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Protocol for the examination of specimens from patients with primary non-small cell carcinoma, small cell carcinoma, or carcinoid tumor of the lung.

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the "Surgical Pathology Cancer Case Summary (Checklist)" portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.

The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs.

Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.


The seventh edition TNM staging system for lung of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) is recommended.


Lung: Resection

Select a Single Response Unless Otherwise Indicated

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


-- Lung

-- Lobe(s) of lung (specify): --

-- Bronchus (specify): --

-- Other (specify): --

-- Not specified


-- Major airway resection

-- Wedge resection

-- Segmentectomy

-- Lobectomy

-- Bilobectomy

-- Pneumonectomy

-- Other (specify): --

-- Not specified

Specimen Integrity

-- Intact

-- Disrupted

-- Indeterminate

Specimen Laterality

-- Right

-- Left

-- Not specified

Tumor Site (select all that apply)

-- Upper lobe

-- Middle lobe

-- Lower lobe

-- Other(s) (specify): --

-- Not specified

Tumor Size

Greatest dimension: -- cm

* Additional dimensions: -- x -- cm

-- Cannot be determined

Tumor Focality (note A)

-- Unifocal

-- Separate tumor nodules in same lobe

-- Separate tumor nodules in different lobes (specify sites): --

-- Synchronous carcinomas (specify sites):--

-- Cannot be determined

Histologic Type (note B)

-- Carcinoma, type cannot be determined

-- Non-small cell carcinoma, subtype cannot be determined

-- Small cell carcinoma

-- Combined small cell carcinoma (small cell carcinoma and non-small cell component) (specify type of non-small cell carcinoma component: --)

-- Squamous cell carcinoma

-- Squamous cell carcinoma, papillary variant

-- Squamous cell carcinoma, clear cell variant

-- Squamous cell carcinoma, small cell variant

-- Squamous cell carcinoma, basaloid variant

-- Adenocarcinoma

-- Adenocarcinoma, mixed subtype

-- Acinar adenocarcinoma

-- Papillary adenocarcinoma

-- Bronchioloalveolar carcinoma

-- Bronchioloalveolar carcinoma, nonmucinous

-- Bronchioloalveolar carcinoma, mucinous

-- Bronchioloalveolar carcinoma, mixed nonmucinous and mucinous

-- Solid adenocarcinoma

-- Fetal adenocarcinoma

-- Mucinous (colloid) adenocarcinoma

-- Mucinous cystadenocarcinoma

-- Signet ring adenocarcinoma

-- Clear cell adenocarcinoma

-- Large cell carcinoma

-- Large cell neuroendocrine carcinoma

-- Combined large cell neuroendocrine carcinoma (specify type of other non-small cell carcinoma component: --)

-- Basaloid carcinoma

-- Lymphoepithelioma-like carcinoma

-- Clear cell carcinoma

-- Large cell carcinoma with rhabdoid phenotype

-- Adenosquamous carcinoma

-- Sarcomatoid carcinoma

-- Pleomorphic carcinoma

-- Spindle cell carcinoma

-- Giant cell carcinoma

-- Carcinosarcoma

-- Pulmonary blastoma

-- Typical carcinoid tumor

-- Atypical carcinoid tumor

-- Mucoepidermoid carcinoma

-- Adenoid cystic carcinoma

-- Epithelial-myoepithelial carcinoma

-- Other (specify):--

Histologic Grade (note C)

-- Not applicable

-- GX: Cannot be assessed

-- G1: Well differentiated

-- G2: Moderately differentiated

-- G3: Poorly differentiated

-- G4: Undifferentiated

-- Other (specify):--

Visceral Pleura Invasion (note D)

-- Not identified

-- Present

-- Indeterminate

Tumor Extension (select all that apply) (note E)

-- Not applicable

-- Not identified

-- Superficial spreading tumor with invasive component limited to bronchial wall

-- Tumor involves main bronchus 2 cm or more distal to the carina

-- Parietal pleura

-- Chest wall

* Specify involved structure(s):--

-- Diaphragm

-- Mediastinal pleura

-- Phrenic nerve

-- Parietal pericardium

-- Tumor in the main bronchus less than 2 cm distal to the carina but does not involve the carina

-- Mediastinum

* Specify involved structure(s):--

-- Heart

-- Great vessels

-- Trachea

-- Esophagus

-- Vertebral body

-- Carina

-- Other (specify):--

Margins (select all that apply) (note F)

