ADENOCARCINOMA

There has been a shift in the predominant histological subtype
of non–small cell carcinoma. Adenocarcinoma (Figs. 18.3 and
18.4) has surpassed the incidence of squamous cell carcinoma,
once the foremost culprit of lung carcinomas. 8 Like squamous
cell carcinoma, adenocarcinoma is linked to smoking,
but it is also prevalent among nonsmokers and women. 19,20
Adenocarcinoma, defined by glandular differentiation or mucin
synthesis, tends to present peripherally. The World Health
Organization classifies adenocarcinoma into acinar, papillary,
bronchioloalveolar, solid with mucin production, and mixed
patterns; less common variants such as fetal, mucinous cystadenocarcinoma,
mucinous colloid , signet ring, and clear cell
adenocarcinomas also comprise this category. 12 Most adenocarcinomas
demonstrate pattern heterogeneity and therefore
are mixed subtype, 21 whereas pure subtypes are comparatively
infrequent.
The histological features of adenocarcinoma, including
well, moderate, and poor differentiation, are often mirrored
in cytology specimens. In general, adenocarcinoma
has a clean or necrotic background, 9 and has cyanophilic yet
more translucent cytoplasm than squamous cell carcinoma. 12
The cytoplasm may be foamy, granular, lacy, or vacuolated.
Based on the underlying architecture and differentiation, the
neoplastic cells are arranged as single cells, two-dimensional
sheets, three-dimensional clusters, syncytial groups, acini, or
papillae. Similarly, the cellular (cytoplasmic vacuolization) and
nuclear features (intranuclear inclusions, intranuclear grooves,
chromasia, chromatin pattern, and nucleoli) reflect the differentiation
of the tumor.
Bronchioloalveolar Carcinoma Bronchioloalveolar carcinoma
(BAC) is the in situ component of adenocarcinoma, which
may be mucinous or nonmucinous. Histologically, BAC is defined
as adenocarcinoma with predominantly lepidic growth along alveolar
walls without stromal (desmoplastic reaction), vascular, or
pleural invasion. 12,22 Pure BAC is rather uncommon, 23 but intermingling
with other patterns, as in mixed subtype, is quite frequent.
Among adenocarcinomas, BAC has a greater predilection
among women 24 and is more prevalent in nonsmokers. Because
most BACs present peripherally, they are less likely to occur in
sputum, lavages, and washes and are more amenable to aspiration
biopsies. Relatively benign biological behavior and propensity for
multifocality 24 make identification of BAC significant rather than
mere academic interest.
Several studies have demonstrated BAC cytological and
histological correlation. 23,25–27 BACs tend to have a clean
background, monolayered sheets 23 in orderly arrangement
without nuclear overlap, 26 single relatively uniform cells containing
moderate to abundant cytoplasm, pale fine chromatin,
and inconspicuous nuclei; intranuclear inclusions and
invaginations may also be present. 25 Most BACs are deceptively
bland, but low-grade cytology should exclude neither a
reactive process (over BAC) nor a well-differentiated invasive
adenocarcinoma. 27 Conversely, mild cellular pleomorphism is
evident in BACs 23 and does not imply invasive adenocarcinoma.
Significant features distinguishing mucinous BAC from
adenocarcinoma include abundant nuclear grooves, extracellular
mucin, 23 and greater propensity toward three-dimensional
groups than sheets. 28
Pure BAC or predominant BAC pattern in mixed adenocarcinoma
is associated with better prognosis, 26,29 so rendering
a diagnosis of adenocarcinoma with BAC prominence on aspiration
biopsy may guide therapeutic options. Lesions with
a predominantly BAC may be amenable to relatively conservative
surgical excision 30 and preoperative testing for sensitivity
to specific drugs. 31,32 Detecting BAC on cytology also
preoperatively alerts to the tendency of aerogenous spread and
multifocal disease. 26,33
Diagnostic accuracy of BAC is achieved by correlation
with radiologic presentation (i.e., ground-glass opacity and
solid component), operator expertise and adequate sampling.
BAC features by cytology may yield predominantly non-BAC
adenocarcinoma upon resection (or vice versa) as consequence
of inadequately or peripherally sampled tumor. 27 Although
cytological examination can indicate BAC features, histological
examination to unequivocally exclude invasion is necessary
for definitive diagnosis. 27
Adenocarcinoma In contrast to BAC, other subtypes of
adenocarcinoma tend to have greater architectural complexity
with three-dimensional clusters, cell balls, and syncytia.
Presence of papillary fronds (often containing intranuclear
inclusions, psammoma bodies 34,26 ) and luminal/glandular
formations echo histological papillary and acinar architectures,
respectively. Micropapillary morphology, associated with aggressive
behavior in breast, has also been described in the cytology
literature. 35 Cells of non-BAC tend to have conspicuous
nucleoli, 27 chromatin ranging from finely granular to coarse
and hyperchromatic and minimal to marked pleomorphism in
well to poorly differentiated adenocarcinomas, respectively. In
poorly differentiated carcinomas, a non–small cell carcinoma
rather than either squamous cell carcinoma or adenocarcinoma
27 diagnosis is sometimes rendered. If available, material
for immunostains to distinguish the two is beneficial as the
tumors have different levels of sensitivity and adverse effects to
therapeutic agents.
