diagnostic immunohistochemistry of adenocarcinoma

a major practical question facing the pathologist
on discovery of adenocarcinoma in the lung is the organ site
of origin since many adenocarcinomas found in the lung are
metastatic. the detailed immunophenotypic characterization
of lung adenocarcinoma has done much to address this
question. perhaps the most useful protein biomarker in this
regard is ttf-1 (fig. 22. 13). this protein is one of the master
regulatory genes for lung development. it is a transcription
factor that regulates the expression of surfactant, clara cell
proteins, and several others that are important in lung development.
283, 284 ttf-1 is first expressed in the laryngotracheal
diverticulum, then, for the next few weeks, in the bronchial
epithelium. expression then shifts to the alveolar epithelium
where it is found in the adult. 285 in lung cancers, this protein
is expressed by many types of primary lung tumors including
adenocarcinoma, sclc, lclc, and carcinoid but usually not
by squamous carcinoma (table 22. 3). the ttf1 gene has recently
been shown to reside in a region of amplification. 286, 287
gene amplification is associated with overexpression of the
protein, but overexpression may occur in the absence of amplification.
a second marker set that addresses the question of tumor site
of origin are the cks. well-differentiated lung adenocarcinoma
has a ck profile that is distinct from squamous carcinoma and
from metastasic adenocarcinomas arising below the diaphragm.
most pulmonary adenocarcinomas are ck5/6 /ck7 /p63 /
ck20 , while squamous tumors are usually ck 5/6 /ck7 /
p63/ck20 . other primaries such as breast, ovary, pancreas,
and endometrium may also be ck7 /ck20 . 289, 290
carcinomas of colon are usually ck7 /ck20 291, 292 and
may, in addition, produce the gastrointestinal marker, caudalrelated
homeobox 2 (cdx2). 290, 293, 294 a ck7/ck20/cdx
immunohistochemical panel may thus be useful in the distinction
of pulmonary adenocarcinoma from tumors of the gastrointestinal
tract metastatic to the lung. 295
other proteins that could reflect peripheral airway origin
are the surfactant proteins including surfactant protein a
(spa) and surfactant protein c (spc), which are expressed in
more than half of adenocarcinomas. 296–299 the utility of these
markers is limited by relatively low sensitivity 70, 300–302 of the
immunohistochemical assay and by expression of many of the
surfactant proteins by nonpulmonary tumors. 303 ttf-1 and
the cks are generally the more specific and useful of the discriminators
of pulmonary adenocarcinoma.