Bronchial Margin

-- Not applicable

-- Cannot be assessed

-- Uninvolved by invasive carcinoma

-- Involved by invasive carcinoma

-- Squamous cell carcinoma in situ (CIS) present at

bronchial margin

-- Squamous cell carcinoma in situ (CIS) not identified at bronchial margin

Vascular Margin

-- Not applicable

-- Cannot be assessed

-- Uninvolved by invasive carcinoma

-- Involved by invasive carcinoma

Parenchymal Margin

-- Not applicable

-- Cannot be assessed

-- Uninvolved by invasive carcinoma

-- Involved by invasive carcinoma

Parietal Pleural Margin

-- Not applicable

-- Cannot be assessed

-- Uninvolved by invasive carcinoma

-- Involved by invasive carcinoma

Chest Wall Margin

-- Not applicable

-- Cannot be assessed

-- Uninvolved by invasive carcinoma

-- Involved by invasive carcinoma

Other Attached Tissue Margin (specify):--

-- Not applicable

-- Cannot be assessed

-- Uninvolved by invasive carcinoma

-- Involved by invasive carcinoma

If all margins uninvolved by invasive carcinoma:

Distance of invasive carcinoma from closest margin:-- mm Specify margin:--

Treatment Effect (note G)

-- Not applicable

-- Cannot be determined

-- Greater than 10% residual viable tumor

-- Less than 10% residual viable tumor

* Tumor-Associated Atelectasis or Obstructive Pneumonitis (note H)

*-- Extends to the hilar region but does not involve entire lung

*-- Involves entire lung

Lymph-Vascular Invasion (note I)

-- Not identified

-- Present

-- Indeterminate

* Lymph Nodes (note J)

* Extranodal extension

*-- Not identified

*-- Present

Pathologic Staging (pTNM) (note J)

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

-- m (multiple primary tumors)

-- r (recurrent)

-- y (posttreatment)

Primary Tumor (pT)

-- pTX: Cannot be assessed, or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

-- pT0: No evidence of primary tumor

-- pTis: Carcinoma in situ

-- pT1a: Tumor 2 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus); or Superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus

-- pT1b: Tumor greater than 2 cm, but 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus)

-- pT2a: Tumor greater than 3 cm, but 5 cm or less in greatest dimension surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus); or

Tumor 5 cm or less in greatest dimension with any of the following features of extent: involves main bronchus, 2 cm or more distal to the carina; invades the visceral pleura; associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

-- pT2b: Tumor greater than 5 cm, but 7 cm or less in greatest dimension

-- pT3: Tumor greater than 7 cm in greatest dimension; or

Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium; or

Tumor of any size in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or

Tumor of any size associated with atelectasis or obstructive pneumonitis of the entire lung; or

Tumors of any size with separate tumor nodule(s) in same lobe

-- pT4: Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; or

Tumor of any size with separate tumor nodule(s) in a different lobe of ipsilateral lung (note A)

Regional Lymph Nodes (pN)

-- pNX: Cannot be assessed

-- pN0: No regional lymph node metastasis

-- pN1: Metastasis in ipsilateral peribronchial and/ or ipsilateral hilar lymph nodes, and intrapulmonary nodes, including involvement by direct extension

-- pN2: Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

-- pN3: Metastasis in contralateral mediastinal, con tralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)


Number examined--

Number involved--

Number cannot be determined (note J)

If lymph node(s) involved, specify involved nodal station(s):--

Distant Metastasis (pM)

-- Not applicable

-- pM1a: Separate tumor nodule(s) in contralateral lung; tumor with pleural nodules or malignant pleural (or pericardial) effusion (note A)

-- pM1b: Distant metastases outside the lung/pleura

* Specify site(s), if known:--

* Additional Pathologic Findings (select all that apply)

*-- None identified

*-- Atypical adenomatous hyperplasia

*-- Squamous dysplasia

*-- Metaplasia (specify type):--

*-- Diffuse neuroendocrine hyperplasia

*-- Inflammation (specify type):--

*-- Emphysema

*-- Other (specify):--

* Ancillary Studies (note K)

