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Tumour vascularity and proliferation clear evidence of a close relationship

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J. Pathol. 189: 297?299 (1999)
EDITORIAL
TUMOUR VASCULARITY AND PROLIFERATION:
CLEAR EVIDENCE OF A CLOSE RELATIONSHIP
???? ???????*
Professor of Pathology and Director of Surgical Pathology, University of California, San Francisco, California, U.S.A.
SUMMARY
Evaluation of various prognostic factors often reveals that some are closely related. In this issue of the Journal of Pathology, evidence
is presented linking intratumoural microvessel density with tumour cell proliferation. This is expected, because an adequate blood
vascular system is necessary for effective tumour cell proliferation. The blood vascular supply of a tumour is critical not only in providing
tumour cells with nutrients, oxygen, and waste elimination, but also because activated endothelial cells release important paracrine
growth factors for tumour cells and secrete collagenases, urokinases, and plasminogen activator. The latter allow capillary ingrowth and
the spread of tumour cells into and through the adjacent fibrin?gel matrix, connective tissue stroma, and into the lymphatic and/or
vascular spaces. Finally, an adequate vascular supply helps to ?switch off? apoptosis and prevent other forms of tumour necrosis, thus
contributing to overall tumour growth and spread. Copyright 1999 John Wiley & Sons, Ltd.
KEY WORDS?breast;
carcinoma; angiogenesis; proliferation; mitosis; microvessel density; survival
In this issue of the Journal of Pathology, Belien et al.1
report that areas of highest intratumoural microvessel
density (iMVD) are topographically close to, or even
overlap, the areas of tumour with the most mitotic
figures (i.e. ?hot spots?), and that both areas are almost
always located at the periphery or growing front of the
tumour. Moreover, the density of mitoses in these
tumour ?hot spots? strongly correlated with that of
the microvessels (r=0�, p=0�8), and necrosis was
generally observed at distances of more than 150 靘
from the nearest vessel. The authors suggest that these
necrotic areas developed as a consequence of the tumour
cells ?outgrowing? their vascular system.
Many studies have shown a correlation between
tumour cell proliferation rates and outcome in breast
carcinoma, including many using mitotic figure counting
as a measure of tumour cell proliferation.2?9 In some,
mitotic figure counts were the single best prognosticator.5 Mitotic figure content also correlates well with
other measures of tumour cell proliferation, such as
tumour cell bromodeoxyuridine (BRDU) labelling
and Ki-67 (MIB-1) expression.10,11 Indeed, mitotic
figure counting, when carefully done, may be the most
cost-effective method for estimating tumour cell proliferation. Also, like measuring ?hot spot? iMVD, it is
important that the fields selected for counting mitotic
figures be those containing the highest density of mitotic
figures (i.e. ?hot spots?). Jannink et al.9 have shown that
mitotic activity in random tumour fields is much less
prognostically useful than mitotic activity assessed in
?hot spots?.
*Correspondence to: Noel Weidner, MD, Box 0102, Department of
Pathology, University of California, San Francisco, San Francisco,
CA 94143-0102, U.S.A.
CCC 0022?3417/99/120297?03$17.50
Copyright 1999 John Wiley & Sons, Ltd.
That intratumoural mitotic activity correlates with
iMVD comes as no surprise. Tumour cell proliferation
occurs in part because the growth of new tumour vessels
allows for exchange of nutrients, oxygen, and waste
products by a crowded cell population for which simple
diffusion is inadequate; but it is also important that
activated intratumoural endothelial cells release important paracrine growth factors for tumour cells, such as
basic fibroblast growth factor (bFGF), insulin growth
factors, platelet-derived growth factor, and colony
stimulating factors.12?14 Furthermore, activated endothelial cells located at the tips of growing capillaries
secrete collagenases, urokinases, and plasminogen activator, which allow capillary ingrowth and the spread of
tumour cells into and through the adjacent fibrin?gel
matrix, connective tissue stroma, and into the lymphatic
and/or vascular spaces. Thus, the combined impact of
the perfusion and paracrine tumour effects with the
endothelial cell-derived invasion-associated enzymes
all likely contribute to a phase of rapid tumour growth
and signal a switch to a potentially lethal angiogenic
phenotype. Endothelial cell growth and proliferation
contribute to metastases as well.12?14
Finally, as with measurements of tumour cell proliferation, many studies performed on different patient databases by different investigators at different medical
centres have shown an association of iMVD with various indicators of tumour aggressiveness such as higher
stage at presentation, greater incidence of metastases,
and/or decreased patient survival.12?14 This has been
shown not only in studies of patients with carcinoma of
the breast, but also in those with prostate carcinoma,
head-and-neck squamous carcinoma, non-small-cell
lung carcinoma, malignant melanoma, gastrointestinal
carcinoma, testicular germ-cell malignancies, multiple
Received 17 May 1999
Accepted 27 May 1999
298
EDITORIAL
myeloma, central nervous system tumours, ovarian
carcinoma, cervical squamous carcinoma, endometrial
carcinoma, transitional cell carcinoma of the bladder, tumours of unknown primary site, vulvar carcinoma, nasopharyngeal carcinoma, laryngeal squamous
carcinoma, oesophageal squamous carcinoma, and
medullary thyroid carcinoma.12?14
In the current article,1 the authors suggest that
tumour necrosis occurs when tumour cells ?outgrow?
their blood supply. What ?outgrow? means has never
been clear to me; but recent research findings allow
refinement of concepts regarding the causes of tumour
necrosis. Jain reports that blood flow through tumours
is both spatially and temporally heterogeneous.15 The
central zones of tumours have a uniformly elevated
interstitial pressure (i.e. interstitial hypertension), while
the peripheries are surrounded by a zone of almost
normal interstitial pressure. Moreover, there appears to
be no functional intratumoural lymphatic system, and
there is a relatively increased resistance to blood flow
through tumours. These abnormalities result from an
abnormal tumoural vascular system, which is highly
disorganized both structurally and functionally.15
Invasive tumours may show various combinations of
several types of necrosis, which include infarct-like
necrosis, apoptosis, and/or peritheliomatous necrosis.
