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Pleura ...

Protocol for the Examination of Specimens from Patients

    with Malignant Pleural Mesothelioma

Based on AJCC/UICC TNM, 7th edition

    Protocol web posting date: October 2009

    Protocol effective date: January 2010


    • Resection


    Kelly J. Butnor, MD, FCAP*

    Department of Pathology and Laboratory Medicine, Fletcher Allen Health Care/University

    of Vermont, Burlington, Vermont

    Mary Beth Beasley, MD, FCAP

     Department of Pathology, Mt. Sinai Medical Center, New York, New York

    Philip T. Cagle, MD, FCAP

     Department of Pathology, The Methodist Hospital, Houston, Texas

    Steven M. Grunberg, MD

    Department of Hematology/Oncology, Fletcher Allen Health Care/University of Vermont,

    Burlington, Vermont

    Alberto Marchevsky, MD, FCAP

    Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California Nader T. Okby, MD, FCAP

     Orange Pathology Associates, Middletown, New York

    Victor L. Roggli, MD, FCAP

    Department of Pathology, Duke University Medical Center, Durham, North Carolina Saul Suster, MD, FCAP

    Department of Pathology, The Medical College of Wisconsin, Milwaukee, Wisconsin Henry D. Tazelaar, MD, FCAP

    Department of Laboratory Medicine and Pathology, Mayo Clinic Scottsdale, Scottsdale,


    For the Members of the Cancer Committee, College of American Pathologists

*denotes the primary author. All other contributing authors are listed alphabetically.

Previous lead contributors: Gerald Nash, MD; Christopher N. Otis, MD; Andrew Folpe, MD;

    Mahul Amin, MD

Copyright 2009. College of American Pathologists. All rights reserved.

CAP Approved Thorax • Pleural Mesothelioma

    Surgical Pathology Cancer Case Summary (Checklist)

Protocol web posting date: October 2009

Protocol effective date: January 2010

PLEURA: Resection

    Select a single response unless otherwise indicated.


    ___ Pleura

    ___ Other (specify): ____________________________ ___ Not specified


    ___ Pleural decortication

    ___ Pleurectomy

    ___ Extrapleural pneumonectomy

    ___ Other (specify): ____________________________ ___ Not specified

Specimen Integrity

    ___ Intact

    ___ Disrupted

    ___ Indeterminate

Specimen Laterality

    ___ Right

    ___ Left

    ___ Not specified

Tumor Site (select all that apply)

    ___ Parietal pleura

    ___ Visceral pleura

    ___ Diaphragm

    ___ Other (specify): ____________________________ ___ Not specified

*Tumor Size (for localized tumors only)

*Greatest dimension: ___ cm

    *Additional dimensions: ___ x ___ cm

    *___ Cannot be determined (see Comment)

Tumor Focality (Note A)

    ___ Localized

    ___ Diffuse

    * Data elements with asterisks are not required. However, these elements may be 2 clinically important but are not yet validated or regularly used in patient management.

CAP Approved Thorax • Pleural Mesothelioma

    ___ Cannot be determined

Histologic Type (Note B)

    ___ Epithelioid mesothelioma

    ___ Sarcomatoid mesothelioma

    ___ Biphasic mesothelioma

    ___ Desmoplastic mesothelioma

    ___ Other (specify): ____________________________

Tumor Extension (select all that apply) (Note C)

    ___ Parietal pleura without involvement of ipsilateral visceral pleura ___ Parietal pleura with focal involvement of ipsilateral visceral pleura ___ Confluent visceral pleural tumor (including fissure) ___ Into but not through diaphragm

    ___ Lung parenchyma

    ___ Endothoracic fascia

    ___ Into mediastinal fat

    ___ Solitary focus invading soft tissue of the chest wall ___ Diffuse or multiple foci invading soft tissue of chest wall ___ Into but not through the pericardium

    ___ Rib(s)

    ___ Mediastinal organ(s) (specify): _________________ ___ Other (specify): ____________________________

Margins (Note D)

    ___ Not applicable

    ___ Cannot be assessed

    ___ Margins negative for mesothelioma

    ___ Margin(s) involved by mesothelioma

     Specify margin(s): ____________________________

Treatment Effect (Note E)

    ___ Not applicable

    ___ Cannot be determined

    ___ Greater than 50% residual viable tumor

    ___ Less than 50% residual viable tumor

Pathologic Staging (pTNM) (Note F)

TNM Descriptors (required only if applicable) (select all that apply)

    ___ m (multiple primary tumors)

    ___ r (recurrent)

    ___ y (post-treatment)

* Data elements with asterisks are not required. However, these elements may be 3 clinically important but are not yet validated or regularly used in patient management.

