered tumor cells were positive for calretinin and keratin 5/6. The patient died 14 months after the first operation.

This observation confirms the poor prognosis of this entity and the importance of the differential diagnosis of pseudotumoral deciduosis.
Epithelial Mesothelioma With Deciduoid Features
Report of Four Cases Nelson G. Ordóñez, M.D.
From the University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.		 Am J Surg Pathol 2000;24:816-823 Abstract quote Deciduoid mesothelioma is the designation given to an unusual morphologic variant of epithelial mesothelioma that closely simulates exuberant ectopic decidual reaction. Because all four previously reported cases involved the peritoneum and occurred in young women without a history of asbestos exposure, it was suggested that deciduoid mesothelioma was a subtype of epithelial mesothelioma characterized by its unique morphology, that it affects a distinct patient population, and that it is unrelated etiologically to asbestos.
The author reports four cases of mesothelioma with deciduoid features, all of which originated in the pleura. Three of the patients were men and one was a woman. Their ages ranged from 46 to 78 years (mean age, 67 yrs). Two of the patients had a history of asbestos exposure.
These findings indicate that this morphologic variant of mesothelioma is not limited to a specific patient population nor is it restricted to the peritoneum.
Mesotheliomas With Deciduoid Morphology A Morphologic Spectrum and a Variant Not Confined to Young Females
Jonathan H. Shanks, M.D., M.R.C.Path; Martin Harris, M.D., F.R.C.Path; S. Sankar Banerjee, M.D., F.R.C.Path; Brian P. Eyden, Ph.D.; Vijay M. Joglekar, F.R.C.Path; Anne Nicol, F.R.C.Path; Philip S. Hasleton, M.D., F.R.C.Path; Andrew G. Nicholson, M.R.C.Path, D.M.
From the Departments of Histopathology Christie Hospital, Manchester, England (J.H.S, M.H., S.S.B., B.P.E.); Furness General Hospital, Barrow-in-Furness, England (V.M.J.); Mid-Cheshire Hospitals Trust, Crewe, England (A.N.), Wythenshawe Hospital, Manchester, England (P.S.H.); and Royal Brompton and Harefield N.H.S. Trust, London, England (A.G.N.). 		Am J Surg Pathol 2000;24:285-294 Abstract quote
Deciduoid mesotheliomas are rare with only four previously reported cases, all affecting the peritoneum of young females.
We describe another six cases (three men and three women; age range 52–65 yrs, median 55 yrs; five peritoneal and one pleural). Three patients had an occupational history of asbestos exposure.
The deciduoid appearance predominated in four cases, whereas in two it represented a minor component within conventional tubulopapillary epithelioid mesothelioma. All tumors were strongly cytokeratin-positive (including CK5/6) and all showed at least focal staining for thrombomodulin, HBME-1, and calretinin. All were negative for epithelial mucin (D/PAS), CEA, BerEP4, LeuM1 (CD15), CD21, CD35, and S100 protein. Five of six cases (83%) were vimentin-positive and two (33%) were focally positive for -smooth muscle actin.
A differential diagnosis of gastrointestinal autonomic nerve tumor (GANT) had been initially considered from the morphology of one case, and we found positivity for some of the ``neuronal'' markers described in GANTs. This prompted us to apply such a panel to the other five tumors, accepting that the cytokeratin positivity encountered in all of our cases would exclude GANT. All cases of deciduoid mesothelioma (100%) were positive for PGP 9.5 and NSE and four of six (66%) were positive for NKI/C3. Weak focal staining (<5% cells) for synaptophysin was seen in two of six tumors. All cases were chromogranin-negative. All cases examined by electron microscopy showed desmosomes and smooth microvilli without rootlets but no neuroendocrine granules.
In conclusion, a deciduoid morphology appears to be part of the histopathologic spectrum encountered in epithelioid mesothelioma. This variant is not confined to female patients and occurs over a wider age range than previously recognized. The overlapping immunophenotype with GANTs illustrates that caution should be exercised when interpreting positivity for ``neuronal'' markers in this context. An immunohistochemical panel that includes cytokeratins should always be used.
  Ann Diagn Pathol 2001;5:168-171
EPITHELIOID  

Diffuse malignant epithelial mesotheliomas of the peritoneum in women: a clinicopathologic study of 25 patients.
Kerrigan SA, Turnnir RT, Clement PB, Young RH, Churg A.
Department of Pathology, Vancouver Hospital and Health Sciences Center, British Columbia, Canada.
 Cancer 2002 Jan 15;94(2):378-85 Abstract quote BACKGROUND: The behavior of diffuse peritoneal mesotheliomas in women and the possible relation between tumor morphology and outcome are uncertain. Reported survival has ranged from < 1 month to > 14 years, and a previous study found that tumor morphology could not be used reliably for predicting outcome. The authors examined the behavior of diffuse epithelial peritoneal mesotheliomas in women and the possible relation between pathologic features and outcome.
METHODS: Twenty-five female patients with diffuse peritoneal epithelial malignant mesotheliomas were divided into two groups: those who survived for < 4 years (60%) and those who survived for > 4 years (40%). Both groups were compared in terms of age, presentation, treatment, survival, tumor architecture, mitotic rate, necrosis, nuclear grade, and immunohistochemical profile.
RESULTS: Patients in the two groups were similar in terms of age at diagnosis (median ages, 50.7 years and 49.9 years), presentation, initial tumor burden, and treatment. In both groups, the most common initial clinical presenting features were ascites and abdominal pain. The tumors typically took the form of multiple nodules measuring < 1.5 cm in greatest dimension. Slightly less than 50% of patients in both groups received some form of chemotherapy or radiation therapy after undergoing tumor-reductive surgery or biopsy. Overall survival ranged from 1 month to 15 years. The median survival was 12 months in the group of women who survived for < 4 years and 7 years in the group of women who survived for > 4 years. Overall, 10 of 25 patients survived for > or = 5 years. One patient was alive with disease 15 years after diagnosis. Although there was a suggestion that the tumors in patients with short survival more often had solid architecture and high-grade nuclei, these findings were not significant statistically. The frequency of necrosis and the mitotic activity were the same in both groups.
CONCLUSIONS: The spectrum of diffuse epithelial peritoneal mesotheliomas in women includes tumors that are highly aggressive and behave much like pleural mesotheliomas, although a sizeable number of tumors, unlike the pleural tumors, are relatively indolent. However, because there do not appear to be morphologic features that reliably identify favorable tumors versus unfavorable tumors, aggressive therapy for all women with diffuse peritoneal mesotheliomas may be warranted.
MYXOID  

Extensive myxoid change in well-differentiated papillary mesothelioma of the pelvic peritoneum.
Diaz LK, Okonkwo A, Solans EP, Bedrossian C, Rao MS.
Departments of Pathology, Northwestern Memorial Hospital and Northwestern University Medical School, Chicago, IL; and the Ingalls Memorial Hospital, Harvey, IL.		 Ann Diagn Pathol 2002 Jun;6(3):164-7 Abstract quote We present a unique case of papillary mesothelioma of the pelvic peritoneum with extensive myxoid change in a 44-year-old woman.
The patient presented with lower abdominal pain; imaging studies revealed a pelvic mass. Microscopic examination of the surgically resected specimen showed extensive areas of myxoid stroma and only focal areas of classical papillary mesothelioma. A small biopsy of this lesion might have been misinterpreted as a soft tissue neoplasm with myxoid stroma or pseudomyxoma peritonei.
It is suggested that mesothelioma with myxoid change should be included with differential diagnoses of myxoid lesions of the peritoneum.
PAPILLARY  

Well-differentiated papillary mesothelioma of the pleura: a series of 24 cases.

Galateau-Salle F, Vignaud JM, Burke L, Gibbs A, Brambilla E, Attanoos R, Goldberg M, Launoy G; Mesopath group.

Department of Pathology CHU Caen, France
Am J Surg Pathol. 2004 Apr;28(4):534-40. Abstract quote  


Well-differentiated papillary mesothelioma (WDPM) of the pleura represents a distinct mesothelial tumor presenting with unilateral pleural effusion and superficial spreading of stout papillary formations with myxoid cores, lined by bland, flattened, or epithelioid cells, without or with limited invasion of the submesothelial layer. The majority of cases have been reported in the peritoneum in women of reproductive age with no history of asbestos exposure and also in the tunica vaginalis of men.

We report 24 cases of pleural WDPM and compared their histologic, epidemiologic, and clinical features with those of classic mesothelioma. Men and women were equally affected, with a mean age of 60 years. Half of the patients had a history of occupational asbestos exposure. In 11 patients with a minimal follow-up period of 24 months, the survival ranged from 36 to 180 months with an average of 74 months as compared with 9.89 months for 1248 paired patients with diffuse malignant mesothelioma. Ten-year survival was 30.8%.

We conclude that WDPM is a rare and unusual mesothelial tumor, characterized by a lack of deep invasion and associated with an indolent clinical course and long survival. For these reasons, WDPM is best considered as a specific clinico-pathologic entity distinct from conventional diffuse malignant mesothelioma.
Well-Differentiated Papillary Mesothelioma
Kelly J. Butnor, M.D.; Thomas A. Sporn, M.D.; Samuel P. Hammar, M.D.; Victor L. Roggli, M.D.
From the Department of Pathology (K.J.B., T.A.S., V.L.R.), Duke University Medical Center, Durham, North Carolina; the Department of Pathology and Laboratory Services (V.L.R.), Durham Veterans Administration Medical Center, Durham, North Carolina; and Diagnostic Specialties Laboratory (S.P.H.), Bremerton, Washington, U.S.A. 		Am J Surg Pathol 2001;25:1304-1309 Abstract quote
Well-differentiated papillary mesothelioma is an unusual variant of epithelial mesothelioma considered to be of low malignant potential. The majority of previously reported cases developed in the peritoneum of young women without a history of asbestos exposure.
The authors report 14 cases of well-differentiated papillary mesothelioma, seven of which originated in the pleura, six in the peritoneum, and one in the tunica vaginalis. Eleven of the patients were male and three were female, with an average age at presentation of 58 years (range 32–82 years). Six of the patients had a quantifiable history of asbestos exposure. Of the nine cases with complete follow-up, six had clinically indolent disease, one showed resolution after adjuvant chemotherapy, one pursued an aggressive course, and one died of other causes.
These findings indicate that well-differentiated papillary mesothelioma is a rare variant of mesothelioma with a variable clinical prognosis that is etiologically related to asbestos exposure in some cases.
RHABDOID  

Mesothelioma with rhabdoid features: an ultrastructural and immunohistochemical study of 10 cases.