*-- Epidermal growth factor receptor (EGFR) analysis results (specify method):--

*-- K-ras mutational analysis results:--

*-- Other (specify):--

* Comment(s):--


A: Tumor Focality.--There is evidence that patients with multiple tumor nodules of similar histology in the same lobe have markedly better survival than patients with tumors that meet the AJCC, 7th edition, TNM classification criteria for T4 (ie, invasion of mediastinal structures), and, in fact, their survival is similar to patients categorized as T3 in the AJCC, 6th edition. For this reason, the presence of grossly recognizable, multiple tumor nodules of similar histology in the same lobe are to be categorized as T3. (1) Survival among patients with multiple tumor nodule(s) of similar histology in ipsilateral separate lobes is similar to patients classified as T4, and, therefore, such tumors are to be categorized as T4. (1,2) However, if separate tumors of similar histology in different segments, lobes, or lungs show an origin from CIS, no carcinoma in lymphatics common to both tumors, and no extrapulmonary metastases at the time of diagnosis, they should be categorized as synchronous primary carcinomas and staged independently. (3) Physically distinct and separate tumors of different histologic types are generally considered separate, synchronous primaries and are staged separately. (1-3) In such cases, the highest T category is reported, followed in parentheses by multiplicity or number of tumors (eg, T2(m) or T2(5)).

B: Histologic Type.--For consistency in reporting, the histologic classification published by the World Health Organization (WHO) for tumors of the lung, including carcinoids, is recommended. (4,5) The histologic types are listed in this protocol in the order in which they appear in the WHO classification. This protocol does not preclude the use of other systems of classification of histologic types. (6)

The diagnosis of bronchioloalveolar carcinoma requires exclusion of stromal, vascular, and pleural invasion--a requirement that demands that the tumor be evaluated histologically in its entirety. (4) It is, therefore, recommended that a definitive diagnosis of bronchioloalveolar adenocarcinoma not be made on specimens in which the tumor is incompletely represented.

C: Histopathologic Grade (G).--To standardize histologic grading, the following grading system is recommended (4):

* Grade X (GX): Cannot be assessed

* Grade 1 (G1): Well differentiated

* Grade 2 (G2): Moderately differentiated

* Grade 3 (G3): Poorly differentiated

* Grade 4 (G4): Undifferentiated

Undifferentiated (grade 4) is reserved for carcinomas that show minimal or no specific differentiation in routine histologic preparations. According to the definition of grading, a squamous cell carcinoma or an adenocarcinoma arising in the lung can be classified only as grade 1, grade 2, or grade 3 because, by definition, these tumors show squamous or glandular differentiation, respectively. If there are variations in the differentiation of a tumor, the least favorable variation is recorded as the grade, using grades 1 through 3. By definition, small cell and large cell carcinomas of the lung are assigned grade 4 because they are high-grade tumors with poor prognosis.

D: Visceral Pleural Invasion.--The presence of visceral pleural invasion by tumors smaller than 3 cm changes the T category from pT1 to pT2 and increases the stage from IA to IB in patients with N0, M0 disease, or from stage IIA to IIB in patients with N1, M0 disease (M0 is defined as no distant metastasis). (1) Studies have shown that tumors smaller than 3 cm that penetrate beyond the elastic layer of the visceral pleura behave similarly to similar-sized tumors that extend to the visceral pleural surface. (7,8) Visceral pleural invasion should, therefore, be considered present not only in tumors that extend to the visceral pleural surface, but also in tumors that penetrate beyond the elastic layer of the visceral pleura (Figure). (7-9) Elastic stains may aid in the assessment of visceral pleural invasion. (7,10)

Based on available data, a tumor with local invasion of another ipsilateral lobe without tumor on the visceral pleural surface should be classified as T2. (10)

Pleural tumor foci that are separate from direct pleural invasion should be categorized as M1a. (2)

E: Tumor Extension.--According to the AJCC, direct invasion of the parietal pleura is categorized as T3, as is direct invasion of the chest wall. (11) Although not required, specifying the chest wall structures directly invaded by tumor (eg, intercostal muscle[s], rib[s], pectoralis muscle, latissimus muscle, serratus muscle) may facilitate patient management.

In addition to containing the heart and great vessels, the mediastinum includes the thymus and other structures between the lungs; direct invasion of any of which is considered T4.

Occasionally, lung cancer specimens consist of en bloc resections that incorporate other structures directly invaded by tumor that are not referred to in AJCC pathologic staging but are discussed under the clinical staging section of the AJCC manual.11 The T categories that correspond to direct invasion of these structures are summarized in the collaborative staging manual. (12) These should be reported under the "Other" designation and include the following:

* Tumors with direct invasion of the phrenic nerve or brachial plexus (inferior branches or not otherwise specified) from the superior sulcus are categorized as T3.

