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PLEURAL MESOTHELIOMA AND ITS DIFFERENTIAL DIAGNOSIS

By Jeanette Shaw,2014-06-26 21:06
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PLEURAL MESOTHELIOMA AND ITS DIFFERENTIAL DIAGNOSIS ...

    MESOTHELIOMA AND ITS DIFFERENTIAL

    DIAGNOSIS

    Thomas V. Colby MD

Clinical Features of Mesothelioma

    ? Males >> females thth? Age: 7 and 8 decades (with broad range)

    ? Signs and symptoms shortness of breath, chest pain, recurrent effusions

    ? Sites: Pleura >> peritoneal >> other sites

    ? Majority associated with asbestos exposure

    ? Treatment: None proven; recent interest in extrapleural pneumonectomy and

    chemo/radiotherapy

    ? Prognosis: Survival 6 to 18 months (epithelioid greater than

    sarcomatoid/desmoplastic)

     Survival over five years is rare, but well documented.

Patterns of Presentation of Mesothelioma

    ? Diffuse process of pleura, peritoneum, or pericardium by far the most

    common

    ? Localized pleural, mediastinal, or intraabdominal mass (all rare)-see below

    ? Metastatic disease, usually as lymphadenopathy (also rare)

    DIFFERENTIAL DIAGNOSIS

When confronted with a potential mesothelioma, one needs to know as much clinical and

    radiologic information as is available. The gross findings at the time of surgery or

    autopsy are extremely useful and these can often be inferred from radiologic studies. If

    these features do not fit with the diagnosis that is being considered, then the pathologist

    should go back and re-assess the problem.

The differential diagnosis of malignant mesothelioma depends on whether one is

    dealing with:

    1) An epithelial/epithelioid proliferation

    2) A spindle cell/fibroblastic proliferation and the approach to these two

    settings is entirely different.

The basic questions are whether the process is reactive or neoplastic, and if neoplastic is

    it mesothelioma or some other neoplasm mimicking a mesothelioma? The diagnostic

approach, criteria of malignancy, and ancillary tests, particularly immunostains, for these

    two groups are entirely different:

     Epithelioid proliferations:

    Reactive mesothelial hyperplasia vs. neoplasm

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

    For spindled/fibroblastic proliferations:

    Fibrous pleurisy vs. neoplasm

    If neoplastic, desmoplastic/sarcomatoid mesothelioma vs. other (sarcoma,

    melanoma, sarcomatoid carcinoma, etc.)

1. The distinction of benign mesothelial proliferations from mesothelioma is covered by

    Churg and recommendations summarized below:

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2. The distinction between mesothelioma and metastatic carcinoma involving the pleura

    is the most common problem and the one that has engendered the largest number of

    papers in the literature and the situation in which immunohistochemical staining is

    most useful. The following are some of the features that I personally have found

    helpful over the years in distinguishing mesothelioma from carcinoma:

Fibrous stroma produced by the proliferation? This favors a neoplasm.

    Stromal invasion? This favors a neoplasm; beware of entrapment of mesothelial cells

    particularly in the pericardium.

    Complex cellular proliferation or cohesive sheet-like proliferation? Favors neoplasm. Are papillae present? Favors a neoplasm.

    Is necrosis present? Favors a neoplasm.

    Cytologic features? Cytologically bland, cells can be seen in reactive mesothelial

    proliferations and mesothelioma; marked nuclear atypia usually favors carcinoma.

    Nuclear molding? Favors carcinoma.

    Columnar cell shape? Favors carcinoma.

    Mucous production? Faint mucicarmine positivity not uncommon in mesothelioma;

    intracellular droplet positivity with PASd favors carcinoma (but rarely reported in

    mesothelioma).

    Cytokeratin stain: Good to confirm the cells actually stain; strong diffuse positivity

    characteristic of mesothelioma (as well as, obviously, some carcinomas); CK may

    highlight stromal invasion

    Electron microscopy? Rarely helpful (to me!); cases that are diagnostic

    ultrastructurally tend to be easy light microscopy diagnoses (my bias).

The issue of carcinoma versus mesothelioma remains the most common problem and the

    vast majority of these cases are recognized with clinical history, knowledge of

    gross/radiologic findings, knowledge of prior neoplasms, and careful attention to routine

    histology. Carcinomas look like carcinomas and mesotheliomas look like mesotheliomas!

    Immunohistochemistry is usually confirmatory.

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Nevertheless, immunohistochemistry is considered by most to be the mainstay in this

    differential diagnostic problem and the horizon is ever changing as new antibodies are

    added and older ones are cast aside. The recommendation of an international

    mesothelioma working group is that one use at least two positive markers for

    mesothelioma and at least two positive markers for carcinoma in making this distinction.