Many tumours, especially those that are biologically
aggressive, have regions or patches where confluent
sheets or patches of tumour cells have undergone
infarct-like necrosis. In these areas, tumour cells appear
only as pale-staining ?ghosts? of their previous viable
cytomorphological state. The contiguous or sheet-like
nature of the necrosis indicates that the cause of death
was likely ischaemic injury, affecting a field or group of
tumour cells fed or drained by a single vessel. It is highly
unlikely that these tumour cells, which are in a contiguous necrotic mass, suddenly ?outgrew? their blood supply
all at once. Instead, this confluent necrosis suggests that
the large feeding artery or exit vein became obstructed,
leading to either an arterial or a venous infarct. Jain and
co-workers16 have presented convincing evidence that
intratumoural mechanical stresses, caused by tumour
cell proliferation, can create focal large-vessel obstruction, leading to ischaemic intratumoural infarcts. This
solid stress is generated by tumour cells growing within
a confined space.17 This stress, which greatly exceeds
blood pressure in tumour vessels, is sufficient to induce
the collapse of vascular structures;16 and, like the intratumoural vascular supply, these intratumoural mechanical stresses are likely to be heterogeneous, both spatially
and temporally. This would explain the patchy nature of
intratumoural infarct-like necrosis. Moreover, the high
intratumoural interstitial pressures, which may approximate intravascular pressures, as well as the increased
blood flow resistance, combine to create a permissive
environment for vascular stasis and necrosis.
The second type of tumour cell death is apoptosis, or
programmed cell death, which usually affects individual
tumour cells and is spotty or multifocal throughout the
tumour. Although likely triggered by many types of
stimuli, apoptosis may also be related to tumour angiogenesis. Folkman and co-workers18 have shown that in
Copyright 1999 John Wiley & Sons, Ltd.
some cancer models, dormant micrometastases are often
asymptomatic and clinically undetectable for months or
years until they reactivate. They studied dormant lung
metastases under angiogenesis suppression in mice. The
metastases exhibited rapid growth when the inhibition of
angiogenesis was removed and tumour angiogenesis was
activated. Tumour cell proliferation, as measured by
bromodeoxyuridine incorporation and immunohistochemical staining of proliferating cell nuclear antigen,
was not significantly different in dormant and growing
metastases. However, tumour cells of dormant nonangiogenic metastases exhibited a more than three-fold
higher incidence of apoptosis. These data show that
metastases can remain dormant when tumour cell proliferation is balanced by an equivalent rate of cell death
and suggest that angiogenesis inhibitors control metastatic growth by indirectly increasing apoptosis in
tumour cells. Thus, in a sense, apoptotic cell death can
be triggered when tumour cells proliferate or ?outgrow?
their supporting vascular system.
A third form of intratumoural necrosis follows a
peritheliomatous pattern, in which a cord or sheath of
viable tumour cells surrounds or clings to a centrally
disposed blood vessel. The sheath of viable cells appears
to remain as thick as diffusion allows exchange of
nutrients, oxygen, and waste products by the crowded
cell population; a thickness of 150 靘 was suggested by
Belien et al.1 Tumour cells that proliferate beyond this
diffusion limit undergo necrosis, which may be caused
by ischaemic hypoxia and/or apoptosis. Peritheliomatous pattern necrosis is probably related to the comedotype necrosis found in most high-grade ductal
carcinomas in situ (DCIS) of the breast. In this setting,
diffusion from blood vessels around the DCIS limits the
thickness of the sheath of viable tumour cells attached to
or clinging to the ductal wall. As with apoptosis, peritheliomatous pattern necrosis could be conceptualized
as resulting from tumour cells ?out growing? their
adjacent blood supply.
Thus, I believe that tumour cell necrosis occurs by at
least three mechanisms: one, infarct-like necrosis created
by intratumoural local-regional stresses, causing vascular obstruction; two, increased multifocal apoptosis
caused by tumour cell proliferation ?outgrowing? a
?switched-off? blood vascular system; and three, peritheliomatous pattern necrosis developing as tumour cells
proliferate beyond the viable diffusion limit created
around a central functional blood vessel. Comedo-type
necrosis observed in high-grade DCIS is probably
closely related to peritheliomatous pattern necrosis, but
in reverse, as tumour cells grow centrally and away from
periductal blood vessels. The first of these patterns of
tumour cell death is caused by mechanical obstruction of
large vessels within the tumour and the latter two might
be caused when tumour cells proliferate beyond, or
?outgrow?, the nourishing effects of their adjacent blood
supply.
REFERENCES
1. Belie?n JAM, van Diest PJ, Baak JPA. Relations between vascularization
and proliferation in invasive breast carcinoma. J Pathol 1999; 189: 309?318.
J. Pathol. 189: 297?299 (1999)
EDITORIAL
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Copyright 1999 John Wiley & Sons, Ltd.
299
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J. Pathol. 189: 297?299 (1999)
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