Ordonez NG.

1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2006 Mar;19(3):373-83. Abstract quote  

Mesotheliomas with rhabdoid morphology are rare and only two individual case reports have been documented in the literature.

This author reports a series of 10 cases of mesotheliomas with rhabdoid features, nine of which originated in the pleura and one in the peritoneum. Eight of the patients were men and two were women. Six patients had a history of asbestos exposure.

Histologically, seven of the mesotheliomas were epithelioid, two sarcomatoid, and one biphasic. The proportion of the rhabdoid cells seen in these cases constituted 15-75% of the individual tumors. Cytoplasmic staining in the rhabdoid cells was seen for pan-keratin and vimentin in all 10 cases, for keratin 7 in eight of eight, for calretinin in nine of 10, and for keratin 5/6 in seven of nine. Nuclear positivity for WT1 was observed in the rhabdoid cells of four of seven cases and membranous reactivity for mesothelin in four of six, and for podoplanin in two of six. Only one case showed desmin positivity in sparse cells in the nonrhabdoid component of the tumor. All of the cases were negative for CEA, MOC-31, TAG-72, CD15, CD34, bcl2, muscle-specific actin, and TTF-1. Ultrastructural studies revealed paranuclear collections of intermediate filaments, but no evidence of rhabdomyoblastic differentiation was seen. The mean survival of five of the six patients for whom this information was available was 3.8 months. The remaining patient had a survival time of 1 year. It is important for pathologists to be aware that mesotheliomas can present rhabdoid features, not only because they can be confused with other malignancies that can exhibit a similar morphology, but also because of their apparently unusually aggressive behavior.

The value of immunohistochemistry and electron microscopy in the differential diagnosis of these tumors is discussed.

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER		 CHARACTERIZATION
GENERAL  

Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma: identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity.

Yaziji H, Battifora H, Barry TS, Hwang HC, Bacchi CE, McIntosh MW, Kussick SJ, Gown AM.
Mod Pathol. 2006 Apr;19(4):514-23. Abstract quote  

We evaluated the sensitivity and specificity of 10 monoclonal and two polyclonal antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma (AdCA) using immunohistochemistry (IHC). The antibodies were directed against the mesothelial-associated antigens mesothelin, calretinin, cytokeratin 5, thrombomodulin, Wilms' tumor-1 (WT-1) gene product and HBME-1, and the nonmesothelial antigens Lewis-Y blood group (antibody BG8), MOC-31, BerEp4, CD15, and carcinoembryonic antigen (CEA) family. The 133 tumors evaluated included 65 malignant epithelioid mesotheliomas, 22 lung AdCAs, 27 ovarian serous carcinomas, 24 breast carcinomas, and five gastric carcinomas. Diagnoses were based on clinical, histologic, ultrastructural, and/or IHC findings.

Calretinin had the best sensitivity for mesothelioma (95%), followed by HBME-1 (84%), WT-1 (78%), cytokeratin 5 (76%), mesothelin (75%), and vimentin and thrombomodulin (68%). Thrombomodulin had the best specificity for mesothelioma (92%), followed by cytokeratin 5 (89%), calretinin (87%) vimentin (84%), and HBME-1 (45%). When ovarian carcinomas were excluded from the analysis, the specificity of mesothelin and WT-1 for the diagnosis of mesothelioma increased to 90 and 81%, respectively. The sensitivity of the nonmesothelial antigens for AdCA was organ dependent, with BG8 performing best in the breast cancer group (96%), and BerEp4, BG8, MOC-31 performing best in the lung cancer group (100%). The specificity of the nonmesothelial antigens for AdCA was 98% for BG8 and CEA, 97% for CD15, 95% for BerEp4, and 87% for MOC-31.

A novel statistical analysis technique employing logic regression analysis identified a three-antibody immunohistochemical panel including calretinin, BG8, and MOC-31, which provided over 96% sensitivity and specificity for distinguishing epithelioid mesothelioma from AdCA.


Diffuse malignant mesothelioma of the peritoneum and pleura, analysis of markers.

Trupiano JK, Geisinger KR, Willingham MC, Manders P, Zbieranski N, Case D, Levine EA.

Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Mod Pathol. 2004 Apr;17(4):476-81. Abstract quote

Diffuse malignant mesothelioma of the peritoneum is a rare diagnosis. Despite many histopathologic similarities between peritoneal and pleural tumors, clinical and prognostic features may be quite different. There is a paucity of data evaluating molecular features of peritoneal mesotheliomas.

Therefore, we compared the results of a battery of immunohistochemical markers, some with therapeutic implications, in patients with primary peritoneal or pleural mesotheliomas.

We examined 24 peritoneal and nine pleural malignant mesotheliomas with a battery of immunohistochemical markers (cytokeratin AE1/3, calretinin, c-kit/CD117, desmin, epidermal growth factor receptor (EGFR), estrogen receptors (ER), progesterone receptors (PR), MIB-1, and cleaved caspase-3) in an attempt to distinguish any differences in this tumor arising in these two distinct locations.

The results indicate that the only marker to show a significant difference in its staining pattern between these two sites was EGFR (P=0.0004). In all, 92% (22/24) of peritoneal tumors demonstrated 3+ or 4+ immunoreactivity with EGFR, opposed to only 33% (3/9) pleural tumors. There was no significant difference in immunoreactivity between the pleural and peritoneal tumors with c-kit, ER, PR, cleaved caspase 3, calretinin, and desmin. There was a trend toward increased cytokeratin (P=0.07) and MIB-1 (P=0.08) expression in the peritoneal group. There was no significant difference in age, sex, or histologic subtype between the two locations.

In conclusion, despite similarities between peritoneal and pleural mesothelioma, there are differences between this neoplasm arising in these two sites. The EGFR expression is more pronounced in peritoneal tumors compared to pleural tumors. The increased expression of EGFR in the peritoneal lesions may be of clinical significance with the recent emergence of epidermal growth factor receptor-targeted therapies.

The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma.
Ordonez NG.
 Am J Surg Pathol. 2003 Aug;27(8):1031-51. Abstract quote A large number of immunohistochemical markers that can facilitate the distinction between epithelioid pleural mesotheliomas and pulmonary peripheral adenocarcinomas have recently become available.

The aim of this study is to compare the value of these new markers with others that are already commonly used for this purpose and to determine which are, at present, the best for discriminating between these malignancies.

Sixty epithelioid mesotheliomas and 50 lung adenocarcinomas were investigated for expression of the following markers: calretinin, cytokeratin 5/6, WT1, thrombomodulin, mesothelin, CD44S, HBME-1, N-cadherin, E-cadherin, MOC-31, thyroid transcription factor-1 (TTF-1), BG-8 (Lewisy), carcinoembryonic antigen (CEA), Ber-EP4, B72.3 (TAG-72), leu-M1 (CD15), CA19-9, epithelial membrane antigen (EMA), and vimentin. All (100%) of the mesotheliomas reacted for calretinin, cytokeratin 5/6, and mesothelin, 93% for WT1, 93% for EMA, 85% for HBME-1, 77% for thrombomodulin; 73% for CD44S, 73% for N-cadherin, 55% for vimentin, 40% for E-cadherin, 18% for Ber-EP4, 8% for MOC-31, 7% for BG-8, and none for CEA, B72.3, leu-M1, TTF-1, or CA19-9. Of the adenocarcinomas, 100% were positive for MOC-31, Ber-EP4, and EMA, 96% for BG-8, 88% for CEA, 88% for E-cadherin, 84% for B72.3, 74% for TTF-1, 72% for leu-M1, 68% for HBME-1, 48% for CD44S, 48% for CA19-9, 38% for mesothelin, 38% for vimentin, 30% for N-cadherin, 14% for thrombomodulin, 8% for calretinin, 2% for cytokeratin 5/6, and none for WT1.

After analyzing the results, it is concluded that calretinin, cytokeratin 5/6, and WT1 are the best positive markers for differentiating epithelioid malignant mesothelioma from pulmonary adenocarcinoma.

The best discriminators among the antibodies considered to be negative markers for mesothelioma are CEA, MOC-31, Ber-EP4, BG-8, and B72.3. A panel of four markers (two positive and two negative) selected based upon availability and which ones yield good staining results in a given laboratory is recommended.

Because of their specificity and sensitivity for mesotheliomas, the best combination appears to be calretinin and cytokeratin 5/6 (or WT1) for the positive markers and CEA and MOC-31 (or B72.3, Ber-EP4, or BG-8) for the negative markers. An extensive and detailed review of the literature is also provided.

Expression of calretinin, thrombomodulin, keratin 5, and mesothelin in lung carcinomas of different types: an immunohistochemical analysis of 596 tumors in comparison with epithelioid mesotheliomas of the pleura.
Miettinen M, Sarlomo-Rikala M.