Practically speaking most experts do at least 6 antibodies for the carcinoma vs

    mesothelioma differential. In addition, sex and site of the biopsy are issues in selecting

    antibody panels; ER/PR stains may be indicated in women and the differential for

    carcinomas in the abdomen is different for that in the chest. I like a pancytokeratin, not

    for its discriminatory value, but to highlight the architecture of the proliferation, help

    highlight invasion, etc.

All cases

    ? Pankeratin to assess positivity and pattern

Markers favoring mesothelioma:

    ? Cytokeratin 5/6*

    ? Calretinin*

    ? WT-1*

    ? Thrombomodulin

    ? HBME1

    ? Membrane pattern with EM

    ? D2-40 (new, and many are excited about this one)

    ? Podoplanin (new, and many are excited about this one)

Markers favoring carcinoma:

    ? CEA*

    ? CD15*

    ? B72.3*

    ? MOC 31*

    ? TTF-1 (for lung ca)*

    ? BerEp4

    ? BG8

    ? EMA with cytoplastic pattern

    ? Surfactant (for lung ca)

    ? Others (e.g. ER/PR, CDX-2, PSA, etc. depending on situation)

    None of these antibodies is perfect and occasional mesotheliomas stain positively (usually only a few cells focally) with carcinoma markers and carcinomas may stain with

    mesothelioma markers. Squamous carcinoma, transitional carcinoma, and some others

    are frequently positive with cytokeratin 5/6 and adenocarcinomas of the lung not

    uncommonly stains with calretinin. It is said that cytoplasmic and nuclear staining with

    calretinin is a good marker for mesothelioma. The greater number of antibodies that one

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uses the greater the likelihood for discrepant staining and then one has to take a step back

    and try to prioritize the findings and keep a mental tally sheet of the positive and negative features that favor one diagnosis over the other. In a small minority a confident diagnosis

    is not possible.

There have been a number of studies suggesting specific panels to use in the differential

    diagnosis of mesothelioma and adenocarcinoma. Again, no panel is perfect and the

    antibodies suggested vary from study to study since some labs have their own favorite

    antibodies. In the study by Yaziji, et al. a three antibody panel, including calretinin, BG8, and MOC 31 provided 96% sensitivity and specificity for distinguishing epithelioid

    mesothelioma from adenocarcinoma. In clinical practice, the senior author (Dr. Gown)

    said that he would rarely follow this recommendation and usually did at least six

    antibodies as mentioned above.

Ordonez has reviewed immunohistochemistry and electron microscopy in the distinction

    of peritoneal mesothelioma and serous carcinoma and concluded that BerEp-4 and MOC

    31 are the best negative mesothelioma markers in this situation and that the best positive

    markers are D2-40, podoplanin, and calretinin.

3. Desmoplastic mesothelioma versus fibrous pleuritis. As defined above, a

    desmoplastic mesothelioma is a sarcomatoid mesothelioma that has greater than 50%

    dense collagenized stroma sometimes with a vague storiform appearance. These

    regions are not overtly sarcomatous. Since desmoplastic mesotheliomas may over

    grow hyaline pleural plaques it is sometimes difficult, if not impossible, to separate

    the pre-existing benign fibrotic reaction of the pleura from a desmoplastic

    mesothelioma since the latter may produce regions that are nearly indistinguishable

    from hyaline pleural plaque. Abrupt transitions in cellularity are one of the most

    useful clues that the process is neoplastic. The separation of desmoplastic

    mesothelioma from fibrous pleurisy is summarized as follows (from Churg):

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The series by Mangano et al. nicely showed that desmoplastic mesothelioma could be

    separated from fibrous pleurisy on the basis of the presence of a diffuse storiform

    proliferation of the pleura and one or more of the following features:

    ? Invasion of the chest wall or lung

    ? Foci of bland necrosis

    ? Frankly sarcomatoid foci

    ? Distant metastases

Immunostaining in the setting of desmoplastic mesothelioma vs. fibrous pleurisy is

    helpful in highlighting invasion of cytokeratin positive cells into structures adjacent to the

    pleura such as lung or chest wall. Doing carcinoma markers in this setting is

    inappropriate.

While rarely a problem, desmoid tumors may present as pleural masses and could mimic

    a desmoplastic mesothelioma. In general these are more localized and have a more

    extensive soft tissue component. These have recently been reviewed by Andino, et al.

