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Epidermal growth factor receptor (EGFR) is a protein on the cell surface to which epidermal growth factor (EGF) binds. When EGF attaches to EGFR, it activates the enzyme tyrosine kinase and triggers cell growth. EGFR may be found at abnormally high levels on the surface of many cancer cells. New nonchemotherapy agents such as the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib (Iressa and Tarceva) are now available to treat non-small cell lung cancer alone or in the adjuvant setting. The TKIs "target" the EGFR to turn off cell activity and help control the growth of non-small cell lung cancer, or NSCLC.
Attempts were made to predict pretreatment which patients
would respond to these agents, and it became obvious that the category
of NSCLC was no longer sufficient. Before the era of targeted therapy,
the important pathologic distinction in lung cancer was between small
cell and non-small cell. Small cell got chemotherapy, and non-small cell
got surgery, if possible, and chemotherapy in the adjuvant, neoadjuvant,
or palliative setting. There was no real difference in the treatment of
NSCLC, whether adenocarcinoma, squamous cell carcinoma, large cell carcinoma,
or any other combination.
Adenocarcinoma has begun to emerge as a different kind
of NSCLC. It has now surpassed squamous cell as the most common primary
lung cancer. The incidence in women is rising, and it is the subtype found
in never smokers, particularly in the West and in Japan. And, most important,
it is the type of NSCLC most likely to respond to tyrosine kinase inhibitors.
The mutations that underlie the sensitivity of adenocarcinoma
to tyrosine kinase inhibitors were discovered in 2004. These activating
mutations, mostly in exons 19 and 21 on chromosome 7, are found in tumors
from patients responsive to TKIs. These tumors have all been adenocarcinomas.
Patients with squamous cell carcinoma or small cell carcinoma do not carry
these mutations and do not respond to TKI therapy. A great deal of attention
has been paid to determining just what types of the usually heterogeneous
adenocarcinomas respond. Many studies suggest that adenocarcinomas with
a bronchoalveolar component, or BAC, are most likely to harbor the EGFR
mutations. There is some disagreement about the importance of BAC, with
some investigators suggesting that papillary subtype is more often associated
with mutations. This may be due to intra- and interobserver variability
in diagnosis or in the difficulty of separating papillary subtype from
BAC in a heterogeneous tumor. Interestingly, EGFR mutations are never
found in mucinous BAC. These tumors are strongly associated with KRAS
mutations. EGFR and KRAS mutations are mutually exclusive.
Another small-molecule, nonchemotherapy drug called
bevacizumab or Avastin is a monoclonal antibody against endothelial growth
factor and is now being used in the treatment of NSCLC. While no factors
similar to TKIs seem to underlie tumor responsiveness to Avastin, histopathology
plays a major role in the selection of patients for treatment. Patients
with squamous cell carcinoma of the lung are at high risk for the development
of fatal pulmonary hemorrhage when exposed to Avastin. Whether this is
due to histology alone or anatomic location of the tumor or cavity formation
by the squamous cell carcinoma is unclear. Based on a number of deaths
in a phase one trial of Avastin where the common feature among the patients
with lethal complications was squamous histology, patients with tumors
of squamous type in the lung were ineligible for a phase two trial.
So the distinction between small cell and non-small
cell lung cancer is no longer good enough in the practice of cytopathology
or surgical pathology. Every attempt must be made to categorize lung cancer
accurately to allow optimal treatment outcomes.
Immunohistochemistry plays a strong role in separating
adenocarcinoma from squamous cell carcinoma. Markers such as TTF-1 and
PE 10, when positive, will statistically support adenocarcinoma, and positivity
in 4A4, P63, and 34bE12 will suggest squamous differentiation. Mucin,
while somewhat "old fashioned," remains very useful in this setting. Tumors
found to be adenocarcinoma should be sent for molecular testing for EGFR
mutations.
The pathologist is in an ideal position to influence
appropriate testing and treatment in the era of targeted therapy.
Dr. Zakowski, a member of the CAP Cytopathology Committee, is attending pathologist, Memorial Sloan-Kettering Cancer Center, New York, NY, and professor of pathology, Weill Cornell Medical College.
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