 		Am J Surg Pathol 2003 Feb;27(2):150-8 Abstract quote Several immunohistochemical markers, among them calretinin, thrombomodulin (CD141), keratin 5, and mesothelin, have been documented or suggested as useful markers for positive identification of mesothelioma and to differentiate it from pulmonary adenocarcinoma; numerous studies have documented their variable specificity. However, expression of these markers in other types of lung carcinomas has not been systematically explored, although these tumors can enter in the differential diagnosis of mesothelioma.
In this study we immunohistochemically evaluated 596 lung carcinomas of different types for the four above-mentioned mesothelioma markers, all of which reacted with a great majority of epithelioid mesotheliomas studied for comparison. Calretinin expression was common in giant cell carcinomas (67%), small cell carcinomas (49%), and large cell carcinomas (38%), whereas it was rare in usual adenocarcinomas but slightly more common in those with neuroendocrine differentiation (11% and 17%, respectively). Thrombomodulin was present in all keratinizing squamous carcinomas and the great majority (87%) of nonkeratinizing tumors in a membrane-staining pattern. It was moderately common in small cell (27%) and large cell carcinomas (25%) but relatively rare in adenocarcinomas (13%). Keratin 5 was expressed in all keratinizing and the great majority (87%) of nonkeratinizing squamous carcinomas, and a majority of large cell carcinomas (56%) and some small cell carcinomas (27%). It was rare in acinar adenocarcinomas (12%) and absent in those with neuroendocrine differentiation. Mesothelin was present in more than half (53%) of adenocarcinomas and a minority (13%) of large cell carcinomas but was absent in small cell carcinomas. In squamous carcinomas it was more often seen in nonkeratinizing versus keratinizing tumors (31% vs 16%).
These results show that each of these "mesothelioma" markers reacts with different subsets of pulmonary carcinomas with a variable frequency; this should be considered when using these markers in the differential diagnosis of thoracic tumors.
Value of Thyroid Transcription Factor-1, E-Cadherin, BG8, WT1, and CD44S Immunostaining in Distinguishing Epithelial Pleural Mesothelioma From Pulmonary and Nonpulmonary Adenocarcinoma
Nelson G. Ordóñez, M.D.
From the University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.		 Am J Surg Pathol 2000;24:598-606 Abstract quote
The distinction between malignant pleural mesotheliomas and adenocarcinomas, particularly those originating in the lung, is a difficult diagnostic problem that can be facilitated by the use of immunohistochemical markers.
In this study, the immunoreactivity of thyroid transcription factor-1 (TTF-1), E-cadherin, BG8, WT1, and CD44S was investigated in 50 epithelial mesotheliomas, and 40 pulmonary and 95 nonpulmonary adenocarcinomas. After analyzing the results, it was concluded that E-cadherin and BG8 are useful markers for distinguishing between epithelial mesotheliomas and adenocarcinomas of various origins, including the lung.
Because TTF-1 expression is found almost exclusively in adenocarcinomas of the lung but is absent in mesotheliomas, immunostaining for this marker is particularly useful for distinguishing between these two malignancies. Although WT1 immunostaining may also be useful, its value, as determined in this study, is lower than that reported by other investigators. CD44S immunostaining does not have any practical value in discriminating between epithelial mesothelioma and lung adenocarcinoma.
Immunohistochemical Analysis Still Has a Limited Role in the Diagnosis of Malignant Mesothelioma A Study of Thirteen Antibodies
Fiona Roberts, MRCPath, Christina M. Harper, MBChB, Ian Downie, MSc, and Rodney A. Burnett, FRCPath 		Am J Clin Pathol 2001;116:253-262 Abstract quote
To identify the most accurate and useful panel to diagnose mesothelioma, we immunostained sections from 112 mesotheliomas, 18 adenocarcinomas, and 11 reactive pleural specimens with 13 antibodies.
Positive results for mesotheliomas, adenocarcinomas, and reactive pleura, respectively, were CAM5.2, 111, 18, and 11; vimentin, 30, 3, and 3; HBME-1, 75, 10, and 8; thrombomodulin, 31, 2, and 2; calretinin, 43, 6, and 11; and CD44H, 68, 10, and 4. Positive results for adenocarcinoma markers in mesotheliomas and adenocarcinomas, respectively, were carcinoembryonic antigen, 1 and 15; LeuM1, 7 and 9; and Ber-EP4, 5 and 12. All reactive pleura were negative.
Positive results for markers to help distinguish mesothelioma from reactive pleura in mesotheliomas, adenocarcinomas, and reactive pleura, respectively, were epithelial membrane antigen, 76, 17, and 6; p53, 78, 16, and 9; P-170 glycoprotein, 37, 4, and 2; and platelet-derived growth factor receptor beta, 31, 1, and 2.
The differential diagnosis of mesothelioma from adenocarcinoma is based on negative markers. Individual mesothelial markers are of low sensitivity and specificity for mesothelioma. However, diagnostic accuracy is improved by the use of antibody panels. To date there are no antibodies that help distinguish mesothelioma from reactive pleura.
Use of a Panel of Markers in the Differential Diagnosis of Adenocarcinoma and Reactive Mesothelial Cells in Fluid Cytology
Ellen C. Ko, MD, Nirag C. Jhala, MD, Jana J. Shultz, MT(ASCP)SH, QIHC, and David C. Chhieng, MD		 Am J Clin Pathol 2001;116:709-715 Abstract quote
To evaluate the use of a panel of markers to differentiate adenocarcinoma and reactive/ inflammatory process in fluid cytology, we stained 29 formalin-fixed, paraffin-embedded cell blocks of effusion fluid from patients with metastatic adenocarcinoma and 24 cell blocks from patients with benign effusion with mucicarmine and antibodies to carcinoembryonic antigen (CEA), B72.3, and calretinin.
Positive staining with CEA, B72.3, and mucicarmine was seen in 22 (76%),20 (69%), and 18 (60%) adenocarcinoma cases, respectively. All except 1 adenocarcinoma was negative for calretinin. No benign cases were positive for B72.3 and mucicarmine. In 1 benign case, scattered epithelial cells demonstrated weak positivity for CEA. The majority of combinations were 100% specific for adenocarcinoma. The highest sensitivity (86%) for adenocarcinomas was achieved with the staining combination of negative for calretinin and positive for any adenocarcinoma marker (CEA, B72.3, or mucicarmine).
The use of a panel of markers that recognize adenocarcinoma and mesothelial cells is useful in the differential diagnosis between metastatic adenocarcinoma and reactive/inflammatory process. The profile of positive staining with at least one of the adenocarcinoma markers and negative calretinin staining is highly specific and sensitive for identifying adenocarcinoma in fluid cytology.
The Role of Desmin and N-Cadherin in Effusion Cytology A Comparative Study Using Established Markers of Mesothelial and Epithelial Cells
Ben Davidson, M.D. , Ph.D. ; Søren Nielsen, C.T. ; Jette Christensen, C.T. ; Pia Asschenfeldt, M.D. ; Aasmund Berner, M.D. , Ph.D. ; Bjørn Risberg, M.D. , Ph.D. ; Preben Johansen, M.D.
From the Department of Pathology (Division of Cytology) (B.D., A.B., B.R.), Norwegian Radium Hospital, Oslo, Norway; and the Department of Pathology (S.N., J.C., P.A., P.J.), Aalborg Hospital, Aalborg, Denmark. 		Am J Surg Pathol 2001;25:1405-1412 Abstract quote
The objective of the present study was to analyze the role of the mesothelial markers desmin and N-cadherin in the diagnostic panel of serous effusions.
A total of 181 pleural and peritoneal effusions consisted of 101 cases cytologically diagnosed as malignant (89 carcinomas, 12 mesotheliomas), 78 benign, and 2 inconclusive specimens. All specimens were immunostained using 11 antibodies, against epithelial membrane antigen, Ber-EP4, carcinoembryonic antigen, E-cadherin, CA 125, N-cadherin, desmin, calretinin, p53, vimentin, and CD45. After evaluation of immunocytochemistry results, 110 specimens were diagnosed as malignant (98 carcinomas, 12 mesotheliomas) and 71 as benign (56 cellular, 15 paucicellular). The presence of desmin was detected in benign mesothelial cells in 47 of 56 (84%) reactive cellular specimens compared with 1 of 12 (8%) malignant mesotheliomas and 2 of 98 (2%) carcinomas. N-cadherin was expressed in 48 of 56 (86%) reactive cases, 12 of 12 (100%) mesotheliomas, and 47 of 98 (48%) carcinomas.
In carcinomas, N-cadherin expression was most often seen in ovarian carcinoma but was also found in other carcinomas. Calretinin, an established marker of mesothelial cells, was detected in 52 of 56 (93%) reactive specimens, 11 of 12 (93%) mesotheliomas, and 3 of 98 (3%) carcinomas. Evaluation of staining results led to reclassification of six malignant specimens as benign, whereas 17 cases diagnosed as benign and the two diagnosed as inconclusive were classified as malignant.
In conclusion, desmin appears to be a promising marker for the distinction between reactive mesothelium and malignant epithelial cells in terms of both specificity and sensitivity, and its complementary use with calretinin is recommended. Unlike calretinin, it may also prove valuable for the distinction between benign and malignant mesothelial cells. N-cadherin does not have a role in the distinction between mesothelial and epithelial cells. However, it may prove useful in the characterization of carcinomas of unknown origin. As has previously been shown, a significant number of diagnoses that are based on morphologic examination alone are modified after the use of a broad antibody panel.

Immunohistochemical diagnosis of epithelioid mesotheliomas: A critical review of old markers, new markers.
Ordonez NG.
University of Texas M.D. Anderson Cancer Center, Houston, TX.		 Hum Pathol 2002 Oct;33(10):953-67 Abstract quote Numerous new immunohistochemical markers that can be used in the diagnosis of mesothelioma have recently become available. As a result, new panels of antibodies that could be useful for distinguishing between epithelioid mesotheliomas and adenocarcinomas have been proposed. However, great differences of opinion exist regarding the individual value of some of these markers, especially when compared with those whose value has already been established.
This article provides a critical review of the currently available information on those markers that could be useful in the diagnosis of epithelioid mesotheliomas or whose utility remains controversial. A practical approach to the diagnosis of these tumors is also provided.
h-CALDESMON  

h-Caldesmon, a Useful Positive Marker in the Diagnosis of Pleural Malignant Mesothelioma, Epithelioid Type.