4. Sarcomatoid mesothelioma versus other sarcoma. Distinguishing sarcomatoid

    mesotheliomas from other sarcomas involving the pleura is such an uncommon

    scenario that it is rarely encountered by the surgical pathologist. In such cases careful

    attention to any prior history of sarcoma, the pattern of growth in the pleural space

    (sarcomas tend to be multiple nodules rather than more diffuse growth) and selected

    immunostains based on the histology of the process should allow resolution of most

    cases. The only sarcomas seen in the pleura with any frequency, and ones which not

    uncommonly closely mimic a mesothelioma, are malignant vascular tumors. When

    synovial sarcoma is in the differential, molecular studies for the X:18 translocation

    are useful.

Localized Malignant Mesotheliomas

The US & Canadian Mesothelioma Panel has put together a series of 22 cases that

    included both pleural and peritoneal locations (see Allen ref.).

    ? 15 men, 7 women; age 37-83 years; mean 62.4

    ? 20 pleural, 2 peritoneal

    ? Mean size: 6.1 cm

    ? 15 epithelial, 6 biphasic, 1 sarcomatous

    ? Immunohistochemistry and ultrastructural studies as for diffuse mesothelioma

    ? Follow-up in 11 cases; 7 dead of disease at 7 months to 6 years, 1 dead of

    unrelated causes, 3 (27%) alive at 6-18 months. Those who died tended to die of

    metastatic disease as opposed to local spread.

Based on these studies, localized malignant mesothelioma is now recognized as an

    unusual variant of malignant mesothelioma. These appear as localized masses that are

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usually pleural based. In the peritoneum they may involve adjacent structures and

    simulate primary tumors of the colon, stomach, liver, etc.

ASBESTOS AND MESOTHELIOMAS

While the vast majority of mesotheliomas are associated with asbestos exposure (the

    exact percent varies with the series) one essentially never encounters asbestos bodies in

    routine histologic sections of the pleura and the tumors that arise therein. The search for asbestos bodies should be in lung tissue if it is included with the pleural biopsy. The

    identification of asbestos bodies (even a single body) in routine histologic material of the lung suggests significant prior exposure and can be used to support an asbestos-

    associated mesothelioma. An attribution of cause or association between a mesothelioma

    and asbestos exposure can also be made if there is sufficient documentation of exposure

    in the clinical history.

References

Allen TC, Cagle PT, Churg AM, Colby TV, Gibbs AR, Hammar SP, Corson JM,

    Grimes MM, Ordonez NG, Roggli V, Travis WD, Wick MR. Localized Malignant Mesothelioma. Am

    J Surg Pathol. 2005;29:866-873.

    Andino L, Cagle PT, Murer B, Lu L, Popper HH. Galateau-Salle F, Sienko AE, Barrios R, Zander DS.

    Pleuropulmonary desmoid tumors. Immunohistochemical comparison with solitary fibrous tumors and

    assessment of β-Catenin and cyclin D1 expression. Arch Pathol Lab Med 2006;130:1503-1509.

    Argani P, Rosai J. Hyperplastic mesothelial cells in lymph nodes: Report of six cases of a benign process

    that can simulate metastatic involvement by mesothelioma or carcinoma. Hum Pathol 1998;29:339-46. Attanoos RL, Biggs AR. Pathology of malignant mesothelioma. Histopathology 1997;30:403-418.

    Battifora H, McCaughey WTE. Tumors of the serosal membranes. Atlas of Tumor Pathology. Third

    Series, Fascicle 15. AFIP, Washington, DC, 1994.

    Brockstedt U, Gulyas M, Dobra K, Dejmek A, Hjerpe A. An optimized battery of eight antibodies that can

    distinguish most cases of epithelial mesothelioma from adenocarcinoma. Am J Clin Pathol

    2000;114:203-9. ndChurg A, Green FHY. Pathology of Occupational Lung Disease. 2 Ed. Williams and Wilkins, Baltimore,

    1998.

    Churg A, Roggli V, Colby TV, and the US Canadian Mesothelioma Panel. The separation of benign and

    malignant mesothelioma proliferations. Am J Surg Pathol 2000;24:1183-1200. Crotty TB, et al. Localized malignant mesothelioma. Am J Surg Pathol 1994;18:357-63.

    Cugell DW, Kamp DW. Asbestos and the pleura: a review. Chest 2004;125:1103-1117.

    Cury PM, Butcher DN, Fisher C, Corrin B, Nicholson AG. Value of the mesothelium-associated

    antibodies thrombomodulin, cytokeratin 5/6, calretinin, and CD44H in distinguishing epithelioid

    pleural mesothelioma from adenocarcinoma metastatic to the pleura. Mod Pathol 2000;13:107-112. Dejmek A, Hjerpe A. The combination of CEA, EMA, and BerEp4 and hyaluronan analysis specifically

    identifies 79% of all histologically verified mesotheliomas causing an effusion. Diagn Cytopathol.

    2005;32:160-6.

