Staging system for small cell carcinoma of the lung
Small cell lung carcinomas (SCLC) account for 15-20% of patients with lung cancer [19, 20] . Patients with SCLC are stratified into two stages: limited stage disease (LD) with tumor confined to one hemithorax only and extensive stage disease (ED) with metastases in the contralateral chest or at distant sites. About 20-25% of patients with SCLC present with LD disease, which can be treated with curative intent with radiation therapy and systemic chemotherapy [19, 20, 21] . The role of surgery in these patients remains controversial [21]. In practice, pathologists are expected to diagnose SCLC and most patients are staged based on imaging studies. Therefore, this discussion will deal mostly with a description of the problems resulting from the pathologic staging of patients with NSCLC.

Differential diagnosis between SCLC and NSCLC
Pathologists can readily distinguish SCLC and its variant, SCLC, combined (with adenocarcinoma, squamous cell carcinoma or large cell carcinoma component) from NSCLC in over 90% of cases [22, 23, 24] . It is beyond the scope of this lecture to discuss this problem in detail but SCLC can be difficult to distinguish from the small cell variant of squamous cell carcinoma, adenoid cystic carcinoma, other neuroendocrine carcinomas of the lung, particularly from atypical carcinoid tumor and large cell neuroendocrine carcinoma and infrequent neoplasms such as peripheral neuroectodermal tumors (PNET) and others [25, 26] . Features other than cell size that aid in the distinction between SCLC and NSCLC include the presence of nucleoli and visible cytoplasm in the cells of large cell neuroendocrine carcinoma and other NSCLC.

Pathologic Staging of Patients with NSCLC
The sixth edition of the book published by the American Joint Commission on Cancer (AJCC) in collaboration with the International Union Against Cancer (UICC) compiles the most recent guidelines available for the clinical and pathologic staging of patients with lung cancer and other neoplasms [27]. The Cancer Committee of the College of American Pathologists published a Protocol explaining in some detail how to apply these guidelines for the staging of individual patients with lung cancer [28]. The protocol has a description of various aspects of staging and a Cancer Summary Checklist, which is shown as the end of this handout.

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 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 (e.g.,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.

Primary Tumor (T)

TX	Primary tumor cannot be assessed, or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus# (i.e., not in the main bronchus)
T2	Tumor with any of the following features of size or extent: • more than 3 cm in greatest dimension • 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
T3	Tumor of any size that directly invades any of the following: • chest wall (including superior sulcus tumors) • diaphragm • mediastinal pleura • 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 atelectasis or obstructive pneumonitis of the entire lung
T4	Tumor of any size that invades any of the following: • mediastinum • heart • great vessels • trachea • esophagus • vertebral body • carina
	or Tumor of any size with separate tumor nodule(s) in same lobe
	or Tumor of any size with a malignant pleural effusion##

^# 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 also classified as T1.

^## 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.

Regional Lymph Nodes (N)

NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes, including intrapulmonary nodes involved by direct extension of the primary tumor
N2	Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3	Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s)

Distant Metastasis (M)

MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis; includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral)

TNM Stage Groupings

Occult	T0	N0	M0
Stage 0	Tis	N0	M0
Stage IA	T1	N0	M0
Stage IB	T2	N0	M0
Stage IIA	T1	N1	M0
Stage IIB	T2	N1	M0
	T3	N0	M0
Stage IIIA	T1	N2	M0
	T2	N2	M0
	T3	N1	M0
	T3	N2	M0
Stage IIIB	Any T	N3	M0
	T4	Any N	M0
Stage IV	Any T	Any N	M1

Practical problems classifying NSCLC into a specific pT status

A. Is the Tumor pT1 or pT2?
As shown above, NSCLC are classified as pT1 lesions if they measure up to 3.0 cm in diameter, lack pleural invasion and are at a 2 cm or greater distance from the carina. It is controversial whether 3.0 cm in largest diameter is the best size cut-off to distinguish pT1 from pT2 lesions [9]. Patients with negative lymph nodes (pN0) and pT1 NSCLC lesions are staged as Stage IA, while those with pT2 tumors are classified as Stage IB. The distinction between lung cancer patients in Stage IA or IB was not considered a significant problem in the recent past, as there is only a small difference in the survival rates of both groups of individuals [29, 30] . However, recent clinical trials of Stage I-III NSCLC patients treated with post-operative chemotherapy alone or in combination with radiation therapy have shown improvements in survival rates ranging from 4-5% to 15% in patients with Stage IB or higher [8, 15] .