Immunohistochemistry Lung adenocarcinomas are frequently
cytokeratin 7 (CK7)-positive and cytokeratin 20 (CK20)-
negative. TTF-1, 36 although specific for pulmonary (and thyroid)
origin, is not 100% sensitive; incorporating thyroglobulin stain
into the immunohistochemical panel, especially in presence of
papillary architecture, is beneficial for excluding thyroid metastasis.
Surfactant apoprotein, associated with lung origin, is also
expressed in a fraction of nonpulmonary adenocarcinomas. 37
Mucinous adenocarcinomas are often immunoreactive with CK7
and CK20, but not TTF-1. 36
A CK7 , CK20 , TTF-1 immunoprofile in a lung
mass is not uncommon. Because breast and upper gastrointestinal
tract adenocarcinomas also exhibit this staining pattern,
excluding metastatic disease is crucial. Inclusion of estrogen
and progesterone receptors, 38 gross cystic disease fluid protein,
mammaglobin, and caudal-type homeobox transcription
factor-2 (CDX-2) in the battery of stains is prudent in such
cases. Estrogen/progesterone 38 and CDX-2 39 expression have
been also described in a subset of pulmonary adenocarcinomas.
Adenocarcinoma, BAC, and reactive atypia are morphological
diagnosis. Although limited, evidence supporting application
of p53 in discriminating BAC from non-BAC adenocarcinoma
may have a role in cytology. 28
Differential Diagnosis The main differential diagnosis
problem is the distinction between peripheral adenocarcinoma
of the lung and malignant pleural mesothelioma of epithelioid
type. Malignant epithelioid mesothelioma has tubular and
papillary architecture and CK7 /CK20 /TTF-1 profile
like adenocarcinoma. Immunostains CD15, CEA, BerEP4
(for adenocarcinoma) and calretinin, CK 5/6, WT-1 (for
mesothelial origin) can resolve the diagnosis of an epithelioid
pleural-based lesion.
Several entities mimic adenocarcinoma including nonneoplastic
lesions, metastases, mesothelial cells, and benign pulmonary
neoplasms. Benign processes such as chemotherapy/
radiation, pneumonia, and infarcts can mimic adenocarcinoma
(see section on pitfalls). Reactive atypical pneumocytes can be
challenging to differentiate from BAC on aspirates. Hyperplastic
reactive cells display cilia and terminal bars. Also cellular enlargement,
pleomorphism, binucleation, and nucleoli tend to
be more prominent in reactive cells than BAC. 27
Metastatic adenocarcinoma can appear histologically
identical to pulmonary adenocarcinoma, and cytological features,
although not unequivocally diagnostic, may steer in the
distinction. Metastatic colon cancer is characterized by dirty
necrosis and elongated nuclei. Primary lung adenocarcinoma
often has mixed subtype with bronchioloalveolar features,
whereas metastasis tends to illustrate morphological homogeneity.
12 Although these morphological features are helpful,
confirmatory immunostains are necessary.
Sheets of mesothelial cells may result in misdiagnosis of
BAC 25 ; presence of intercellular bridges in mesothelial cells is
helpful in separating the two entities.
Histologically, BAC is separated from its precursor AAH,
with the latter measuring 5 mm and absence of interstitial
inflammation and fibrosis. 12 In cytology, lesions that are suspicious
but not diagnostic of adenocarcinoma, defined as scant
clusters of bland, yet atypical bronchioloalveolar cells with
uniform round nuclei, pinpoint nucleoli in a histiocytic background,
are designated atypical bronchioloalveolar cell proliferation
(ABP) and demonstrate BAC or invasive adenocarcinoma
on resections, 27 the discrepancy possibly a consequence of
inadequate sampling.
Sclerosing hemangioma and hamartoma are benign/
low-grade pulmonary neoplastic mimickers of adenocarcinoma,
and their differentiation from adenocarcinoma can alter
surgical management. Sclerosing hemangioma is defined histologically
by its constellation of architectural patterns including
solid, papillary, hemorrhagic, and sclerotic and relatively bland
stromal and surface cells. 12 The architectural patterns of sclerosing
hemangioma resemble those of adenocarcinoma, and
the cells with bland cytology, inconspicuous nucleoli, intranuclear
inclusions, and sparse/absent mitotic activity recapitulate
features of BAC. 40 Presence of hyalinized stromal tissue, foamy
and/or hemosiderin-laden macrophages, two cell populations,
and absence of marked pleomorphism are consistent with sclerosing
hemangioma. 40
Pulmonary hamartoma is a benign neoplasm composed
of mesenchymal tissue (connective tissue, muscle, adipose
tissue, and cartilage) with entrapped respiratory epithelium.
12 The undifferentiated fibromyxoid component and
bronchiolar cell proliferation with intranuclear inclusions
and mild atypia resemble mucin and atypical cellular proliferation,
respectively, suggestive of mucinous adenocarcinoma.
41 Smears of the fibromyxoid stroma display fibrillar
edges and entrapped spindle-shaped cells, whereas mucin
is devoid of these characteristics; mildly atypical epithelial
hyperplasia is described in hamartomas. 41 Cartilaginous
fragments and “popcorn calcification” on imaging are diagnostic
of hamartoma.