OBJECTIVES
– To know and be able to describe the main phases of history with the help of examples.
natural cancer: pre-cancerous phase (predisposition, dysplasia), local phase
(micro-invasion, loco-regional extensions), general phase (metastatic).
– To know the principles of the TMM classification of tumors.
INTRODUCTION
The natural history of cancer can be divided schematically into several stages:
– the cancerous transformation of a cell;
– the clonal expansion of the cancer cell;
– the growth of the tumor mass that becomes clinically detectable and the invasion
local with a locoregional invasion of cancerous tissue ;
– the spread of cancer cells away from the initial tumor site and the
formation of secondary tumor foci = metastasis.
This tumor progression is linked to the genetic instability of the cancer cells. From spontaneous genetic modifications will occur progressively, with the appearance of variants of the original clone, resulting in tumor heterogeneity. These variant clones will have heterogeneous proliferative, invasive, antigenic, and metastatic behaviors, or still uneven sensitivity to chemotherapy.
1 – PRECANCEROUS STATES AND INITIAL PHASE OF CANCER
All epithelia rest on a basement membrane that separates the epithelial cells of the underlying connective-vascular tissue called the chorion. The stages of development of carcinoma (cancer of epithelial origin) prior to the invasion phase correspond to the following stages strictly intraepithelial carcinogenesis.
There are two stages: dysplasia and carcinoma in situ.
1. 1 – Precancerous conditions and lesions, the notion of dysplasia
Precancerous conditions are clinical conditions associated with a significant risk of the high incidence of cancer. They are used to identify populations at risk for cancer donated.
Precancerous lesions are histopathological abnormalities that are detectable before the onset of cancer.
Some cancers also appear on pre-existing lesions, such as carcinomas.
developed on burn scars or radiodermatitis lesions.
Some precancerous lesions are called dysplasias. Dysplasia is a disorder
acquired from cellular homeostasis resulting from genetic abnormalities that alter the control of cell proliferation and maturation. Dysplasias are only described in the epithelia (cervix, digestive tract, airways, mammary gland, urinary tract…) and are precancerous lesions because the dysplastic cells can, inconsistently and in a very variable time, transforming into cancer cells by the accumulation of other genetic anomalies.
Note! The term “dysplasia” has a second meaning, closer to its etymology (dys/anomaly ;
flat/constructed). It refers to any lesion resulting from an abnormality in the development of an tissue, organ or part of the body (e.g. kidney dysplasia, dental dysplasia). It is also used to refer to certain rare constitutional diseases, which are of a more or less obvious malformation (e.g. fibrous dysplasia of the bones).
Pre-cancerous dysplastic states may be observed.
– During a chronic inflammatory state (e.g., chronic helicobacter’s gastritis), the patient may have to be treated with a combination of antibiotics and antibiotics;
endobrachyesophagus by chronic acid reflux; certain inflammatory conditions intestinal chronicles).
– During viral infections (e.g. cervical papillomavirus condylomata).
– In benign tumours (ex: adenomas of the colon).
Microscopic features of dysplasias
Dysplastic state can be diagnosed by pathological, cytological examination. and/or histological :
– Tissue architecture: increase in cell density, decrease in
cell differentiation, cell polarity abnormalities, disorganization of
the epithelium;
These microscopic abnormalities are more or less intense and extensive, and this is the basis for the notion of grade: the pathologist must not only recognize a dysplasia, but also must indicate its grade, i.e. its intensity. As a general rule, the more marked the dysplasia, the more the risk of transformation into cancer in the more or less short term is high.
The purpose of the grade is therefore to evaluate the prognosis to guide a therapeutic attitude.
Different terminologies are used to qualify the different grades of dysplasia:
– mild, moderate and severe dysplasia;
– intraepithelial neoplasia (IEN) grades I, II and III;
– low grade and high grade dysplasia.
1. 2 – Carcinoma in situ (CIS)
1. 2. 1 – Definition
At the level of the epithelium, separated from the connective tissue by a basal membrane well stage of carcinoma in situ can be described as a distinct stage of carcinoma: cell proliferation cancerous epithelial cells that do not cross the basement membrane of the epithelium, and thus does not invade the connective tissue. Carcinoma in situ is also known as “non-invasive”.
At this stage, the cancer cells are not accompanied by a stroma and metastases are not accompanied by a stroma.
are impossible.
1. 2. 2 – Locations
The locations of CIS are those of dysplasia:
– cervix;
– other squamous mucous membranes (lips and mouth, oesophagus, larynx, mucous membranes genitals, bronchi after squamous metaplasia) and skin
– urothelium (especially bladder);
– digestive mucous membranes (especially from the adenomas, sometimes also in the mucous membrane flat: e.g. on a gastric intestinal metaplasia or lower esophagus (endobrachyesophagus);
– breast: lobular carcinoma in situ affecting small mammary acini, or carcinoma intrachannel into the galactophoric excretory ducts.