CAP Approved Thorax • Pleural Mesothelioma

    Primary Tumor (pT) ___ pTX: Primary tumor cannot be assessed

    ___ pT0: No evidence of primary tumor

    ___ pT1a: Tumor limited to ipsilateral parietal pleura with or without mediastinal or

    diaphragmatic pleural involvement. No involvement of the visceral pleura ___ pT1b: Tumor involves ipsilateral parietal pleura with or without mediastinal or

    diaphragmatic pleural involvement. Tumor also involving the visceral pleura ___ pT2: Tumor involves each of the ipsilateral pleural surfaces (parietal, mediastinal,

    diaphragmatic, and visceral pleura) with at least 1 of the following features:

    involvement of diaphragmatic muscle, extension of tumor from visceral pleura

    into the underlying pulmonary parenchyma

    ___ pT3: Locally advanced but potentially resectable tumor that involves all of the

    ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral

    pleura), with at least 1 of the following features: involvement of the

    endothoracic fascia, extension into mediastinal fat, solitary completely

    resectable focus of tumor extending into the soft tissues of the chest wall,

    nontransmural involvement of the pericardium ___ pT4: Locally advanced technically unresectable tumor involving all of the ipsilateral

    pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura),

    with at least 1 of the following features: diffuse extension or multifocal masses

    of tumor in the chest wall with or without associated rib destruction, direct

    transdiaphragmatic extension to the peritoneum, direct extension to the

    contralateral pleura, direct extension to mediastinal organs, direct extension

    into the spine, extension through the internal surface of the pericardium with

    or without a pericardial effusion, tumor involving the myocardium

Regional Lymph Nodes (pN)

    ___ pNX: Regional lymph nodes cannot be assessed

    ___ pN0: No regional lymph node metastases

    ___ pN1: Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes

    ___ pN2: Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes

    including the ipsilateral internal mammary and peridiaphragmatic nodes ___ pN3: Metastases in the contralateral mediastinal, contralateral internal mammary,

    ipsilateral or contralateral supraclavicular lymph nodes Specify: Number examined: ___

     Number involved: ___

     ___ Number cannot be determined

    Distant Metastasis (pM) ___ Not applicable

    ___ pM1: Distant metastasis

     *Specify site(s), if known: ____________________________

    * Data elements with asterisks are not required. However, these elements may be 4 clinically important but are not yet validated or regularly used in patient management.

CAP Approved Thorax • Pleural Mesothelioma

*Additional Pathologic Findings (select all that apply)

    *___ None identified

    *___ Asbestos bodies

    *___ Pleural plaque

    *___ Pulmonary interstitial fibrosis

    *___ Inflammation (type): __________________________

    *___ Other (specify): ____________________

*Ancillary Studies (Note G)

    *___ Immunohistochemical stain(s) result(s) (specify stains): _________________ *___ Histochemical stain(s) result(s) (specify stains): __________________ *___ Electron microscopy results: _____________________

    *___ Other (specify): ___________________

*Clinical History

    *___ Neoadjuvant therapy

    *___ Other (specify): ___________________


    * Data elements with asterisks are not required. However, these elements may be 5 clinically important but are not yet validated or regularly used in patient management.

Background Documentation Thorax • Pleural Mesothelioma

    Explanatory Notes

A. Tumor Focality

    The majority of malignant mesotheliomas exhibit diffuse growth and may take the form of multiple small nodules, plaque-like masses, or confluent rindlike sheets. However, a small proportion of malignant mesotheliomas are sharply circumscribed. These are designated by the term localized malignant mesothelioma. Localized malignant 1mesotheliomas appear to have a far better prognosis than their diffuse counterpart.

B. Histologic Type

    For consistency in reporting, the histologic classification published by the World Health 2Organization (WHO) is recommended. However, other classifications have been

    proposed, such as the detailed histologic classification of malignant mesothelioma by 3 Hammar. In these other schema, epithelioid mesothelioma is sometimes referred to as

    epithelial, sarcomatoid mesothelioma is also referred to as fibrous, biphasic mesothelioma is also referred to as mixed, and desmoplastic mesothelioma is considered a variant of sarcomatoid mesothelioma. As defined by the WHO, at least 50% of a tumor should be composed of dense collagenized tissue separated by atypical cells arranged in a storiform or “patternless” pattern in order to designate it as desmoplastic mesothelioma, whereas in biphasic mesotheliomas, which contain both epithelioid and 2 sarcomatoid patterns, each component should represent at least 10% of the tumor.