Comin CE, Dini S, Novelli L, Santi R, Asirelli G, Messerini L.

Department of Human Pathology and Oncology, University of Florence Medical School, Florence, Italy.
Am J Surg Pathol. 2006 Apr;30(4):463-9. Abstract quote  

Although a large number of immunohistochemical markers that can facilitate the differential diagnosis between epithelioid pleural mesothelioma and lung adenocarcinoma involving the pleura have proven to be valuable, no single antibody has demonstrated absolute sensitivity and/or specificity in making this distinction.

Using immunohistochemical analysis with h-caldesmon, a specific marker for smooth muscle tumors, we examined 70 cases of epithelial mesotheliomas and 70 cases of lung adenocarcinomas. In addition, immunohistochemistry for muscle markers, such as desmin, alpha-smooth-muscle actin, muscle-specific actin, myoglobin, myogenin, myosin, and MyoD-1, was performed on all mesothelioma cases. Reactivity for h-caldesmon was obtained in 68 (97%) of the 70 epithelial mesotheliomas, but in none of the adenocarcinoma cases. All mesothelioma cases were found to be negative for the other muscle markers examined.

We conclude that h-caldesmon is a highly sensitive and specific marker and suggest its inclusion in the immunohistochemical panel for the differential diagnosis of epithelioid mesothelioma versus lung adenocarcinoma.
CALRETININ  
Calretinin and Other Mesothelioma Markers in Synovial Sarcoma Analysis of Antigenic Similarities and Differences With Malignant Mesothelioma
Markku Miettinen, etal.		 Am J Surg Pathol 2001;25:610-617 Abstract quote
Synovial sarcoma (SS) is a mesenchymal neoplasm that typically shows epithelial differentiation. SS commonly metastasizes to lung and pleura, and has also been reported as the primary in these locations. The histologic distinction of SS from mesothelioma may be difficult because of the combination of epithelioid and spindle cells, potentially shared locations, and antigenic expression.
In this study the authors examined 103 well-documented SSs including 41 biphasic, 44 monophasic, and 18 poorly differentiated SSs in comparison with 23 epithelioid and seven sarcomatous mesotheliomas. Most biphasic SSs (29 of 41, 71%) had fields or foci of calretinin-positive tumor cells. The spindle cell components were more often positive (55%), whereas 14% of tumors had positive epithelial cells.
The monophasic and poorly differentiated SSs commonly had foci of calretinin-positive cells (in 52% and 56% of cases respectively). In comparison, all 23 epithelioid mesotheliomas (EM) were extensively calretinin positive and seven sarcomatoid mesotheliomas were variably calretinin positive. HBME-1 positivity was similarly detected in biphasic SS and EM (100% and 87% respectively). Among the other sarcomas, two of 15 malignant peripheral nerve sheath tumors were focally calretinin positive, whereas 16 epithelioid sarcomas, 20 leiomyosarcomas, 20 gastrointestinal stromal tumors, and 20 angiosarcomas were negative. Biphasic SSs differed from mesotheliomas by their more common BerEp4 positivity (90%) whereas EMs showed focal reactivity in 13% cases. Marked CD15 reactivity was rare in both. Wilms tumor protein-1 (WT1) was not detected in SS, but was present in 12 of 17 EMs. CD141 was rare in SS, limited to spindle cell components, whereas EMs typically showed prominent membrane staining in epithelial cells. Simple epithelial keratins were present in all epithelial cells of biphasic SS and mesothelioma (keratin 7[K7], K19), but were only focal in monophasic and poorly differentiated SS. Biphasic SSs were extensively K14 positive (89% of cases), whereas epithelial and sarcomatoid mesotheliomas typically showed only scattered positive cells.
The potentially shared calretinin patterns in SS and mesothelioma require the use of other markers. The discriminating features include extensive BerEp4 positivity, rarity of CD141, and lack of WT1 in SS. Global expression of K7 and K19 in mesotheliomas versus focal expression in monophasic and poorly differentiated SSs, and differential patterns of K14 expression may also be helpful.
CYTOKERATIN  
Expression of Cytokeratin 5/6 in Epithelial Neoplasms: An Immunohistochemical Study of 509 Cases
Peiguo G. Chu, M.D., Ph.D. and Lawrence M. Weiss, M.D.
Department of Pathology, City of Hope National Medical Center, Duarte, California Correspondence: Address reprint requests to: Peiguo G. Chu, M.D., Ph.D., Department of Pathology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010. 		Mod Pathol 2002;15:6-10 Abstract quote
Cytokeratin 5/6 (CK 5/6) immunoreactivity has been observed in the vast majority of cases of malignant mesothelioma but only rarely in pulmonary adenocarcinomas. Thus, CK 5/6 has been used to distinguish malignant mesothelioma from pulmonary adenocarcinoma. However, the utility of CK 5/6 in distinguishing pleural malignant mesothelioma from pleural metastases from nonpulmonary adenocarcinoma, as well as peritoneal malignant mesothelioma from peritoneal metastatic adenocarcinoma, has not yet been adequately addressed because the tissue expression of CK 5/6 in nonpulmonary neoplasms has not been well defined.
We have studied the CK 5/6 expression in 509 cases of various epithelial tumors by immunohistochemistry. We found that the vast majority of cases of squamous cell carcinoma, basal cell carcinoma, thymoma, salivary gland tumor, and biphasic malignant mesothelioma were positive for CK 5/6. In addition, CK 5/6 immunoreactivity was detected in 15 of 24 cases (62%) of transitional cell carcinoma, in 5 of 10 cases (50%) of endometrial adenocarcinoma, in about one third of cases of pancreatic adenocarcinoma (38%) and breast adenocarcinoma (31%), and in one quarter of cases of ovarian adenocarcinomas (25%).
Our study confirms the diagnostic utility of CK 5/6 immunohistochemistry in distinguishing biphasic mesothelioma from pulmonary adenocarcinoma but raises caution about its use for the differential diagnosis of pleural or peritoneal malignant mesothelioma versus pleural or peritoneal metastatic nonpulmonary adenocarcinoma, because many types of nonpulmonary adenocarcinomas may be positive for CK 5/6.
ESTROGEN AND PROGESTERONE RECEPTORS  

Value of estrogen and progesterone receptor immunostaining in distinguishing between peritoneal mesotheliomas and serous carcinomas.

Ordonez NG.

Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Hum Pathol. 2005 Nov;36(11):1163-7. Epub 2005 Sep 22. Abstract quote  

The differential diagnosis between peritoneal mesotheliomas and serous carcinomas involving the peritoneum may be difficult, but it can be facilitated by the use of immunohistochemistry.

To determine whether estrogen receptors (ER) or progesterone receptors (PR) may have any value as immunohistochemical markers for discriminating between these malignancies, 40 serous carcinomas of the ovary metastatic to the peritoneum, 7 primary peritoneal serous carcinomas, 30 epithelioid peritoneal malignant mesotheliomas, 5 well-differentiated papillary mesotheliomas, and 4 adenomatoid tumors were immunostained for ER and PR. Reactivity for ER was obtained in 35 (88%) of the metastatic serous carcinomas of the ovary and 6 (86%) of the primary peritoneal serous carcinomas, whereas positivity for PR was observed in 24 (60%) of the metastatic serous carcinomas and 4 (56%) of the primary peritoneal serous carcinomas. None of the mesotheliomas or adenomatoid tumors expressed ER or PR.

It is concluded that, because of its high sensitivity for serous carcinomas, ER immunostaining could be very useful in distinguishing between serous carcinomas and peritoneal mesotheliomas. Immunostaining for PR, however, has little practical utility.
HER2-NEU (c-ERB-B2)  

Malignant mesothelioma does not demonstrate overexpression or gene amplification despite cytoplasmic immunohistochemical staining for c-Erb-B2.
Horvai AE, Li L, Xu Z, Kramer MJ, Jablons DM, Treseler PA.
Department of Pathology, University of California, San Francisco 94143, USA.		 Arch Pathol Lab Med 2003 Apr;127(4):465-9 Abstract quote BACKGROUND: Previous studies have shown conflicting results regarding the expression of c-Erb-B2 in malignant mesothelioma. Overexpression of the c-erb-B2 gene product in a subset of mesothelioma may have prognostic or therapeutic implications.
OBJECTIVE: To determine whether malignant mesothelioma demonstrates c-Erb-B2 overexpression and, if so, whether such overexpression correlates with gene amplification.
METHODS: Immunohistochemistry, reverse transcription-polymerase chain reaction, and fluorescent in situ hybridization were used to analyze archived tissue from 37 cases of malignant mesothelioma.
RESULTS: Although immunohistochemical staining for c-Erb-B2 was detected in most mesotheliomas, the staining was cytoplasmic and was not consistent between the 2 different primary antibodies used. Moreover, even cases with strong cytoplasmic staining for c-Erb-B2 did not demonstrate increased messenger RNA levels or gene copy numbers compared to cases that demonstrated no staining.
CONCLUSIONS: Cytoplasmic immunoreactivity for c-Erb-B2 in mesothelioma does not represent gene overexpression or amplification and may be an immunohistochemical artifact.
MESOTHELIN  