* Superior sulcus tumors with encasement of subclavian vessels or unequivocal involvement of the superior branches of the brachial plexus are categorized as T4.

* Direct invasion of the visceral pericardium or cervical sympathetic, recurrent laryngeal, or vagus nerve(s) is considered T4.


F: Margins.--Surgical margins represent sites that have either been cut or bluntly dissected by the surgeon to resect the specimen. The presence of tumor at a surgical margin is an important finding because there is the potential for residual tumor remaining in the patient in the area surrounding a positive margin. Peripheral wedge resections contain a parenchymal margin, which is represented by the tissue at the staple line(s). Lobectomy and pneumonectomy specimens contain bronchial and vascular margins, and depending on the completeness of the interlobar fissures and other anatomic factors, may also contain parenchymal margins in the form of staple lines. En bloc resections in which extrapulmonary structures are part of the specimen contain additional margins (eg, parietal pleura, chest wall) that should be designated by the surgeon for appropriate handling. This includes cases in which the visceral pleura is adherent to the parietal pleura. Note that the visceral pleura is not a surgical margin.

G: Treatment Effect.--For patients who have received neoadjuvant chemotherapy and/or radiation therapy before surgical resection, quantifying the extent of therapy-induced tumor regression provides prognostically relevant information. (13) A "y" prefix is applied to the TNM classification in such cases (see note J).

H: Tumor Associated Atelectasis or Obstructive Pneumonitis.--Although the presence and extent of obstructive pneumonitis associated with tumor can sometimes be determined in pneumonectomy specimens, accurate assessment of tumor-associated atelectasis or obstructive pneumonitis typically requires integration of radiographic information. (14)

I: Vascular/Lymphatic Invasion.--There are data showing that lymphovascular invasion by a tumor may represent an unfavorable prognostic finding. (15) Angiolymphatic invasion does not change the pT and pN classifications or the TNM stage grouping.

J: TNM and Stage Grouping.--The TNM staging system of the AJCC and the UICC is recommended for nonsma (ll) cell lung cancer. (11,16) Small cell lung cancer has been more commonly classified according to a separate staging system as either "limited" or "extensive" disease, but based on analysis of the International Association for the Study of Lung Cancer (IASLC) database, TNM staging is also recommended for small cell lung cancer. (17,18) Carcinoid and atypical carcinoid tumors should also be classified according to the TNM staging system.

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 a 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 surgical resection of the primary tumor and 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 unfeasible) 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.

T Category Considerations

The uncommon, superficial spreading tumor, of any size, with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is classified as T1. (11)

Most pleural effusions with lung cancer are due to tumor. However, in a few patients, multiple cytopathologic examinations of pleural fluid are negative for tumor; the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the tumor should be classified as T1, T2, or T3. (11)

Although pneumonectomy specimens allow assessment of tumor involvement of a main bronchus, determining the distance to the carina, which is necessary to accurately assign a T category for centrally located tumors, typically requires consultation with the surgeon, bronchoscopist, or radiologist. (19)

A number of other T category considerations are addressed above (see notes A, D, E, and G).

N Category Considerations

Although extranodal extension of a positive mediastinal lymph node may represent an unfavorable prognostic finding, it does not change the pN classification or the TNM stage grouping. (20-23) Extranodal extension refers to the extension of metastatic intranodal tumor beyond the lymph node capsule into the surrounding tissue. Direct extension of a primary tumor into a nearby lymph node does not qualify as extranodal extension.

In certain situations, in particular, when lymph nodes are obtained by mediastinoscopy, it may not be possible to ascertain the actual number of nodes submitted for evaluation (unless it is specified by the surgeon) because the pieces of tissue submitted may represent multiple discrete nodes or multiple fragments of a single node. If nodal involvement is identified in this setting, the lymph node station(s) (see below) involved, if known, should be reported.

The anatomic classification of regional lymph nodes proposed by the IASLC is shown below, which reconciles differences between the Naruke (11) and Mountain/Dresler (24,25) lymph node maps.

