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Tumor budding in colorectal carcinoma time to take notice.pdf

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Tumor budding


B Mitrovic et al

these small clusters and isolated tumor cells
appeared poorly differentiated, with large nuclei
and a loss of microvilli and basement membrane,
and poorly developed or absent junctional complexes and desmosomes.
When seen in a single section, tumor buds appear
as clusters of cells that have broken off from the
main tumor mass. By examining serial sections of
high budding tumors stained with anti-cytokeratin
antibodies, Prall et al10 demonstrated that most buds
that appear to represent discrete clusters of cells are
in fact connected to adjacent larger glands. Indeed,
Morodomi et al11 coined the term ‘budding’ because
the undifferentiated single cells and tubular tumor
nests that they counted as buds both appeared to be
budding from larger neoplastic glands.
Shinto et al12,13 used immunohistochemistry with
anti-cytokeratin antibodies to highlight another
feature of buds, termed cytoplasmic pseudofragmentation, whereby cytoplasmic fragments, visible only
by immunohistochemistry, are seen in the immediate vicinity of tumor buds. When examined on serial
sections, some of the fragments were shown to be
connected to the buds (hence the term ‘pseudofragments’). The presence of pseudofragments is associated with high-grade budding, but was shown to
be an independent prognostic factor on multivariate
analysis, suggesting that its presence signifies an
aggressive budding phenotype.
Although tumor buds are usually most prominent
at the invasive front, intratumoral budding has been
described as well. Only one study has attempted to
assess the significance of this finding: Lugli et al14
reported that the presence of intratumoral budding
was strongly correlated with peritumoral budding,
but was found to be an independent prognostic
factor on multivariate analysis.
There is a strong association between budding and
the presence of lymph node metastases and lymphovascular invasion,11,12,15–32 defined by the presence of tumor cells within an endothelium-lined
space, and it has been suggested that buds represent
the part of the tumor that has gained the ability to
invade lymphatics and vascular channels. This idea
is supported by two intriguing morphological
studies: Morodomi et al33 examined serial sections
of high-budding areas to demonstrate that budding
nests are often found adjacent to areas of lymphovascular space invasion, and, in a more recent
study, Ohtsuki et al31 performed double staining
for anti-cytokeratin antibodies and anti-lymphatic
antibodies, finding that a number of ‘buds’ at the
invasive edge of a tumor are in fact located in small
lymphatic spaces. Similarly, the presence of budding has been associated with increased risk of
distant metastases,34–36 suggesting that budding may
also be associated with vascular invasion. A few
tumor-budding studies have used vascular markers and/or elastic stains to assess vascular invasion,11,12,19,22,26,32,37,38 but only four have analyzed
the relationship between budding and vascular
Modern Pathology (2012) 25, 1315–1325

invasion: Kazama et al22 found no relationship
between budding and vascular invasion, whereas
three other studies have reported a statistically
significant correlation between budding and venous
invasion, though the association was not as pronounced as the relationship with lymphatic invasion and lymph node metastases.11,12,32
The tumor–host interaction at the invasive front
may be of prognostic importance in the setting of
tumor budding. Several studies have shown peritumoral lymphocytic infiltration to be an independent prognostic factor in colorectal carcinoma.
Lugli et al23 have demonstrated that a peritumoral
lymphocytic reaction is associated with improved
prognosis in the setting of tumor budding, suggesting that the immune response might target the tumor
buds. The nature of the stroma at the invasive
margin may provide further prognostic information,
with myxoid stroma being associated with worse
prognosis,20,39 but further studies are needed to
confirm the reproducibility and prognostic importance of these findings.

Clinical significance of tumor budding
Tumor budding is associated with other histopathological factors known to portend a worse prognosis,
namely higher tumor grade, infiltrating tumor border,
the presence of lymphovascular and perineural
invasion, and lymph node metastases.11,12,15–32 On
multivariate analysis, budding has consistently
emerged as an independent adverse prognostic factor,
associated with local tumor recurrence and distant
metastases, and significantly worse overall and
disease-free survival.12,15,16,21,27,28,31,32,34–36,38,40,41
The adverse prognostic impact of high-grade
tumor budding is seen in both early and advanced
colorectal carcinoma, and there are several scenarios
in which this feature might influence clinical
decision making, particularly in early colorectal
Tumor Budding in Early Colorectal Carcinoma

Submucosally invasive colorectal carcinoma is
associated with excellent outcomes and low rates
of lymph node metastases, and a subset of patients
can be successfully managed with endoscopic
mucosal resection or polypectomy,42 thus avoiding
the risks associated with segmental resection.
Identification of candidates for endoscopic resection
rests mainly on the absence of certain high-risk
histopathological features, namely high tumor
grade, lymphovascular invasion, and tumor budding.26,42 Tumor extending to the cauterized margin
can often be managed by endoscopic follow up.
Several large studies have shown tumor budding
in submucosally invasive colorectal carcinoma to
be an independent prognostic factor associated
with lymph node metastases, local recurrence, and