Value of mesothelin immunostaining in the diagnosis of mesothelioma.
Ordonez NG.
University of Texas M.D. Anderson Cancer Center, Houston, Texas.
 Mod Pathol 2003 Mar;16(3):192-7 Abstract quote Mesothelin is a cell surface antigen of unknown function that is strongly expressed in mesothelial cells. Although it was reported in 1992 that immunostaining with the K1 anti-mesothelin antibody could be very useful in distinguishing between epithelioid mesotheliomas and pulmonary adenocarcinomas, no further studies have been published on the value of this marker in the diagnosis of mesotheliomas.
To determine whether mesothelin can assist in discriminating epithelioid mesotheliomas from lung adenocarcinomas or from other carcinomas metastatic to the serosal membranes, 55 mesotheliomas (44 epithelioid, 3 biphasic, and 8 sarcomatoid), 48 carcinomas of the lung (31 adenocarcinomas, 17 squamous carcinomas), and 86 nonpulmonary adenocarcinomas (14 ovary, 5 peritoneum, 9 endometrium, 11 pancreas, 4 stomach, 16 colon, 12 breast, 9 kidney, 4 thyroid, and 2 prostate) were investigated for mesothelin expression using the recently available 5B2 anti-mesothelin monoclonal antibody.
Reactivity was obtained in all 44 (100%) of the epithelioid mesotheliomas, 12 (39%) of the lung adenocarcinomas, and 42 (49%) of the nonpulmonary adenocarcinomas (14 [100%] ovary; 5 [100%] peritoneum; 6 [67%] endometrium; 10 [91%] pancreas; 2 [50%] stomach; 5 [31%] colon; and in none [0] of the breast, kidney, thyroid, or prostate). Three (18%) of the squamous carcinomas of the lung, but none of the sarcomatoid mesotheliomas, exhibited positivity for this marker, nor was any reactivity seen in the spindle cell component of the biphasic mesotheliomas. It is concluded that despite the low specificity of mesothelin for discriminating between epithelioid mesotheliomas and adenocarcinomas, immunostaining for this marker may have some utility in those instances in which the results obtained with the standard panel of immunohistochemical markers used for the diagnosis of mesotheliomas are equivocal.
Because mesothelin is a highly sensitive positive marker for epithelioid mesotheliomas, a negative staining for this marker is an indication against such a diagnosis; however, because of its limited utility, it is not recommended for inclusion in the standard panel of immunohistochemical markers used in the distinction between mesotheliomas and adenocarcinomas.
MUC4  

Diagnostic value of MUC4 immunostaining in distinguishing epithelial mesothelioma and lung adenocarcinoma.

Llinares K, Escande F, Aubert S, Buisine MP, de Bolos C, Batra SK, Gosselin B, Aubert JP, Porchet N, Copin MC.

Unite INSERM U560 Laboratoire de Recherche Gerard Biserte, Place de Verdun, Lille, France.
Mod Pathol. 2004 Feb;17(2):150-7. Abstract quote  

The distinction between pleural malignant mesothelioma and pleural infiltration by adenocarcinomas has complex therapeutic and medicolegal implications.

Although the panel of adenocarcinoma-associated antibodies and one or two mesothelioma markers is useful in this purpose, most of these antibodies are not totally specific. We determined the diagnostic value of MUC4 immunostaining in this issue. MUC4 gene expression was also studied by in situ hybridization and RT-PCR. MUC4 is a membrane-bound mucin that has been suggested to be implicated in malignant progression in humans and rats. The MUC4 gene is expressed in various normal epithelial tissues of endodermic origin and carcinomas. In the respiratory tract, MUC4 transcripts have been detected in normal respiratory epithelium and lung carcinomas. MUC4 protein was expressed in 32 of 35 (91.4%) lung adenocarcinomas on paraffin-embedded tissue. None of the 41 malignant mesotheliomas nor the 32 cases of benign mesothelial cells expressed MUC4 at the protein and mRNA levels.

We conclude that MUC4 is a very specific (100%) and sensitive (91.4%) marker of lung adenocarcinomas on paraffin-embedded tissue that could be useful in diagnostic practice in the distinction between malignant mesothelioma and adenocarcinoma.
TELOMERASE REVERSE TRANSCRIPTASE  
Expression of Telomerase Reverse Transcriptase (TERT) in Malignant Mesotheliomas Fumiyuki Kumaki, M.D.; Toshiaki Kawai, M.D., Ph.D.; Andrew Churg, M.D.; Françoise B. Galateau-Sallé, M.D.; Philip Hasleton, M.D.; Douglas Henderson, M.D.; Victor Roggli, M.D.; William D. Travis, M.D.; Philip T. Cagle, M.D.; * Victor J. Ferrans, M.D., Ph.D.
From the Pathology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. (F.K., V.J.F.); National Defense Medical College, Tokorozawa, Japan (T.K.); University of British Columbia, Vancouver, Canada (A.C.); Center Hospitalier Regional et Universitaire de Caen, France (F.B.G.S.); University of Manchester, Manchester, U.K. (P.H.); Flinders Medical Center, Bedford Park, Australia (D.H.); Duke University Medical Center, Durham, North Carolina, U.S.A. (V.R.); Armed Forces Institute of Pathology, Washington, DC, U.S.A. (W.D.T.); and Baylor College of Medicine, Houston, Texas, U.S.A. (P.T.C.).		 Am J Surg Pathol 2002;26:365-370 Abstract quote To evaluate the usefulness of determinations of telomerase activity for distinguishing malignant from benign mesothelial lesions, immunohistochemical (using a rabbit polyclonal antibody and the peroxidase method; n = 68) and in situ hybridization (using sense and antisense oligonucleotide probes; n = 46) studies were made on malignant mesotheliomas (epithelioid, 39; sarcomatoid, 18, including 2 of the desmoplastic type; and biphasic, 11) and 19 benign mesothelial lesions (benign mesothelial hyperplasia, 3; and reactive pleuritis, 16). In addition, biochemical studies of telomerase activity were made in 9 of the malignant mesotheliomas.
Telomerase activity was detected histochemically in all but one of the malignant mesotheliomas, but only in one (pleuritis) of the benign lesions, in which it was present only in activated lymphocytes. Antisense hybridization signals indicated the presence of telomerase mRNA mainly in the cytoplasm of the malignant cells. Sense probes gave negative results. Biochemical determinations revealed a strong telomerase activity in the 9 malignant mesotheliomas examined.
This study demonstrates the usefulness of immunohistochemical staining for the evaluation of mesotheliomas. The required immunostaining can be performed using paraffin sections of formalin-fixed tissues.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Fibrous Pleurisy Desmoplastic Mesothelioma
Cellularity greatest immediately under effusion, becomes more fibrotic away from effusion showing sidedness or zonation No zonation, bulk of lesion is paucicellular, may have abrupt transitions to cellular, frankly sarcomatous foci anywhere in the lesion
Cells immediately under effusion may be very atypical Cytologic atypia often hard to discern
Capillaries perpendicular to pleural surface Capillaries inconspicuous
No stromal invasion Stromal invasion
No necrosis Bland necrosis
No sarcomatous foci Sarcomatous foci
No nodular expansion of stroma Nodular expansions of stroma sometimes present
Malignant epithelioid vascular tumors of the pleura: report of a series and literature review.
Zhang PJ, Livolsi VA, Brooks JJ.
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Hum Pathol 2000 Jan;31(1):29-34 Abstract quote
Primary malignant vascular tumors of the pleura are rare. The significance and difficulty of distinction between pleural epithelioid hemangioendothelioma (EHE) and angiosarcoma have not yet been addressed.
A new series of pleural angiosarcoma is reported, and the relevant literature is reviewed. Five cases were identified from files of the authors' institutions and personal consultation cases (J.J.B.). Twenty-six cases of primary malignant vascular tumors of the pleura were identified in the literature. In a total of 31 cases, 22 were from the West and 9 from Japan. Patients were 22 to 79 years old (average, 57), and the male/female ratio was 9:1. Prior chronic pyothorax was identified only in cases reported from Japan. History of exposure to radiation or asbestos was noted in a few Western cases. The most common presentation was pleural thickening and effusion. Almost all of the patients died of disease shortly after diagnosis.
A spectrum of histology ranging from characteristic high-grade epithelioid to relatively low-grade EHE-like features was observed in our cases and can be found in previous reports. Most cases showed variable spotty cytokeratin immunoreactivity. Endothelial markers (factor 8, CD34, or CD31) were invariably positive.
Pleural angiosarcomas are often epithelioid and can be easily mistaken for mesothelioma or carcinoma clinically and histologically. Awareness of this rare tumor should prompt the use of endothelial markers when faced with a questionable mesothelioma. When cytokeratin is negative, or focal with strong vimentin reactivity, a vascular tumor should be suspected and confirmed with vascular markers. Because of their invariably aggressive behavior, all epithelioid vascular tumors of the pleura should be considered highly malignant regardless of the presence of EHE-like histological features.
The Separation of Benign and Malignant Mesothelial Proliferations
Churg A, Green FHY, eds.; US–Canadian Mesothelioma Reference Panel:Andrew Churg M.D. Chairman Thomas V. Colby M.D. Secretary Philip Cagle M.D. Joseph Corson M.D. Allen R. Gibbs Blake Gilks M.D. Margaret Grimes M.D. Samuel Hammar M.D. Victor Roggli M.D. William D. Travis M.D. The principal authors of this report are A. Churg V. Roggli T. Colby
From the University of British Columbia, Vancouver, BC, Canada (A.C.); Mayo Clinic, Scottsdale, Arizona, U.S.A. (T.V.C.); Baylor College of Medicine, Houston, Texas, U.S.A. (P.C.); Harvard Medical School, Boston, Massachusetts, U.S.A. (J.C.); Llandough Hospital, Cardiff, Wales, U.K. (A.R.G.); University of British Columbia, Vancouver, BC, Canada (B.G.); Medical College of Virginia, Richmond, Virginia, U.S.A. (M.G.); Diagnostic Specialties Lab, Bremerton, Washington, U.S.A. (S.H.); Duke University School of Medicine, Durham, North Carolina (V.R.); and the Armed Forces Institute of Pathology, Washington, DC, U.S.A. (W.D.T.).
 Am J Surg Pathol 2000;24:1183-1200 Abstract quote
The separation of benign from malignant mesothelial proliferations has emerged as a major problem in the pathology of the serosal membranes.
For both epithelial and spindle cell mesothelial processes, true stromal invasion is the most accurate indicator of malignancy, but stromal invasion is often difficult to assess, especially in small biopsies.
In the pleural cavity, deep penetration of a thickened and fibrotic pleura or penetration of mesothelial cells into the fat of the chest wall are good indicators of malignancy; however, superficial entrapment of mesothelial cells and glands by organizing effusions is common in benign reactions and needs to be distinguished from invasion.
In the peritoneal cavity, invasion of fat or of organ walls is again the most reliable indicator of malignancy, but entrapment of benign cells in organizing granulation tissue or between fat lobules is frequent and confusing. Proliferations confined to the pleural or peritoneal space, particularly linear arrays of atypical mesothelial cells on the free surface, should not be called malignant in the absence of unequivocal invasion.
Cytologic atypia is often not helpful in separating benign from malignant reactions, because benign processes are commonly atypical and mesotheliomas are often deceptively monotonous. Densely packed mesothelial cells within the pleural space are frequent in benign reactions, but densely packed mesothelial cells within the stroma favor a diagnosis of malignancy. Organizing effusions (fibrous pleurisy) typically show zonation with high cellularity and cytologic atypia toward the pleural space and increasing fibrosis with decreasing cellularity and lesser atypia toward the chest wall, whereas sarcomatous (including desmoplastic) mesotheliomas do not demonstrate this type of zonation. Elongated capillaries perpendicular to the pleural surface are seen in organizing effusions but are not a feature of sarcomatous mesotheliomas.
The combination of a paucicellular storiform pattern, plus invasion of the stroma (including fat and adjacent tissues), or bland necrosis, overtly sarcomatous foci, or distant metastases, is required for the diagnosis of desmoplastic mesothelioma.
Necrosis is usually a sign of malignancy but is occasionally seen in benign mesothelial reactions. Keratin staining is useful in indicating the distribution of mesothelial cells, and particularly in demonstrating penetration of mesothelial cells into the stroma or adjacent structures, but is of no help in separating benign and malignant proliferations because both are keratin-positive.
Although both p53 and EMA staining have been proposed as markers of mesothelial malignancy, in our experience they are not helpful for the individual case.
Calretinin and Other Mesothelioma Markers in Synovial Sarcoma Analysis of Antigenic Similarities and Differences With Malignant Mesothelioma
Markku Miettinen, etal.
 Am J Surg Pathol 2001;25:610-617 Abstract quote
Synovial sarcoma (SS) is a mesenchymal neoplasm that typically shows epithelial differentiation. SS commonly metastasizes to lung and pleura, and has also been reported as the primary in these locations. The histologic distinction of SS from mesothelioma may be difficult because of the combination of epithelioid and spindle cells, potentially shared locations, and antigenic expression.
In this study the authors examined 103 well-documented SSs including 41 biphasic, 44 monophasic, and 18 poorly differentiated SSs in comparison with 23 epithelioid and seven sarcomatous mesotheliomas.
Most biphasic SSs (29 of 41, 71%) had fields or foci of calretinin-positive tumor cells. The spindle cell components were more often positive (55%), whereas 14% of tumors had positive epithelial cells. The monophasic and poorly differentiated SSs commonly had foci of calretinin-positive cells (in 52% and 56% of cases respectively). In comparison, all 23 epithelioid mesotheliomas (EM) were extensively calretinin positive and seven sarcomatoid mesotheliomas were variably calretinin positive. HBME-1 positivity was similarly detected in biphasic SS and EM (100% and 87% respectively). Among the other sarcomas, two of 15 malignant peripheral nerve sheath tumors were focally calretinin positive, whereas 16 epithelioid sarcomas, 20 leiomyosarcomas, 20 gastrointestinal stromal tumors, and 20 angiosarcomas were negative. Biphasic SSs differed from mesotheliomas by their more common BerEp4 positivity (90%) whereas EMs showed focal reactivity in 13% cases. Marked CD15 reactivity was rare in both. Wilms tumor protein-1 (WT1) was not detected in SS, but was present in 12 of 17 EMs. CD141 was rare in SS, limited to spindle cell components, whereas EMs typically showed prominent membrane staining in epithelial cells. Simple epithelial keratins were present in all epithelial cells of biphasic SS and mesothelioma (keratin 7[K7], K19), but were only focal in monophasic and poorly differentiated SS. Biphasic SSs were extensively K14 positive (89% of cases), whereas epithelial and sarcomatoid mesotheliomas typically showed only scattered positive cells.
The potentially shared calretinin patterns in SS and mesothelioma require the use of other markers. The discriminating features include extensive BerEp4 positivity, rarity of CD141, and lack of WT1 in SS. Global expression of K7 and K19 in mesotheliomas versus focal expression in monophasic and poorly differentiated SSs, and differential patterns of K14 expression may also be helpful.
LUNG-SQUAMOUS CELL CARCINOMA  