N2 Nodes

Station 1.--Lower cervical, supraclavicular, and sternal notch nodes

Upper border--Lower margin of cricoid cartilage

Lower border--Clavicles bilaterally and, in the midline, the upper border of the manubrium; 1R designates right-sided nodes; 1L, left-sided nodes in this region

Station 2.--Upper paratracheal nodes

2R: Upper border--Apex of lung and pleural space

2R: Lower border--Intersection of caudal margin of the innominate vein with the trachea

2L: Upper border--Apex of the lung and pleural space

2L: Lower border--Superior border of the aortic arch

Station 3.--Prevascular and retrotracheal nodes: 3A, prevascular; 3P, retrotracheal

Station 4.--Lower paratracheal nodes:

4R: Includes right paratracheal nodes and pretracheal nodes extending to the left lateral border of trachea

Upper border--Lower border of origin of innominate artery

Lower border--Lower border of azygos vein

4L: Includes nodes to the left of the left lateral border of the trachea, medial to the ligamentum arteriosum

Upper border--Upper margin of the aortic arch

Lower border--Upper rim of the left main pulmonary artery

Station 5.--Subaortic nodes (aortopulmonary window):

Subaortic nodes are lateral to the ligamentum arteriosum

Upper border--The lower border of the aortic arch

Lower border--Upper rim of the left main pulmonary artery

Station 6.--Para-aortic nodes (ascending aorta or phrenic): Nodes lying anterior and lateral to the ascending aorta and the aortic arch

Upper border--A line tangential to the upper border of the aortic arch

Lower border--The lower border of the aortic arch

Station 7.--Subcarinal nodes

Upper border--The carina of the trachea

Lower border--The upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right

Station 8.--Paraesophageal nodes (below carina): Nodes lying adjacent to the wall of the esophagus and to the right or left of the midline, excluding subcarinal nodes

Upper border--The upper border of the lower lobe bronchus on the left; the lower border of the bronchus intermedius on the right

Lower border--The diaphragm

Station 9.--Pulmonary ligament nodes: Nodes lying within the pulmonary ligament

Upper border--The inferior pulmonary vein

Lower border--The diaphragm

N1 Nodes

Station 10.--Hilar nodes: Nodes immediately adjacent to the mainstem bronchus and hilar vessels including the proximal portions of the pulmonary veins and main pulmonary artery

Upper border--The lower rim of the azygos vein on the right; upper rim of the pulmonary artery on the left

Lower border--Interlobar region bilaterally

Station 11.--Interlobar nodes: Nodes lying between the origins of the lobar bronchi

Optional notations for subcategories of Station 11:

11s: Between the upper lobe bronchus and bronchus in termedius on the right

11i: Between the middle and lower lobe bronchi on the right

Station 12.--Lobar nodes: Nodes adjacent to the lobar bronchi

Station 13.--Segmental nodes: Nodes adjacent to the segmental bronchi

Station 14.--Subsegmental nodes: Nodes around the subsegmental bronchi

Isolated tumor cells (ITCs) are single tumor cells or small clusters of cells, not more than 0.2 mm in greatest dimension, detected on routine sections or, more commonly, by immunohistochemistry or molecular methods. Isolated tumor cells in lymph nodes or at distant sites should be classified as N0 or M0, respectively. (11)

The following classification of ITCs may be used:

pN0(i--) No regional lymph node metastasis histologically, negative morphological findings for ITC

pN0(i+) No regional lymph node metastasis histologically, positive morphological findings for ITC

pN0(mol--) No regional lymph node metastasis histologically, negative nonmorphologic findings for ITC

pN0(mol+) No regional lymph node metastasis histologically, positive nonmorphologic findings for ITC

TNM Descriptors

For identification of special cases of TNM or pTNM classifications, the "m" suffix and the "y" and "r" 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 (see note A).

The "y" prefix indicates those cases in which classification is performed during or following 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) (see note F).

The "r" prefix indicates a recurrent tumor when staged after a documented disease-free interval: rTNM.

