Problems in Pathologic Staging of Lung Cancer
Alberto M. Marchevsky
Cedars-Sinai Medical Center
Los Angeles, CA
Lung cancer is the third most frequent neoplasm in the U.S., with 171,900 estimated new cases in the
U.S. in 2003, the year with the most recent data available from the Surveillance, Epidemiology and End
Results (SEER) program of the National Cancer Institute covering about 10 percent of the US population
. Its clinical impact is magnified by the high proportion of patients with lung cancer that
are diagnosed late during the course of their disease and die with tumor; SEER data estimates 157,200
deaths from lung cancer in 2003. Lung cancer is strongly associated with exposure to cigarette smoking
and approximately 90% of lung cancers are attributable to cigarette smoking
. Second hand
smoking may also play a significant role in the causation of lung cancer. For example, a meta-analysis
of epidemiological studies on passive smoking revealed overall relative risks (RR) for lung cancer of
1.25 for home exposure and 1.17 for workplace exposure
Stage is the most important prognostic and predictive factor for patients with lung neoplasms and
pathologists are expected to provide accurate staging information in lung resection specimens
. Indeed, in many instances of patients with non-small cell carcinoma of the lung,
oncologists are more interested in the tumor stage than in the tumor cell type [7-11].
The World Health Organization has recently published a lengthy and very detailed histological
classification of lung neoplasms . In contrast, thoracic surgeons, pulmonologists and
oncologists classify malignant lung neoplasms into only two categories: small cell carcinoma (SCLC) and
non-small cell carcinoma of the lung (NSCLC)
. Separate staging systems have been
proposed for patients with those groups of neoplasms.
Staging system for small cell carcinoma of the lung
Small cell lung carcinomas (SCLC) account for 15-20% of patients with lung cancer
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
. The role of surgery in these
patients remains controversial . 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
. 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
. 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
. 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 . 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)
• 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: |
• great vessels
• vertebral body
|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 .
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
. 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
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
. 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
. 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"
. 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 . Patients with p1 or p2 tumors exhibit similar
prognosis to each other and worse prognosis than patients with p0 tumors
. 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 . 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
. 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 . 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
. Metastatic breast carcinomas may exhibit nuclear immunoreactivity for estrogen receptor
and cytoplasmic immunoreactivity for GCDFP-15 (BRST-2) . Colonic neoplasms can be stained
with antibodies to CDX-2 and usually exhibit cytoplasmic immunoreactivity for cytokeratin 20
. Prostate adenocarcinoma shows cytoplasmic immunoreactivity for PSA and/or PSAP
Martini and Melamed proposed several clinico-pathologic criteria for the diagnosis of multiple primary
lung cancers that are usually followed by thoracic surgeons . 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 . 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 . 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 . 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 .
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 .
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 . 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 . 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 . 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%% . 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
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
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 . 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
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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