The diagnostic utility of immunohistochemistry in distinguishing between epithelioid mesotheliomas and squamous carcinomas of the lung: a comparative study.

Ordonez NG.

1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2006 Mar;19(3):417-28. Abstract quote  

As both mesotheliomas and squamous carcinomas can present a wide variety of morphological patterns, they can on occasion be confused.

Recently, some groups of investigators have called attention to the difficulties that sometimes exist in distinguishing between these malignancies and the need to define a panel of markers that can assist in reaching the correct diagnosis.

The aim of the present study is to compare the value of the various immunohistochemical markers currently available for the diagnosis of mesothelioma and squamous carcinoma of the lung. A total of 30 epithelioid pleural mesotheliomas exhibiting a solid or predominantly solid pattern, and 30 nonkeratinizing squamous carcinomas of the lung were investigated for the expression of the following markers: podoplanin, calretinin, mesothelin, WT1, keratin 5/6, keratin 7, p63, carcinoembryonic antigen (CEA), MOC-31, Ber-EP4, B72.3, BG-8 (Lewis(y)), leu-M1 (CD15), and thyroid transcription factor-1 (TTF-1). All 30 (100%) of the mesotheliomas reacted for calretinin, mesothelin and keratin 7, 93% each for podoplanin, WT1 and keratin 5/6, 13% for Ber-EP4, 7% each for p63, MOC-31 and BG-8, and 0% for B72.3, CEA, leu-M1 and TTF-1. All 30 (100%) of the squamous carcinomas were positive for p63 and keratin 5/6, 97% for MOC-31, 87% for Ber-EP4, 80% for BG-8, 77% for CEA, 57% for keratin 7, 40% for calretinin and B72.3, 30% for leu-M1, 27% for mesothelin, 15% for podoplanin, and 0% for WT 1 and TTF-1.

After analyzing the results, it is concluded that from a practical point-of-view, a combination of two positive mesothelioma markers (WT1 and calretinin or mesothelin) with two negative mesothelioma markers (p63 and MOC-31) would allow the differential diagnosis to be established between epithelioid mesotheliomas and squamous carcinomas of the lung in nearly all instances.
PLEURAL AMYLOIDOSIS  
Pleural amyloidosis mimicking mesothelioma: A clinicopathologic study of two cases

Amy L. Adams, MD
Claudia Y. Castro, MD
Satinder P. Singh, MD
Cesar A. Moran, MD
From the Departments of Pathology and Radiology, The University of Alabama at Birmingham, AL.
 Ann Diagn Pathol 5: 229-232, 2001. Abstract quote
Two cases of pleural amyloidosis are presented. The patients are two men, 70 and 72 years of age respectively. Neither patient had evidence of systemic amyloidosis. Each presented clinically with symptoms of chest pain and dyspnea. Radiologically, both patients showed diffuse pleural thickening similar to that observed in malignant mesothelioma. In both patients, surgical decortication of the pleura was performed.
Histologically, the lesions were characterized by the presence of an amorphous eosinophilic material with focal collections of a lymphoplasmacytic infiltrate. Focal clusters of giant cells were admixed with the lymphoplasmacytic infiltrate. Histochemical stains for Congo red showed strong positive apple-green birefringency. Immunohistochemical studies using kappa and lambda light chains showed polyclonality. The cases discussed herein represent an unusual presentation of amyloid and one that needs to be considered in the differential diagnosis of malignant mesothelioma.
OVARIAN AND PERITONEAL SEROUS TUMORS  

The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study.

Ordonez NG.

1Department of Pathology, MD Anderson Cancer Center, The University of Texas, TX, USA.
Mod Pathol. 2006 Jan;19(1):34-48. Abstract quote  

The histologic distinction between peritoneal epithelioid mesotheliomas and serous carcinomas diffusely involving the peritoneum may be difficult, but it can be facilitated by the use of immunohistochemistry and electron microscopy. D2-40 and podoplanin are two recently recognized lymphatic endothelial markers that can be expressed in normal mesothelial cells and mesotheliomas.

The purpose of this study is to compare the value of these new mesothelial markers with those that are commonly used for discriminating between mesotheliomas and serous carcinomas, and also to determine the current role of electron microscopy in distinguishing between these malignancies. A total of 40 peritoneal epithelioid mesotheliomas and 45 serous carcinomas of the ovary (15 primary, 30 metastatic to the peritoneum) were investigated for the expression of the following markers: D2-40, podoplanin, calretinin, keratin 5/6, thrombomodulin, MOC-31, Ber-EP4, B72.3 (TAG-72), BG-8 (Lewis(Y)), CA19-9, and leu-M1 (CD15). All 40 (100%) of the mesotheliomas reacted for calretinin, 93% for D2-40, 93% for podoplanin, 93% for keratin 5/6, 73% for thrombomodulin, 13% for Ber-EP4, 5% for MOC-31, 3% for BG-8, and none for B72.3, CA19-9, or leu-M1. All 45 (100%) serous carcinomas were positive for Ber-EP4, 98% for MOC-31, 73% for B72.3, 73% for BG-8, 67% for CA19-9, 58% for leu-M1, 31% for keratin 5/6, 31% for calretinin, 13% for D2-40, 13% for podoplanin, and 4% for thrombomodulin. After analyzing the results, it is concluded that Ber-EP4 and MOC-31 are the best negative mesothelioma markers for differentiating between epithelioid mesotheliomas and serous carcinomas.