It is not possible for a pathologist to determine the distance from a tumor to the carina to apply the 2 cm cut-off value, but this issue does not pose practical problems as lesions that are that close to the carina are diagnosed endoscopically and the patients are either deemed non-resectable or treated with sleeve-resection pneumonectomy or other methods. It is generally simple to measure whether a tumor has a diameter of 3.0 cm or greater, but it is good practice to compare the measurements based on gross inspection with the microscopic findings as lung neoplasms frequently exhibit variable degrees of endogenous lipoid pneumonia or organizing pneumonia at their periphery that can be included as part of the mass size. This simple error can result in the overestimation of the pT status of a patient and consequent treatment with neo-adjuvant therapy in Centers that follow this practice.

A more difficult problem to distinguish pT1 from pT2 NSCLC is to determine whether a peripheral lung neoplasm invades the visceral pleura [16, 31, 32, 33] . Pleural lavage cytology has been recently introduced as a method to evaluate the presence of malignant cells either intra-operatively or post-operatively, but in most laboratories this distinction is based on histopathologic examination of the visceral pleura with H&E stained sections [16, 32, 34] . However, the histopathologic criteria for the diagnosis of visceral pleura have not been specifically defined in the AJCC/UICC lung cancer staging guidelines. It is not clear whether visceral pleural invasion should be diagnosed only when a tumor extends into the pleural surface, or in the presence of invasion through the elastic lamina or just through the tissues "perceived as pleura" [31, 35] . The Japan Lung Cancer Society classifies visceral pleural invasion as p0, tumor with no pleural involvement beyond its elastic layer; p1, tumor that extends beyond the elastic layer but is not exposed on the pleural surface and p2 as tumor that extends to the pleural surface [35]. Patients with p1 or p2 tumors exhibit similar prognosis to each other and worse prognosis than patients with p0 tumors [31, 35] . These recent studies suggest the need to stain peripheral lung NSCLC with EVG stain to determine whether the neoplasms extend beyond the elastic lamina. In our experience, the interpretation of these stains is frequently difficult, as peripheral lung neoplasms exhibit stromal elastosis and/or chronic pleuritis with elastosis and fibrosis overlying the lesions.

B. Is the tumor pT2 or pT3?
Peripheral lung tumors may exhibit chronic pleuritis with fibrosis overlying the lesion. If the neoplasm extends into the parietal pleura or other chest wall tissues such as skeletal muscle, the neoplasm is classified as pT3, "upstaging" pN0 patients to either Stage IIB or IIIA. Patients with Stage IIB peripheral neoplasms are usually treated with additional chest wall resection or are deemed unresectable, depending on the tumor location and other factors [36]. It is difficult to distinguish chest wall invasion from pleural fibrosis using imaging methods such as chest CT or MRI and thoracic surgeons cannot reliably distinguish tumor invasion from dense fibrosis based on gross intraoperative inspection [36, 37] . Therefore peripheral tumors with possible parietal pleura or chest wall invasion are frequently evaluated intraoperatively by frozen section. To my knowledge, there are no definitive histopathologic criteria to help differentiate with accuracy whether a neoplasm is still within the visceral pleura or has extended into an adherent portion of parietal pleura. Invasion of the pleural adipose tissue or skeletal muscle facilitate the diagnosis of a pT3 lesion. In the absence of these findings, pathologists need to assess the plane of invasion at the interface between the lung and the adherent parietal pleura to determine the extent of invasion. In general, it is a good idea to interpret conservatively the intraoperative findings, as patients with equivocal findings can be treated with local stripping of the parietal pleura with negative margins without the need for a more aggressive resection of rib portions and other components of the chest wall. In these instances it is important to ink the pleural margins to assess the extent of tumor.

Pathologists are also asked to evaluate intraoperatively whether there are tumor nodules located at a distance from a neoplasm being considered for resection. The potential metastatic tumor nodules, which would upgrade a patient from pT1 or pT2 to pT4 need to be distinguished in these specimens from reactive mesothelial hyperplasia. Mesothelial cells can exhibit considerable pleomorphism, increased nuclear size, prominent nucleoli and enlarged nuclear size, but they usually show relatively low N:C ratios and a characteristic amphophilic cytoplasm.

