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
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.
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.
Ann Diagn Pathol. 2003 Oct;7(5):321-32. Abstract quote
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
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 Large polygonal-cell tube
Tubulopapillary type
Mucin-containing polyhedral-cell type
Small cell type
Clear cell type
Oncocytoid or granular-cell typesFibrosarcoma or malignant fibrous histiocytoma-like
With divergent differentiation (eg osteochondroid, myogenous)
Lymphohistiocytoid (lymphoma-like)
DesmoplasticINFLAMMATORY 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
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 | |||
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| DECIDUOID FEATURES | |||
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| 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 |
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| 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. | ||
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| 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 | |||
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| 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 | |||
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| 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. |
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 | |||
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| 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 | |||
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| 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. | ||
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