The best discriminators among the positive markers for mesotheliomas are D2-40, podoplanin, and calretinin. From a practical point of view, Ber-EP4 and MOC-31, in combination with calretinin, and/or D2-40 or podoplanin allow the differential diagnosis to be established between mesothelioma and serous carcinoma in nearly all instances. As a clear distinction could be made between these two malignancies in all of the cases in which electron microscopy was performed, this technique can be very useful in establishing the correct diagnosis when the immunohistochemical results are equivocal or further support of a diagnosis of either mesothelioma or serous carcinoma is needed.


Differential Expression of WT-1 in Serous Carcinomas in the Peritoneum With or Without Associated Serous Carcinoma in Endometrial Polyps.

Euscher ED, Malpica A, Deavers MT, Silva EG.

From the Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX.

Am J Surg Pathol. 2005 Aug;29(8):1074-8. Abstract quote  

Although differential WT-1 expression between ovarian and uterine serous carcinoma has been discussed in the literature, there have been no studies of WT-1 expression in serous carcinomas in the peritoneum with or without concurrent serous carcinoma in an endometrial polyp.

This study addresses this issue and includes a small series of uterine and ovarian serous carcinomas for comparison. Nine peritoneal serous carcinomas with coexistent serous carcinoma in an endometrial polyp, 10 peritoneal serous carcinomas without serous carcinoma in an endometrial polyp, 9 uterine serous carcinomas, and 12 ovarian serous carcinomas were stained with antibody to WT-1. Ninety-two percent of ovarian serous carcinomas and 80% of peritoneal serous carcinomas without serous carcinoma involving an endometrial polyp expressed WT-1. In contrast, 12% of peritoneal serous carcinomas with serous carcinoma in an endometrial polyp expressed WT-1 with the serous carcinoma in the endometrial polyp staining concordantly.

For uterine serous carcinoma without an endometrial polyp, only 11% expressed WT-1. Peritoneal serous carcinomas without coexistent serous carcinoma in an endometrial polyp have a WT-1 expression pattern similar to ovarian serous carcinoma while peritoneal serous carcinomas with coexistent serous carcinoma in an endometrial polyp have a staining pattern similar to uterine serous carcinoma.

The difference in WT-1 expression among serous carcinomas suggests a difference in biology based on the site of origin. Additionally, the difference in WT-1 expression between peritoneal serous carcinomas with and without coexistent serous carcinoma in endometrial polyps suggests that peritoneal serous carcinoma may have different pathogenetic pathways.

Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum.
Attanoos RL, Webb R, Dojcinov SD, Gibbs AR.
Department of Histopathology, Llandough Hospital, Cardiff & Vale NHS Trust, Penarth, UK.

 Histopathology 2002 Mar;40(3):237-44 Abstract quote Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum
Aims: To evaluate the role of mesothelial markers (calretinin, thrombomodulin, cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum.
Methods and results: Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcin- oma. Thrombomodulin, cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas.
Conclusions: Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.
SARCOMATOID RENAL CELL CARCINOMA  
 
Hum Pathol. 2004 Jun;35(6):697-710. Abstract quote

Both mesotheliomas and renal cell carcinomas can present a wide variety of morphological patterns. Because of this, renal cell carcinomas that metastasize to the pleura and lung may be confused with mesotheliomas.

The aim of the present study was to compare the value of the various immunohistochemical markers currently available for the diagnosis of mesothelioma and renal cell carcinoma. A total of 48 mesotheliomas (40 epithelioid, 8 sarcomatoid), and 48 renal cell carcinomas (24 conventional, 12 chromophobe, 8 papillary, 4 sarcomatoid) were investigated for the expression of the following markers: calretinin, mesothelin, cytokeratin 5/6, WT1, thrombomodulin (TM), N-cadherin, CD15 (leu-M1), MOC-31, Ber-EP4, BG-8 (Lewis(y)), CD10, renal cell carcinoma marker (RCC Ma), carcinoembryonic antigen (CEA), and B72.3. All (100%) of the epithelioid mesotheliomas reacted for calretinin, mesothelin, and cytokeratin 5/6; 93% for WT1; 78% for TM; 75% for N-cadherin, 48% for CD10, 15% for Ber-EP4, 8% for MOC-31, 8% for RCC Ma, 5% for BG-8, and none for CEA, B72.3, or CD15. Of the sarcomatoid mesotheliomas, 88% expressed calretinin, 75% N-cadherin, 38% CD10, and 13% each expressed cytokeratin 5/6, WT1, and TM. All of the remaining markers were negative. Among the RCCs, 81% expressed CD10, 75% N-cadherin, 63% CD15, 50% RCC Ma, 50% MOC-31, 42% Ber-EP4, 8% BG-8, and 2% TM. The remaining markers were negative.

The results indicate that calretinin, mesothelin, and cytokeratin 5/6 are the best positive mesothelioma markers for differentiating epithelioid mesotheliomas from renal cell carcinomas. The best discriminators among the antibodies considered negative markers for mesothelioma are CD15, MOC-31, and RCC Ma. An accurate differential diagnosis can be reached with the use of any 2 of the 3 recommended positive markers, which should be selected based on availability and on which ones yield the best staining results in a given laboratory. One of the recommended negative markers may be added to the panel if deemed necessary. If confirmation of renal origin is needed, RCC Ma could be useful.

Calretinin is the only marker that appears to have any utility in distinguishing between sarcomatoid mesotheliomas and sarcomatoid renal cell carcinomas.

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSIS  
GENERAL  
Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.
Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, DeCamp MM Jr, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ.
Division of Thoracic Surgery and the Department of Pathology, Brigham and Women's Hospital, Boston, Mass 02115, USA.
J Thorac Cardiovasc Surg 1999 Jan;117(1):54-63; discussion 63-5 Abstract quote
OBJECTIVES: Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma.
METHODS: From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy.
RESULTS: Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05).
CONCLUSIONS: (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.
BASEMENT MEMBRANE  
Presence and reduplication of basal lamina
 Hum Pathol 2000;31:1341-1345

