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A 42-year-old man presented with shortness of breath and
a cough productive of copious sputum. CT examination revealed
extensive consolidation of the right upper and middle
lobes. Following a diagnostic biopsy, a right bilobectomy
was performed. The lung parenchyma was firm, tan, and
diffusely consolidated. The cut surface had a slightly
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 08 and is a bronchioloalveolar carcinoma, mucinous type.
Criteria for Diagnosis and Comments:
Bronchioloalveolar carcinoma (BAC) is defined in the current
World Health Organization (W.H.O.) classification as an adenocarcinoma
with a purely lepidic pattern of growth, i.e. growth along
pre-existing alveolar structures, without evidence of stromal,
vascular or pleural invasion. Tumors that show invasion of
stroma, blood vessels or pleura should not be classified as
BAC. The W.H.O. classification divides BAC into non-mucinous,
mucinous and mixed subtypes.
This case demonstrates typical morphology for a mucinous
BAC. The existing alveolar septa are lined, either partially
or completely, by a continuous layer of tall columnar cells
with abundant apical cytoplasmic mucin. Cytologic atypia is
characteristically minimal. The tumor in this case also shows
“multifocality”, which is not infrequently encountered
in BAC. It is thought that this is secondary to aerogenous
spread of tumor rather than true multifocal growth. The mucinous
variant of BAC has a propensity to involve entire lobes, mimicking
pneumonia grossly and radiographically.
The definition of BAC has undergone considerable evolution in recent years.
Prior to the 1999 W.H.O. classification, Clayton, et al, divided
BAC into four types: mucinous, non-mucinous, mixed and sclerosing.
The sclerosing variant proposed by Clayton does not meet the
rigid criteria for the current W.H.O. definition and is not
included in the current classification of BAC. The reasoning
behind the current strict definition lies primarily in studies
of non-mucinous BAC’s, which have shown that solitary
small tumors (<3.0 cm) with a pure lepidic growth pattern
do not have lymph node metastasis and have a 100% five year
survival. Stage 1 tumors with a lepidic growth pattern but
with areas of stromal invasion were found to have a five-year
survival similar to that of “conventional” adenocarcinomas
(approximately 75%). Additionally, tumors with stromal invasion
were found to have lymph node metastases in approximately
30% of cases. Similar survival advantages appear to apply
to multifocal BAC, particularly if the tumors are in the same
lobe, but further study is needed to clarify this issue.
As many conventional pulmonary adenocarcinomas may contain areas of lepidic
growth, particularly around the periphery, the diagnosis of
BAC should not be made on a small biopsy or cytology specimen,
given that invasive areas may be present in the tumor which
have not been sampled. A diagnosis of BAC should only be made
on a large or resected specimen in order to rule out any areas
of invasion. Generally, proper classification of BAC has implications
for prognosis but not necessarily for treatment. However,
BAC and tumors with a prominent BAC component have recently
been shown to respond more readily than conventional adenocarcinomas
and other non-small cell lung carcinomas to the tyrosine kinase
inhibitor, gefitinib (IressaTM), which targets the epidermal
growth factor receptor (EGFR).
The differential diagnosis of mucinous BAC includes a variety of primary pulmonary
carcinomas as well as metastatic adenocarcinomas, particularly
of gastrointestinal origin. Mucinous, a.k.a. “colloid”
carcinoma of the lung, like mucinous carcinoma of the breast
or colon, is characterized by dissecting pools of mucin containing
islands of neoplastic epithelium, which are often free floating.
Unlike mucinous BAC, colloid carcinoma destroys the underlying
architecture. Colloid carcinomas may be difficult to diagnose
due to the paucity of malignant cells in some cases. The finding
of pools of mucin within alveoli in the presence of a radiographic
mass should prompt a careful search for malignant cells. Some
reports indicate a slightly better prognosis for colloid carcinoma
than for conventional adenocarcinomas. Unlike BAC, they do
metastasize to lymph nodes and distant sites.
Mucinous cystadenomas are rare benign tumors consisting of a fibrous-walled
cyst filled with mucin and lined by well-differentiated columnar
mucinous epithelium. Definitive diagnosis usually requires
a resected specimen to appreciate the morphologic features.
The vanishingly rare cystadenocarcinoma is typically partially
circumscribed but shows areas of invasion or lepidic growth
of tumor cells along alveolar walls. It is likely that many
of these cases are actually colloid carcinomas according to
Primary signet ring cell carcinoma and pulmonary adenocarcinoma with goblet
cell morphology are relatively recently described variants
of pulmonary adenocarcinoma. Signet ring carcinomas have essentially
identical morphologic features to those encountered in the
more common gastric signet ring carcinomas. Goblet cell carcinoma
resembles conventional colonic adenocarcinoma with tall columnar
cells and atypical columnar goblet cells. Both of these entities
are often associated with dissecting mucin and are currently
considered as probable variants of mucinous (colloid) carcinoma,
although both are evolving areas of study. The importance
of these entities is to recognize that such morphology can
be encountered in a pulmonary primary.
Metastatic carcinomas, particularly of gastrointestinal origin, should be considered
when a mucinous carcinoma of any type is encountered in the
lung. Immunohistochemical studies are frequently used to attempt
to establish the primary site of origin, and one should be
aware of the potential pitfalls peculiar to mucinous carcinomas
of the lung. Cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid
transcription factor (TTF-1) and CDX2 are antibodies often
employed to determine pulmonary vs. gastrointestinal origin.
Typically, conventional primary pulmonary adenocarcinomas
and the non-mucinous type of BAC are positive for CK7 and
negative for CK20. Primary GI tumors, particularly those of
colonic origin, characteristically show the opposite staining
pattern. Nearly all non-mucinous BAC and most well to moderately
differentiated pulmonary adenocarcinomas are positive for
TTF-1, a marker which has proven very useful in supporting
a primary pulmonary origin for a given tumor. In contrast,
while mucinous BAC is positive for CK7, the majority are also
positive for CK20 and negative for TTF-1. The recently described
goblet cell variant of pulmonary adenocarcinoma is also positive
for CK20 as well as CK7 in the majority of cases. Unlike mucinous
BAC, goblet cell adenocarcinoma has been positive for TTF-1
in most cases thus far. CDX2 is a homeobox gene encoding a
nuclear transcription factor involved in the differentiation
of intestinal epithelium. CDX2 has emerged as a sensitive
and specific marker for differentiating gastrointestinal carcinomas,
particularly of colorectal origin, from primary pulmonary
carcinomas. Recent reports have shown that the goblet cell
variant of pulmonary adenocarcinoma shows strong staining
with CDX2 in nearly all cases. While TTF-1 should also be
positive, awareness of this aberrant staining pattern with
CDX2 and CK20 in this lung carcinoma variant is important
to avoid misclassifying a tumor as a gastrointestinal primary.
Mucinous BAC has not shown staining with CDX2 but awareness
of the CK20 positive, TTF-1 negative phenotype is important
to avoid misclassification. The signet ring cell variant of
pulmonary adenocarcinoma has shown a CK7 positive, CK20 negative,
TTF-1 positive pattern typical of pulmonary adenocarcinomas.