K. Ancillary Studies.--The tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva, Genentech, South San Francisco, California) and gefitinib (Iressa, AstraZeneca, Wilmington, Delaware) exhibit activity in some advanced nonsmall cell lung cancers. Individuals most likely to benefit from these agents include never smokers, individuals of Asian ethnicity, women, patients with adenocarcinoma, and those whose tumors show EGFR gene amplification and/or somatic mutations in the kinase domain of EGFR. (25-28) Up to 20% of non-small cell carcinomas contain these EGFR mutations, and around 80% to 85% of patients with such mutations respond to TKI treatment. (24-25)

Methods that have been purported to predict responsiveness to treatment with TKIs include polymerase chain reaction-based EGFR mutational analysis and EGFR fluorescent in situ hybridization amplification. (26-29) The polymerase chain reaction method is designed to detect the most frequent EGFR mutations (exon 19 deletions and exon 21 L858R substitutions), which account for 85% to 90% of reported EGFR mutations. DNA is prepared from either frozen or formalin-fixed, paraffin-embedded tissue, and exons 18 through 21 of the tyrosine kinase domain of the EGFR gene are amplified and bidirectionally sequenced to identify mutations. Mutations are confirmed by repeat sequencing of the tumor sample. EGFR gene amplification by fluorescent in situ hybridization detects both gene amplification (>2.0 copies of EGFR as compared with a centromeric chromosome 7 control probe) and high polysomy ([greater than or equal to] 4 copies of EGFR per nucleus in >40% of nuclei).

Although immunohistochemical expression of EGFR is weakly correlated with increased EGFR copy number, neither EGFR or phosphorylated-EGFR immunoexpression correlate well with the presence of activating mutations.30 Based on current data, EGFR immunohistochemistry appears not to have a significant role in the selection of patients likely to respond to TKIs.

In contrast to EGFR mutations, mutations in the K-ras gene (KRAS) are strongly correlated with a substantial smoking history, an overall poor prognosis, and a lack of response to EGFR inhibitors. (31-32) Treating patients who have KRAS-mutated non-small cell lung cancer with EGFR TKIs may, in fact, be detrimental. (33) KRAS mutations, which are point mutations (most commonly affecting codon 12 and less often, codon 13), are present in about one-quarter of lung adenocarcinomas. As with EGFR mutation analysis, testing for KRAS mutations is, at present, considered an investigational technique for guiding TKI treatment decisions.

Accepted for publication June 2, 2009.


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From the Departments of Pathology and Laboratory Medicine (Dr Butnor) and Hematology/Oncology (Dr Grunberg), Fletcher Allen Health Care, University of Vermont, Burlington; the Department of Pathology, Mount Sinai Medical Center, New York, New York (Dr Beasley); the Department of Pathology, The Methodist Hospital, Houston, Texas (Dr Cagle); the Department of Radiation Oncology, Veterans Administration Ann Arbor Health Care System University of Michigan Ann Arbor (Dr Kong); the Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California (Dr Marchevsky); Orange Pathology Associates, Orange Regional Medical Center, Middletown, New York (Dr Okby); the Department of Pathology, Duke University Medical Center, Durham, North Carolina (Dr Roggli); the Department of Pathology, The Medical College of Wisconsin, Milwaukee (Dr Suster); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona (Dr Tazelaar); and the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York (Dr Travis).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Kelly J. Butnor, MD, Department of Pathology and Laboratory Medicine, Fletcher Allen Health Care, University of Vermont, 11 Colchester Ave, Burlington, VT 05401-1473 (e-mail: kelly.butnor@

Kelly J. Butnor, MD; Mary Beth Beasley, MD; Philip T. Cagle, MD; Steven M. Grunberg, MD; Feng-Ming Kong, MD, PhD, MPH; Alberto Marchevsky, MD; Nader T. Okby, MD; Victor L. Roggli, MD; Saul Suster, MD; Henry D. Tazelaar, MD; William D. Travis, MD; for the Members of the Cancer Committee, College of American Pathologists
TNM Stage Groupings

Stage IA     T1a       N0        M0
             T1b       N0        M0
Stage IB     T2a       N0        M0
Stage IIA    T1a       N1        M0
             T1b       N1        M0
             T2a       N1        M0
             T2b       N0        M0
Stage IIB    T2b       N1        M0
             T3        N0        M0
Stage IIIA   T1a       N2        M0
             T1b       N2        M0
             T2a       N2        M0
             T2b       N2        M0
             T3        N1-2      M0
             T4        N0-1      M0
Stage IIIB   T1a       N3        M0
             T1b       N3        M0
             T2a       N3        M0
             T2b       N3        M0
             T3        N3        M0
             T4        N2-3      M0
Stage IV     Any T     Any N     M1a or M1b
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Author:Butnor, Kelly J.; Beasley, Mary Beth; Cagle, Philip T.; Grunberg, Steven M.; Kong, Feng-Ming; Marche
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Oct 1, 2009
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