Transmission electron microscopic analysis found better outcome in patients with tumors that expressed either basal lamina or reduplicated basal lamina in 35 cases
FLOW CYTOMETRY  
Prognostic significance of flow cytometric DNA analysis in patients with malignant pleural mesothelioma.
Emri S, Akbulut H, Zorlu F, Dincol D, Akay H, Gungen Y, Icli F.
Department of Chest Diseases, Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey.
Lung Cancer 2001 Aug-Sep;33(2-3):109-14 Abstract quote
Malignant pleural mesothelioma (MPM) due to environmental exposure to asbestos and erionite is a relatively common cancer in Turkey.
In this study, we investigated the value of flow cytometric (FCM) DNA analysis and other prognostic factors such as age and etiologic factor in the patients with MPM, treated with surgery+/-combination chemotherapy+/-radiotherapy. A total of 40 patients with a median age of 50 (range 30-68) were included in the study. Twenty-nine patients had asbestos exposure in etiology, while 11 had fibrous zeolite (erionite). Paraffin-embedded tumor specimens were studied by FCM for DNA analysis. Twelve patients (30%) had aneuploid tumors and 28 (70%) had diploid ones. Mean S-phase fraction (SPF; %) was 9.1+/-1.1 and proliferation index (PI, SPF+G2/M phase; %) was 11.3+/-0.9. While the median overall survival (OS) was 10+/-2 months (6-14; 95% CI), 1-year survival rate was 45.2%. Only PI was found to be statistically significant for OS in univariate analysis (P=0.013). PI was also found to be an independent prognostic factor for all patients (P=0.035). Aneuploidy was significantly higher in erionite group compared with asbestos group. Male predominance and poor survival were also prominent in erionite group, though not statistically significant.
In conclusion, PI is an independent prognostic factor for patients with MPM and the biologic features of the disease may show differences with respect to different etiologies.
HYALURON CONTENT  
Hyaluronan content in pleural fluid as a prognostic factor in patients with malignant pleural mesothelioma.
Thylen A, Hjerpe A, Martensson G.
Division of Pulmonary Medicine, Sahlgrenska University Hospital, Goteborg, Sweden.
Cancer 2001 Sep 1;92(5):1224-30 Abstract quote
BACKGROUND: Regardless of the modality of therapy used, malignant pleural mesothelioma is a highly treatment-resistant and invariably fatal disease. Identification of prognostic variables are important for future investigational therapeutic studies.
METHODS: The prognostic significance of various clinical variables, including hyaluronan levels in pleural fluid, was evaluated in a retrospective analysis in 100 patients with histologically confirmed malignant pleural mesothelioma.
RESULTS: The overall median survival was 11.5 months. Univariate analyses identified histologic subtype, i.e., epithelial or mixed, and elevated content of hyaluronan in the pleural effusion as significant prognostic variables. A multivariate analysis confirmed the independent predictive power of histologic subtype, and an elevated concentration of hyaluronan in the pleural fluid also indicated longer survival in older patients and in patients receiving therapy other than supportive.
CONCLUSIONS: The prognostic value of histologic subtype and the concentration of hyaluronan in pleural effusions should be considered when designing and evaluating treatment trials for patients with malignant pleural mesothelioma.
p27  
p27(kip1) immunoreactivity correlates with long-term survival in pleural malignant mesothelioma.
Bongiovanni M, Cassoni P, De Giuli P, Viberti L, Cappia S, Ivaldi C, Chiusa L, Bussolati G.
Department of Oncology, University of Turin, Turin, Italy.
 Cancer 2001 Sep 1;92(5):1245-50 Abstract quote
BACKGROUND: Pleural malignant mesothelioma (PMM) is a rare and highly aggressive tumor, whose development is strictly related to occupational exposure to asbestos. The prognosis of PMM is generally poor (median survival, 4-12 months), but a few have a relatively long survival. The objective of this study was to evaluate the use of the cell cycle-related proteins p27(kip1) and MIB-1 as prognostic indicators of survival in PMMs.
METHODS: Of 621 PMMs, the authors selected 27 cases with a relatively long-term survival (> 24 months) and a control group of 36 PMMs having a shorter (usual) survival (< 24 months).
RESULTS: The expression of the p27(kip1) was significantly higher in the long-term survival group compared with the control (short survival) group (81.41% vs. 31.94%; P < 0.0001). The PMMs of epithelioid histotype had a significantly higher p27(kip1) immunoreactivity compared with those of biphasic type (59.24% vs. 38.94%; P = 0.02). In agreement with the data in the literature, the proliferative activity (as detected by MIB-1 immunoreactivity) was significantly higher in short than long survival PMMs (43.53% vs. 14.11%; P < 0.0001) and in the biphasic histotype than in the epithelioid type (43.19% vs. 26.02%; P = 0.006).
CONCLUSIONS: The combined expression of high/low p27(kip1) and low/high Ki-67 values identified with 100% specificity and sensitivity long versus short survivors. p27(kip1) represents a reliable additional predictive factor for PMMs and a useful marker to identify patients having a more favorable prognosis.
TREATMENT  
CHEMOTHERAPY  
Results of a phase II trial of combined chemotherapy for patients with diffuse malignant mesothelioma of the pleura.
Kasseyet S, Astoul P, Boutin C.
Department of Pulmonology, University Hospital la Conception, Mediterranean University Medical School, Marseille, France.
Cancer 1999 Apr 15;85(8):1740-9 Abstract quote
BACKGROUND: Malignant pleural mesothelioma is associated with a poor prognosis because of its resistance to treatment. The authors conducted a Phase II trial in which two drugs (etoposide and 5-fluorouracil) were added to the Cancer and Leukemia Group B cisplatin-mitomycin regimen in an effort to define a more effective chemotherapy.
METHODS: Forty-five patients with confirmed Stage II malignant pleural mesothelioma were prospectively enrolled in the study. Thirty-one patients received cisplatin 60 mg/m2 on Day 1, 5-fluorouracil 600 mg on Days 1-4, folinic acid 100 mg/m2 on Days 1-4, mitomycin C 10 mg/m2 on Day 3, and etoposide 100 mg/m2 i.v. on Days 1-3, with prophylactic hematopoietic growth factors. Fourteen patients received cisplatin, 5-fluorouracil, folinic acid, and mitomycin C with the protocol unchanged, and oral etoposide 50 mg on Days 1-21 without growth factors (1 cycle every 28 days). Histology included epithelial (in 33 cases), sarcomatous (in 6), mixed (in 3), and unspecified type (in 3).
RESULTS: Two hundred eleven cycles were administered. Treatment was well tolerated and the major toxicity was hematologic: anemia in 30% of cases, neutropenia in 24%, and 2 probable cases of mitomycin-induced pneumonitis. The objective response rate was 38% (17 of 45 were partial responses), and the median response duration was 12 months. The median survival time was 16 months. There were no differences in response or survival between the 31 patients treated with growth factors and the 14 patients treated without them. Survival was slightly better for responders than for nonresponders who had stable disease or progression (20 vs. 10 months, P < 0.05).
CONCLUSIONS: This four-drug combination was effective, with a notably high response rate, acceptable toxicity, and good adherence to protocol doses. The impact on survival was limited.
Well-differentiated papillary mesothelioma involving the peritoneal and pleural cavities: successful treatment by local and systemic administration of carboplatin.
Shukunami K, Hirabuki S, Kaneshima M, Kamitani N, Kotsuji F.
Department of Obstetrics and Gynecology, Fukui Medical University, Yoshida-Gun, Japan.
Tumori 2000 Sep-Oct;86(5):419-21 Abstract quote
Well-differentiated papillary mesothelioma (WDPM) of the peritoneum is a rare form of epithelial mesothelioma. It usually shows an indolent course and no standard treatment is available. Only a few cases of WDPM in the pleural cavity have been reported.
We report on a 56-year-old post-menopausal woman who presented with ascites and right pleural effusion. Laparotomy followed by biopsy established the presence of WDPM in the peritoneum and pleural cavity. The patient was successfully treated with local and systemic administration of carboplatin.
Prospective trial for the treatment of malignant peritoneal mesothelioma.
Loggie BW, Fleming RA, McQuellon RP, Russell GB, Geisinger KR, Levine EA.
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA.
Am Surg 2001 Oct;67(10):999-1003 Abstract quote
Malignant peritoneal mesothelioma (MPM) is a rare and often rapidly fatal disease with median survival of 5 to 12 months for untreated cases and 16 months reported after multimodality treatment.
We report a prospective clinical treatment study using cytoreductive surgery combined with intraoperative intraperitoneal heated chemotherapy (IPHC) perfusion using mitomycin C for MPM. Twelve patients (11 male with a mean age 51 years) were treated. Seven patients presented with bulky disease and seven with ascites. All underwent exploratory laparotomy with histologically confirmed diagnosis of MPM. Surgical debulking as feasible was performed. Complete gross tumor removal was possible in only one patient. Cytoreduction was followed by a 2-hour closed low-volume IPHC using mitomycin C. One patient died 50 days postoperatively from complications relating to small bowel perforation. Hematologic toxicity of the procedure was minimal. Ascites was controlled in all patients and permanently in 86 per cent of patients presenting with ascites. To date median survival is 34.2 months with median follow-up of 45.2 months. One patient was re-explored for ventral hernia 2 years post-IPHC, had negative peritoneal biopsies, and remains disease-free at 5 years.
Given the dismal prognosis associated with MPM the results of treatment with cytoreductive surgery combined with IPHC perfusion are encouraging. The rarity of MPM makes appropriately powered prospective randomized trials unlikely. Therefore, we now offer this approach off protocol; however, further study of this combined modality therapy is warranted.
Combined regimen of cisplatin, doxorubicin, and alpha-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP).
Parra HS, Tixi L, Latteri F, Bretti S, Alloisio M, Gravina A, Lionetto R, Bruzzi P, Dani C, Rosso R, Cosso M, Balzarini L, Santoro A, Ardizzoni A.
Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano-Milano, Italy.
Cancer 2001 Aug 1;92(3):650-6 Abstract quote
BACKGROUND: The cisplatin-doxorubicin combination has shown moderate activity in malignant pleural mesothelioma (MPM; objective response, 25%), and preclinical studies suggest that interferons (IFNs) may have an antiproliferative effect on mesothelioma cell lines with a marked increase in cisplatin cytotoxicity. Therefore, the combined chemoimmunotherapy regimen is an worthwhile approach to evaluate in a Phase II trial.
METHODS: From December 1995 to June 1999, 37 previously untreated patients with MPM were treated with cisplatin 60 mg/m(2) intravenously on Day 1 plus doxorubicin 60 mg/m(2), recycled every 3-4 weeks and IFN-alpha-2b, 3 x 10((6)) international units subcutaneously 3 times a week for a total of 6 courses or until progression. Inclusion criteria were histologic diagnosis of MPM and measurable disease defined by computed tomography scan or magnetic resonance imaging.
RESULTS: Thirty-four patients were assessable for toxicity and 35 for efficacy according to World Health Organization criteria. One hundred thirty-five courses were administered with a median of 4 cycles per patients. Seventy-six percent of patient presented at least 1 episode of severe myelosuppression (Grade 3 and 4). Severe anemia and thrombocytopenia occurred in 30% and 24% of patients, respectively. Sixty percent of patients presented constitutional symptoms. In the 35 patients assessable for response, the overall response rate was 29% (95% confidence interval, 15-47%). The median duration of response was 8.4 months. With a median follow-up of 19.6 months, the median survival was 9.3 months. One- and 2-year survival was 45% and 34%, respectively.
CONCLUSIONS: This combined regimen has definite activity in MPM. However, toxicity, particularly myelosuppression and fatigue, is not negligible and may limit its application.
SURGERY  
Pleuropneumonectomy in the treatment of malignant pleural mesothelioma.
Grondin SC, Sugarbaker DJ.
Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chest 1999 Dec;116(6 Suppl):450S-454S Abstract quote
STUDY OBJECTIVES: Malignant pleural mesothelioma (MPM) is predominantly a local/regional disease that results in a survival time that ranges from 4 to 12 months without treatment. Single-modality therapy using surgery, chemotherapy, or radiotherapy alone is largely ineffective. The objective of the study was presentation of the use of pleuropneumonectomy in a multimodality treatment setting and the results.
DESIGN: Didactic presentation.
SETTING: Academic tertiary-care hospital.
PATIENTS: One hundred eighty-three patients who underwent multimodality therapy.
INTERVENTIONS: Of all the single-modality treatment approaches, pleuropneumonectomy has been associated most consistently with long-term disease-free survival and has provided the greatest amount of tumor cytoreduction. The technique of pleuropneumonectomy traditionally has been linked with high perioperative mortality and morbidity when compared with that of other cytoreductive techniques such as pleurectomy/decortication. Recently, improvements in operative mortality (< 5%) have been reported, largely due to improvements in patient selection and perioperative management. Multimodality therapy, including chemotherapy, radiotherapy, and extrapleural pneumonectomy, was used to treat patients.
RESULTS: Outcomes were presented for 183 patients with MPM who underwent multimodality therapy.
CONCLUSIONS: With the development of multimodality therapy, pleuropneumonectomy followed by sequential chemotherapy and radiotherapy has demonstrated a significant survival benefit, especially for patients who have epithelial tumor histology, tumor-free resection margins, and tumor-free extrapleural node status.

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