    Doglioni C, Dei Tos AP, Laurino L, Iuzzolino P, Chiarelli C, Celio MR, Viale G. Calretinin: A novel

    immunocytochemical marker for mesothelioma. Am J Surg Pathol 1996;20:1037-46. Hillerdal G. Malignant mesothelioma 1982: Review of 4710 published cases. Br J Dis Chest

    1983;77:321-324.

    Khalidi HS, Medeiros J, Battifora H. Lymphohistiocytoid mesothelioma. Am J Clin Pathol 2000;113:649-

    54.

    Koss M, Travis W, Moran C, Hochholzer L. Pseudomesotheliomatous adenocarcinoma: A reappraisal.

    Sem Diagn Pathol 1992;9:117-23.

     7

Livasy CA, Tishko DJ, Maygarden SJ. Miliary pulmonary metastases from a clinically occult pleural

    mesothelioma. Ann Diagn Pathol 2003;7:249-253.

    Mangano WE, et al. The diagnosis of desmoplastic malignant mesotheliomas and its distinction from

    fibrous pleurisy. Am J Clin Pathol 1998; 110: 191-9.

    Mark EJ, Shin DH. Diffuse malignant mesothelioma of the pleura: a clinicopathological study of six

    patients with a prolonged symptom-free interval or extended survival after biopsy and a review of the

    literature of long-term survival. Virchows Archiv A Pathol Anat 1993;422:445-451. O'Byrne KJ, Edwards JG, Waller DA. Clinico-pathological and biological prognostic factors in pleural

    malignant mesothelioma. Lung Cancer. 2004;45 Suppl 1:S45-8.

    Ordonez NG. Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the

    pleura from lung adenocarcinoma. Am J Surg Pathol 1998;22:1215-21. Ordonez NG. Value of calretinin immunostaining in differentiating epithelial mesothelioma from lung

    adenocarcinoma. Mod Pathol 1998;11:929-33.

    Ordonez NG. The immunohistochemical diagnosis of epithelial mesothelioma. Hum Pathol 1999;30:313-

    23.

    Ordonez NG. Epithelial mesothelioma with deciduoid features. Report of four cases. Am J Surg Pathol

    2000;24: 816-23.

    Ordonez NG. Immunohistochemical diagnosis of epithelioid mesotheliomas: a critical review of old

    markers, new markers. Hum Pathol 2002;33:953-967.

    Ordonez NG. The immunohistochemical diagnosis of mesothelioma. A comparative study of epithelioid

    mesothelioma and lung adenocarcinoma. Am J Surg Pathol 2003;27:1031-1051. Ordonez NG. Mesothelioma with clear cell features: an ultrastructural and

    immunohistochemical study of 20 cases. Hum Pathol. 2005;36:465-73. Ordonez NG. D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of

    epithelioid malignant mesothelioma. Hum Pathol. 2005;36:372-80. Ordonez NG. The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing

    between peritoneal mesotheliomas and serous carcinomas: a comparative estudy. Mod Pathol

    2006;19:34-39.

    Parkash V, Vidwans M, Carter D. Benign mesothelial cells in mediastinal lymph nodes. Am J Surg Pathol

    1999; 23:1264-9.

    Roggli VL, Greenberg SD, Pratt PC. Pathology of Asbestos-Associated Diseases. Little Brown, Boston,

    1992.

    Rossi G, Cavazza A, Turrini E, Costantini M, Casali C, Morandi U, an dDallari R. Exclusive

    intrapulmonary lepidic growth of a malignant pleural mesothelioma presenting with pneumothorax and

    involving the peritoneum. International Journal of Surgical Pathology 2006;14:234-237. Sosolik RC, McGaughy VR, DeYoung BR. Anti-MOC-31: a potential addition to the pulmonary

    adenocarcinoma versus mesothelioma immunohistochemistry panel. Mod Pathol 1997;10:716-19. Sussman J, Rosai J. Lymph node metastasis as the initial manifestation of malignant mesothelioma:

    Report of six cases. Am J Surg Pathol 1990;14;819-28.

    Travis WD, Brambilla E, Harris CC, Muller-Hermelink HK, Ed: World Health Organization Classification

    of Tumours, Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart, IARC, Lyon

    (in press).

    Wick MR, Mills SE. Mesothelial proliferations. Am J Clin Pathol 2000;113:619-22.

    Yao DX, Shia J, Erlandson RA, Klimstra DS. Lymphohistiocytoid mesothelioma: a clinical,

    immunohistochemical and ultrastructural study of four cases and literature review. Ultrastruct Pathol.

    2004;28:213-28.

    Yaziji H, Battifora H, Barry TS, Hwang HC, Bacchi CE, McIntosh MW, Kussick SJ, and Gown AM.

    Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma:

    identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity.

    Mod Pathol 2006;19:514-523.

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