SQUAMOUS CELL CARCINOMA

SQUAMOUS CELL CARCINOMA
Squamous cell carcinoma (Figs. 18.1 and 18.2) is strongly
associated with cigarette smoking. It is a malignant epithelial
tumor that was the most common histological subtype, but its
incidence has now been surpassed by adenocarcinoma reflecting
trends in reduced tobacco exposure with introduction of
filters and low tar contents. 8 Squamous cell carcinoma arises
from dysplastic squamous epithelium and can present centrally
or peripherally. In addition to the classic squamous cell carcinoma,
the World Health Organization recognizes several additional
histological patterns including papillary, clear cell, small
cell, and basaloid variants.
Typically, squamous cell carcinomas are classified into well,
moderately, and poorly differentiated categories, and the cytological
appearance is dependent on the extent of differentiation.
In general, squamous cell carcinomas can be associated with
tumor diathesis, acute inflammation, or foreign body–type
giant cell reaction. 9 In cytological preparations, squamous cell
carcinoma occurs as single cells or loose clusters; tissue fragments
are more common in aspirates. 10 Nuclear:cytoplasmic
ratios may range from low to high, with lower ratios being more
frequent in the well-differentiated carcinomas. 11 The cells have
sharp distinct cell borders, 11 and the nuclei are often hyperchromatic
to pyknotic India ink with coarse chromatin.
On histological sections, squamous cell carcinoma is defined
by keratinization and/or intercellular bridges. In smears
and liquid-based preparations of well-differentiated squamous
cell carcinoma, intact intercellular bridges and keratin
pearls are uncommon, 10 but they may be readily seen in cell
blocks sections. Rather, squamous cells are characterized by
dense dark blue cytoplasm or orangeophilia on Diff-Quik and
Papanicolaou-stained specimens, respectively. Polygonal cells,
bizarre cells with tadpole/caudate and spindle cell configurations,
10 and Herxheimer spirals in cytoplasmic tails are also
associated with squamous differentiation. As squamous cell
carcinoma becomes less differentiated, the aforementioned features
become less prominent. Poorly differentiated carcinomas
form syncytial groups especially in aspirates, and the cells have
cyanophilic cytoplasm, higher nuclear:cytoplasmic ratios, and
prominent nucleoli. 9
The remaining relatively uncommon variants of squamous
cell carcinoma have predominantly been described in surgical
pathology literature but awareness of these variants is important
to preclude misdiagnosis. Histologically, basaloid squamous cell
carcinoma shows cells with peripheral palisading, scant cytoplasm,
and hyperchromatic nuclei admixed with areas of typical
squamous differentiation. 12 The small cell variant has focal
squamous differentiation and small cells with morphologic
traits of non–small cell carcinoma including coarse or vesicular
chromatin, prominent nucleoli, and distinct cell borders. 12,13
Carcinomas are often classified as non–small cell or small
cell carcinoma for appropriate therapeutic management. An
attempt to distinguish between squamous cell carcinoma and
adenocarcinoma, rather than cataloging the two as poorly differentiated
non–small cell carcinoma, is also becoming important
as new agents for treatment are emerging. Bevacizumab, an
antivascular endothelial growth factor monoclonal antibody, is
being implemented for non–small cell lung cancer treatment,
but it is contraindicated in patients with squamous cell carcinoma
because of reports of pulmonary hemorrhage. 14 Tyrosine
kinase inhibitors of epidermal growth receptors are also being
used to treat adenocarcinoma with bronchioloalveolar features
likely being more sensitive than other non–small cell
carcinomas. 15 Given the differences in treatment options,
subclassification of histological subtype can avert side effects as
well as tailor appropriate therapy.
Immunohistochemistry Most squamous cell carcinomas
express high–molecular weight cytokeratin, cytokeratins
5/6 and p63. Thyroid transcription factor-1 (TTF-1) 16 and
cytokeratin 7 (CK7) 17 staining is present in a subset of cases.
Differential Diagnosis Cytology specimens with predominantly
well-differentiated squamous cells have to be
diagnosed cautiously. Such cells may represent mature keratinized
superficial cells of a carcinoma without adequate sampling
of smaller malignant cells, especially on exfoliative respiratory
specimens, 11 or they may reflect reactive, metaplastic, or degenerative
changes, even in the presence of nuclear hyperchromasia
and cellular irregularities. 11 Reparative processes have atypia,
but two-dimensional polarized “school of fish” sheets with
enlarged nuclei, vesicular chromatin, and prominent nucleoli
distinguish them from carcinoma. 9 Atypical squamous cells
can accompany marked acute inflammation and necrosis, suggestive
of an abscess. 11 An infectious process (e.g., aspergillosis)
has to be considered, but intense orangeophilia and increased
number of single cells should raise the possibility of squamous
cell carcinoma. 18 A histiocytic reaction to keratin can erroneously
be interpreted as granulomatous inflamm ation. 11
Basaloid and small cell variants of squamous cell carcinoma
have similarities to (combined) small cell carcinoma. 13
Cytological features, including dense cytoplasm, lack of nuclear
molding, coarse chromatin, and nucleoli favor squamous
cell carcinoma. Immunostains can aid in the diagnosis.
Finally, primary pulmonary squamous cell carcinoma is
morphologically similar to its head and neck counterparts, and
clinical history is necessary in determining the origin.