Page 220 - Textbook of Pathology, 6th Edition

204 4. Degradation of ECM. Tumour cells overexpress proteases subpopulation of tumour cells selectively. The process is
and matrix-degrading enzymes, metalloproteinases, that governed by inappropriate expression of genes which normally
includes collagenases and gelatinase, while the inhibitors of partake in physiologic processes i.e. it is a genetically prog-
metalloproteinases are decreased. Another protease, rammed phenomenon.
cathepsin D, is also increased in certain cancers. These Recent evidence has shown that in metastatic tumours,
enzymes bring about dissolution of ECM—firstly basement survival of host is correlated with some clinical and molecular
membrane of tumour itself, then make way for tumour cells features of tumours which act as prognostic markers. These
through the interstitial matrix, and finally dissolve the are as under:
basement membrane of the vessel wall. i) Clinical prognostic markers: Size, grade, vascular
SECTION I
5. Entry of tumour cells into capillary lumen. The tumour invasion and nodal involvement by the tumour.
cells after degrading the basement membrane are ready to ii) Molecular prognostic markers: Molecular markers indi-
migrate into lumen of capillaries or venules for which the cative of poor prognosis in certain specific tumours are:
following mechanisms play a role: a) expression of an oncogene by tumour cells (C-met);
i) Autocrine motility factor (AMF) is a cytokine derived from b) CD 44 molecule;
tumour cells and stimulates receptor-mediated motility of c) oestrogen receptors;
tumour cells. d) epidermal growth factor receptor;
ii) Cleavage products of matrix components which are formed e) angiogenesis factors and degree of neovascularisation;
following degradation of ECM have properties of tumour and
cell chemotaxis, growth promotion and angiogenesis in the f) expression of metastasis associated gene or nucleic acid
cancer. (MAGNA) in the DNA fragment in metastasising tumour.
After the malignant cells have migrated through the
breached basement membrane, these cells enter the lumen GRADING AND STAGING OF CANCER
of lymphatic and capillary channels.
‘Grading’ and ‘staging’ are the two systems to predict tumour
6. Thrombus formation. The tumour cells protruding in the behaviour and guide therapy after a malignant tumour is
lumen of the capillary are now covered with constituents of detected. Grading is defined as the gross and microscopic degree
the circulating blood and form the thrombus. Thrombus of differentiation of the tumour, while staging means extent of
provides nourishment to the tumour cells and also protects spread of the tumour within the patient. Thus, grading is
them from the immune attack by the circulating host cells. histologic while staging is clinical.
In fact, normally a large number of tumour cells are released
General Pathology and Basic Techniques
into circulation but they are attacked by the host immune Grading
cells. Actually a very small proportion of malignant cells (less
than 0.1%) in the blood stream survive to develop into Cancers may be graded grossly and microscopically. Gross
metastasis. features like exophytic or fungating appearance are
indicative of less malignant growth than diffusely infiltrating
7. Extravasation of tumour cells. Tumour cells in the tumours. However, grading is largely based on 2 important
circulation (capillaries, venules, lymphatics) may histologic features: the degree of anaplasia, and the rate of growth.
mechanically block these vascular channels and attach to Based on these features, cancers are categorised from
vascular endothelium. In this way, the sequence similar to grade I as the most differentiated, to grade III or IV as the
local invasion is repeated and the basement membrane in most undifferentiated or anaplastic. Many systems of grading
exposed. have been proposed but the one described by Broders for
8. Survival and growth of metastatic deposit. The extra- dividing squamous cell carcinoma into 4 grades depending
vasated malignant cells on lodgement in the right upon the degree of differentiation is followed for other
environment grow further under the influence of growth malignant tumours as well. Broders’ grading is as under:
factors produced by host tissues, tumour cells and by Grade I: Well-differentiated (less than 25% anaplastic cells).
cleavage products of matrix components. These growth
factors in particular include: PDGF, FGF, TGF-β and VEGF. Grade II: Moderately-differentiated (25-50% anaplastic cells).
The metastatic deposits grow further if the host immune Grade III: Moderately-differentiated (50-75% anaplastic cells).
defense mechanism fails to eliminate it. Metastatic deposits Grade IV: Poorly-differentiated or anaplastic (more than 75%
may further metastasise to the same organ or to other sites anaplastic cells).
by forming emboli.
However, grading of tumours has several shortcomings.
It is subjective and the degree of differentiation may vary
PROGNOSTIC MARKERS
from one area of tumour to the other. Therefore, it is common
Metastasis is a common event in malignant tumours which practice with pathologists to grade cancers in descriptive
greatly reduces the survival of patient. In the biology of terms (e.g. well-differentiated, undifferentiated, keratinising,
tumour, metastasis is a form of unusual cell differentiation non-keratinising etc) rather than giving the tumours grade
in which the tumour cells form disorderly masses at ectopic numbers.
sites and start growing there. This random phenomenon More objective criteria for histologic grading include use
takes place in a stepwise manner involving only a of flow cytometry for mitotic cell counts, cell proliferation