C. Should multiple lung nodules be staged as synchronous pT1 lesions, pT4 or pM1?
The diagnosis of synchronous and metachronous lung tumors is difficult. Pathologists need to distinguish between metastases to the lung, intrapulmonary metastases from a primary lung lesion that would be staged as pT4 if they are present in the same lobe as the original tumor or as pM1 if they are present in other lobes and synchronous primary lung lesions [30]. A detailed discussion of the differential diagnosis between metastatic lesions to the lung and primary lung neoplasms is beyond the scope of this lecture. In general it is helpful to procure the histologic slides of the extra pulmonary tumors and compare them with the lung lesions, look for the presence of squamous cell carcinoma in-situ in instances of multiple squamous cell carcinomas arising in different locations (e.g. larynx, upper airways, others) and perform a panel of immunostains. For example primary adenocarcinomas of the lung exhibit in about 85% of cases the phenotype: positive cytoplasmic immunoreactivity for cytokeratin 7, positive nuclear immunoreactivity for TTF-1 and negative cytoplasmic immunoreactivity for cytokeratin 20 [38]. Metastatic breast carcinomas may exhibit nuclear immunoreactivity for estrogen receptor and cytoplasmic immunoreactivity for GCDFP-15 (BRST-2) [39]. Colonic neoplasms can be stained with antibodies to CDX-2 and usually exhibit cytoplasmic immunoreactivity for cytokeratin 20 [40, 41] . Prostate adenocarcinoma shows cytoplasmic immunoreactivity for PSA and/or PSAP [42, 43, 44, 45, 46] .

Martini and Melamed proposed several clinico-pathologic criteria for the diagnosis of multiple primary lung cancers that are usually followed by thoracic surgeons [47]. Synchronous neoplasms are considered as independent primary lesions if the arise in different locations (segments, lobes, lung), there is carcinoma in-situ in each of the lesions in patients with multiple squamous cell carcinomas, there is no carcinoma in lymphatics common to both neoplasms and there are no extrapulmonary metastases. Metachronous neoplasms are considered as multiple primary lung cancers of there is a free interval between the tumors of at least 2 years, or the new neoplasms arise from carcinoma in-situ or the second neoplasm is present in a different lobe or lung but exhibits no tumor in lymphatics common to both lesions and no extrapulmonary metastases at the time of diagnosis. Recent studies with molecular techniques have shown that the study of p53 mutation analysis may provide a more definitive tool for the diagnosis of multiple primary lung carcinomas [47]. These studies are time consuming and require frozen tissues and are not routinely performed in most laboratories.

Evaluation of resection margins
Optimal surgical treatment of NSCLC includes complete local resection of the primary tumor. This can be difficult to achieve in patients with central lesions or in patients with poor pulmonary function undergoing segmental resections. Bronchial and parenchymal resection margins are evaluated by frozen section in these patients.

The frozen section evaluation of bronchial margins in lung cancer resection specimens can result in a small number of false positive and false negative diagnoses. For example, a recent review of the experience with 405 lobectomies and pneumonectomies at the University of North Carolina, at Chapel Hill, showed 90.6% true negative cases and 1.5% false positive diagnoses [48]. It is important to ink the bronchial resection margin prior to sample selection for frozen section and to measure the gross and microscopic distance between the tumor and the resection margin. In patients with sleeve resections and other surgical procedures where bronchi are cut at an angle in an attempt to preserve another lobe of lung, communication with the thoracic surgeon is important to label the correct areas as the margin. To my knowledge, it has not been determined whether it is best to cut radial sections of the bronchial margin or sections perpendicular to the margin. The former has the advantage of including the entire margin in the section, while the latter allows for assessment of the microscopic distance between the tumor and the margin.

Residual tumor at a resection margin can be classified as microscopic (R1) or macroscopic (R2) disease. The residual tumor at the margin can be present in the bronchial mucosa or in extramucosal tissues such as adipose tissue or peribronchial lymph nodes or in lymphatics. Patients with submucosal and parabronchial lymphatic tumor have worse prognosis than those with direct submucosal extension of invasive cancer or carcinoma in-situ [49]. A more recent study by Lequaglie of 4530 consecutive NSCLC lung surgeries demonstrated that patients with bronchial R1 disease had a similar prognosis to those with R0 disease [50].