C. Tumor Extension

    Invasion of the endothoracic fascia is categorized as T3. The endothoracic fascia is located external to the parietal pleura beneath the muscles and ribs of the chest wall. Determining the presence or absence of endothoracic fascial invasion can be difficult on pathologic examination, because the endothoracic fascia lacks distinctive gross and histologic features. Assessment of the intactness of the endothoracic fascia is best made by the surgeon at the time of operation.

    Although the American Joint Committee on Cancer (AJCC) designates a solitary focus of tumor invading the soft tissues of the chest wall as T3, it does not specifically delineate the elements that constitute the chest wall. According to the surgical literature, the constituents of the chest wall are the ribs, intercostal muscles, and associated supporting connective tissues, the latter two of which can be inferred to represent the chest wall soft tissues. Note that this definition does not include the layer of adipose tissue, which is sometimes referred to as extrapleural fat, that lies between the chest wall and the parietal pleura. For specimens that incorporate chest wall structures, it is recommended that the surgeon designate the location(s) of such structures to ensure optimal pathologic assessment.

    Although T4 describes locally advanced, technically unresectable tumor, radical extrapleural pneumonectomy specimens may occasionally incorporate structures directly invaded by tumor that fall under the T4 designation. These should be specified under “other” and include tumor extension to the following:

    - Peritoneum (through the diaphragm)

    - Contralateral pleura


Background Documentation Thorax • Pleural Mesothelioma

    - Spine

    - Internal surface of the pericardium

    - Myocardium

    - Brachial plexus

D. Margins

    Because extrapleural pneumonectomy specimens are obtained by dissection of tumor from the thorax with en bloc resection of the lung, pleura, pericardium, and diaphragm, the entire surface of the extrapleural pneumonectomy represents the surgical margin (unless otherwise specified by the operating surgeon).

E. Treatment Effect

    Induction chemotherapy before extrapleural pneumonectomy is being used in some 4 Although a formal scheme centers for locally advanced malignant pleural mesothelioma.for grading histologic response to neoadjuvant treatment has not been established, in applicable specimens, a generalized estimate of the amount of residual viable tumor should be reported.

F. Pathologic Staging

    This protocol recommends the AJCC and the International Union Against Cancer (UICC) 5,6TNM staging system shown below. The AJCC has adopted the staging system 7 proposed by the International Mesothelioma Interest Group (IMIG) in 1995.

    By AJCC/UICC convention, the designation “T” refers to a primary tumor that has not been previously treated. The symbol “p” refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible.

    Pathologic staging is usually performed after attempted surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically infeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer.

Stage Groupings

    Stage I T1 N0 M0

    Stage IA T1a N0 M0

    Stage IB T1b N0 M0

    Stage II T2 N0 M0

    Stage III T1,T2 N1 M0

     T1,T2 N2 M0

     T3 N0,N1,N2 M0


Background Documentation Thorax • Pleural Mesothelioma

    Stage IV T4 Any N M0

     Any T N3 M0

     Any T Any N M1

    TNM Descriptors

    For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they

    indicate cases needing separate analysis.

The “m” suffix indicates the presence of multiple primary tumors in a single site and is

    recorded in parentheses: pT(m)NM. In actuality, this is not a descriptor that readily

    applies to diffuse malignant pleural mesothelioma, which often exhibits a multinodular

    growth pattern but is best considered a single tumor for staging purposes.

The “y” prefix indicates those cases in which classification is performed during or after

    initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both

    chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a “y”

    prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time

    of that examination. The “y” categorization is not an estimate of tumor before

    multimodality therapy (ie, before initiation of neoadjuvant therapy).

The “r” prefix indicates a recurrent tumor when staged after a documented disease-free

    interval and is identified by the “r” prefix: rTNM.

Additional Descriptors

Residual Tumor (R)

    Tumor remaining in a patient after therapy with curative intent (eg, surgical resection for

    cure) is categorized by a system known as R classification, shown below.