1. 2. 3 – Diagnosis
The diagnosis of carcinoma in situ is made histologically, on biopsies or on parts operating theatres. Indeed, there is no tumor mass and the macroscopic changes are minimal and are only used to guide the biopsies.
Distinguishing between carcinoma in situ and severe or high-grade dysplasia is difficult, and sometimes impossible. In practice, this does not matter because the therapeutic attitude is Identical whether it is severe dysplasia or carcinoma in situ. The important point of the diagnosis is here, by definition, the integrity of the basement membrane and therefore the absence of of cancerous invasion of the connective tissue.
N.B.: the term carcinoma in situ is however present in the WHO classification two exceptions that do not strictly comply with this definition: colorectal adenocarcinomas invading the mucous membrane without extending beyond the mucous muscle, and urothelial tumours
not infiltrating the muscularis.
1. 2. 4 – Evolution
Carcinoma in situ can remain non-invasive for several years, but progresses
spontaneously in the vast majority of cases to invasive carcinoma. However, it can spontaneous regressions exist.
The evolutionary pattern {dysplasia →CIS →carcinome invasive}, if it is very frequent, is only probably not applicable to all carcinomas.
Screening for carcinomas in situ is very important for prognosis, as at this stage no metastasis has formed. Treatment can be local and curative.
2 – LOCAL PHASE OF CANCER: INVASION
2. 1 – Fundamental aspects
Tumour cells invade the connective tissue in an active and complex process related to to the acquisition of new biological properties by certain cells of the tumor clone. The cancer stroma (including the necessary angiogenesis as soon as the tumour mass exceeds 1 to 2 mm in diameter) is necessary for tumour growth and develops in the of invasion.
Most carcinomas begin with a phase of intraepithelial proliferation, then
become invasive when crossing the basement membrane. Cancers that are not epithelials are invasive from the outset, with the exception of melanomas, which may present a intraepidermal and testicular seminomas that most often follow the initial intraepidermal phase and testicular seminomas that most often follow an “intratubular germline neoplasia”.
Tumour invasion involves several mechanisms:1. Interaction of the cancer cells with the components of the extracellular matrix.
and especially the basal membranes;
2. degradation of connective tissue (extracellular matrix and basement membranes);
3. mobilization of cancer cells;
4. role of hypoxia and tumour necrosis.
2. 1. 1 – Modulation of cell anchoring to the extra-cellular matrix: the adhesion molecules
Normal cells are bound to each other and to the extracellular matrix by
junction and by adhesion molecules. The modulation of the expression of the molecules adhesion and the reduction of intercellular junctions between tumour cells. are participating in the tumor invasion.
The ability of tumour cells to dissociate also depends on their degree of
differentiation; a morphological characteristic of many tumours is the presence of less well-differentiated cells at the invasion front. This dedifferentiation is probably controlled by tumor-microenvironment peritumor interactions.
2. 1. 2 – Degradation of the extracellular matrix: role of proteases
Cancer cells are capable of degrading the basement membrane constituents and of the extracellular matrix. This proteolysis involves enzymes secreted by the cancer cells and/or by stromal cells (fibroblasts) stimulated by factors
secreted by the cancer cells. These enzymes include matrix metalloproteinases (MMP), constituents of the plasmin system. The
process also involves a disruption in the balance between these enzymes and their inhibitors.
2. 1. 3 – Migration of cancer cells
The migration of the cells takes place through the accumulation of micro-filaments under the membrane.
plasma, allowing pseudopods to move around. It involves mobility autocrines and chemotactic factors: degradation products of the
extra-cellular matrix, cytokines and growth factors.
2. 2 – Practical aspects/local-regional consequences
2. 2. 1 – Diagnostic importance, notion of micro-invasive carcinoma
From the epithelium, carcinoma cells erode the basement membrane and
invade the superficial part of the underlying chorion. At this stage, carcinoma is called “micro-invasive”. These superficial invasive cancers generally have a better prognosis. than that of more advanced cancers of the same type.
For example, in the stomach, it is possible to individualize an “intramucosal” cancer: it is is a cancer that invades the mucosal chorion without crossing the muscle.
mucous membrane. Its prognosis is significantly better than that of cancers that have exceeded the muscular-mucosal and invaded the more external parietal layers: risk of metastatic disease. weak.
It is during the invasion phase that the cancer stroma develops. From the moment the cancer becomes invasive, cancer cells can spread to distant locations to form metastases.