Causes of false negative frozen sections include sampling error, interpretative errors mistaking submucosal lymphoid cells or bronchial glands for invasive tumor, cautery artifact that obscures the presence of tumor and others [48].

The evaluation of lung parenchyma resection margins in patients undergoing wedge resections of lung lesions can be difficult to assess by frozen section, as the lung tissue is technically difficult to cut with a cryostat and has multiple metal staples at the margin that are difficult to remove prior to section selection. It is important to ink the stapled margins prior to sectioning and to blot the ink carefully or soak it briefly with Bouin's solution to avoid extension into other areas during tissue sectioning. It is important to assess grossly whether the tumor extends grossly to the margin and the distance between the tumor and the closest resection margin. In patients with tumor present very close to the margin it is probably more prudent to interpret the margin as positive and request wider margins than to risk the possibility of R1 disease in the frozen section control tissues. In a recent study of 31 T1 N0 M0 peripheral adenocarcinomas diagnosed by wedge resection and treated by lobectomy, Goldstein et al demonstrated R1 disease in the lobectomy mostly in specimens with tumor closer than 2.4 mm to the margin [51]. Two processes affected wedge resection margin distances: stapling-induced parenchymal stretching, resulting in overestimation of pleural surface-based distances, and microscopic extension of adenocarcinoma beyond the gross perimeter of the neoplasm.

Evaluation of lymphatic/vascular (L/V) invasion in specimens resected for NSCLC
The prognostic value of lymphatic/vascular invasion in patients with NSCLC is somewhat controversial. It has been suggested as a poor prognostic feature in patients with pN0 adenocarcinoma and bronchioloalveolar carcinoma of the lung [52]. A more recent study of histological determinants of survival in completely resected T1-2 N1 M0 NSCLC showed that lymphatic invasion had no prognostic significance while vascular invasion was an adverse prognostic factor [53]. EVG stains can be very helpful to determine the presence of vascular invasion in these neoplasms.

Evaluation of lymph node status in patients with NSCLC
Lymph node status is one of the most important features to stage patients with NSCLC. It can be assessed clinically with computerized tomograms (CT) scan of the chest, magnetic resonance imaging (MRI) and other methods but these methods have sensitivities lower than 85-90%% [54]. Positron emission tomography (PET) using glucose analog F-18-fluoro-deoxy-glucosa (FDG) are also currently used for the staging of these patients, but the definitive determination of pN status relies on mediastinoscopy or other invasive procedures like Chamberlain procedure [18, 55, 56, 57, 58, 59, 60, 61] .

Frozen section of mediastinal lymph nodes can be difficult to perform with accuracy. In general, it is recommended to embed all tissues and cut sections at different levels to minimize the chance of under-diagnosing small metastases. Malignant cells in these sections can be difficult to distinguish from histiocytes and mesothelial cells, particularly in poorly fixed and stained sections. Crushed lymphoid cells can be difficult to distinguish from metastatic small cell carcinoma. In general, the cells of metastatic NSCLC exhibit increased nuclear size, with nuclei usually >3x the size of lymphocytes, may exhibit prominent nucleoli, irregular nuclear membranes and tend to present in small cohesive clusters. Mesothelial cells are present in the capsular area of the lymph node and are usually smaller, with lower N:C ratios. The chromatin pattern and nuclear shape of metastatic SCLC cells are different from those of lymphocytes. The neoplastic cells tend to be larger than 2-3 lymphocytes in diameter, have marked hyperchromasia with "salt and pepper" chromatin features and may exhibit an oval or spindle shape, while lymphocytes exhibit "chunky" granular chromatin, indistinct cytoplasm and irregular nuclear shapes.

Lymph node metastasis can be subclassified as intranodal, when they are present within the lymph node capsule, and extranodal when they extend into the adjacent soft tissues [58]. The clinical value of detecting isolated tumor cells with immunostains and of subclassifying nodal metastases by size into micrometastases and metastases measuring at least 2 mm in diameter remains under study [52, 58, 62] .

College of American Pathologists Surgical Pathology Cancer Case Summary (Checklist)
Protocol revision date: January 2004
Applies to invasive carcinomas only
Based on AJCC/UICC TNM, 6th edition

Click here to download the checklist for Lung Biopsy (PDF file, 95KB)
Click here to download the checklist for Lung Resection (PDF file, 110)

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