RX Presence of residual tumor cannot be assessed

    R0 No residual tumor

    R1 Microscopic residual tumor

    R2 Macroscopic residual tumor

For the surgeon, the R classification may be useful to indicate the known or assumed

    status of the completeness of a surgical excision. For the pathologist, the R classification

    is relevant to the status of the margins of a surgical resection specimen. That is, tumor

    involving the resection margin on pathologic examination may be assumed to correspond

    to residual tumor in the patient and may be classified as macroscopic or microscopic

    according to the findings at the specimen margin(s).

Other staging systems for malignant pleural mesothelioma, such as the Brigham Staging

    System, as shown below, have also been devised.8 Use of this protocol does not

    preclude reporting of tumor stage as determined by other systems concurrent with the

    TNM designation.


Background Documentation Thorax • Pleural Mesothelioma

    8 Brigham Staging System for Malignant Pleural MesotheliomaStage Definition

    I Disease confined to within capsule of the parietal pleura: ipsilateral pleural,

    lung, pericardium, diaphragm, or chest wall disease limited to previous biopsy


    II All of stage I with positive intrathoracic (N1 or N2) nodes

    III Local extension of disease into chest wall or mediastinum, heart, or through

    diaphragm, peritoneum; with or without extrathoracic or contralateral (N3)

    lymph node involvement

    IV Distant metastatic disease

According to the Brigham Staging System, stage I represents resectable patients with 8negative nodes, whereas stage II patients are resectable but have positive nodal status.

G. Ancillary Studies

    Histochemistry, immunohistochemistry, and electron microscopy have become

    important adjuncts to routine microscopic evaluation in the diagnosis and classification of

    malignant mesothelioma. These methods are helpful in distinguishing malignant

    epithelioid mesothelioma from metastatic adenocarcinoma and sarcomatoid

    mesothelioma from metastatic or primary pleural sarcomas, but they are less helpful in

    distinguishing malignant mesothelioma from reactive mesothelial hyperplasia. Because

    there is no uniformly sensitive and specific immunohistochemical marker for malignant

    mesothelioma, a panel of stains is generally warranted. The College of American

    Pathologists (CAP) does not endorse a specific panel of markers for the evaluation of

    malignant mesothelioma. The International Mesothelioma Panel recommends a broad-

    spectrum cytokeratin, at least two mesothelial-associated markers, such as calretinin,

    cytokeratins 5/6, and D2-40, and at least two markers that are typically positive in

    pulmonary adenocarcinoma and negative in pleural malignant mesothelioma, such as

    9,10TTF-1, CEA, Ber-Ep4, Leu-M1, and MOC-31.


    1. Allen TC, Cagle PT, Churg AM, et al. Localized malignant mesothelioma. Am J

    Surg Pathol. 2005;29:866-873.

    2. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, eds. World Health

    Organization Classification of Tumours: Pathology and Genetics of Tumours of the

    Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004. nd3. Hammar S. Pleural diseases. In: Dail D, Hammar S, eds. Pulmonary Pathology. 2

    ed. New York, NY: Springer-Verlag; 1994:1494.

    4. Flores RM, Krug LM, Rosenzweig KE, et al. Induction chemotherapy, extrapleural

    pneumonectomy, and postoperative high-dose radiotherapy for locally advanced

    malignant pleural mesothelioma: a phase II trial. J Thorac Oncol. 2006;1:289-295. 5. Pleural mesothelioma. In: Edge SD, Byrd DR, Carducci MA, Compton CC, eds.

    AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009.

    6. Sobin LH, Gospodarowicz M, Wittekind Ch, eds. UICC TNM Classification of

    Malignant Tumours. 7th ed. New York, NY: Wiley-Liss; 2009.

    7. Rusch VW. A proposed new international TNM staging system for malignant pleural

    mesothelioma from the International Mesothelioma Interest Group. Chest.



    Background Documentation Thorax • Pleural Mesothelioma 8. Sugarbaker DJ, Strauss GM, Lynch TJ. Node status has prognostic significance in

    the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol.


    9. Galateau-Salle F, ed. Pathology of Malignant Mesothelioma. London: Springer-

    Verlag; 2006.

    th10. Churg A, Cagle PT, Roggli VL, eds. Tumors of the Serosal Membranes. AFIP Atlas series, fascicle 3. Washington, DC: American Registry of of Tumor Pathology, 4Pathology/Armed Forces Institute of Pathology; 2006.


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