Definition:
Cancer (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and sometimes metastasis, or spreading to other locations in the body via lymph or blood. These three malignant properties of cancers differentiate them from benign tumors, which do not invade or metastasize.
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There is no easy definition of cancer.
We can define cancer as a pathological process during which some cells escape from the physiological control of differentiation and multiplication. These cells then acquire the capability of invading normal surrounding tissues, thus destroying them. Simultaneously or consequently, the cells migrate to various organs and constitute metastases.
The death of the tumor host occurs :
- either by an acute complication (like haemorrhage, brain compression, suffocating dyspnoea)
- or by a progressive deterioration of the functions of normal organs due to massive metastases (respiratory insufficiency, hepatic insufficiency),
- or by a long and complete degradation of the general health of the patient (called cachexia)
Natural history of cancer
The following description is a representation of the natural history of cancer (without treatment). In reality, every type of cancer (every cancer) probably has different initiation and promotion factors as well as progression history. However, this general diagram describes what cancer is..
Initial steps
Three different steps may be schematically described during cancerogenesis, the first two are only known through experimental models and epidemiological studies of human cancers:
- initiation is a rapid and irreversible DNA lesion which occurs after exposure to a carcinogen (physical carcinogen, chemical carcinogen, viral carcinogen)
- promotion is due to prolonged, repetitive or continuous exposure to substances which maintain and stabilise the initiated lesion,
- progression is the acquisition of non controlled multiplication properties, independence acquisition, loss of differentiation, local invasion and metastasis.
Schematic view of the first steps of cancerogenesis |
The biological mechanisms involved throughout these three steps are described in Cours de Cancérologie fondamentale (in French).
Prevention of the initiation of the cancer process involves the protection of cells from carcinogenic agents like tobacco, benzol, various chemical products, radiation, and so on). Prevention is dictated by knowledge acquired through human epidemiological studies as well as experimental cancers in animals.
Preventing the promotion of the cancer process also involves protecting the organism from various products and situations, like alcohol, tobacco, viruses, local irritation processes, and so on). Prevention results from the same type of epidemiological and experimental studies. Knowledge of other diseases linked to developing cancers (such as genital infections or hereditary syndromes) also facilitates cancer prevention.
Preventing the progression of cancer is possible through the same studies but also by active, well designed policies for the screening of pre-cancerous lesions and small cancers, when policies are applicable.
Cancer progression
Cancer progression explains what cancer is: a locally developing tumour generating metastases.
Once cancer progression occurs, there are several possibilities for fighting against it:
- by the screening and treatment of pre-cancerous lesions,
- by the screening and treatment of small cancers(essentially by surgery or radiotherapy),
- by treating cancers that remain localised (frequent association of adjuvant treatment such as chemotherapy or hormonotherapy),
- by treating generalised cancers (by chemotherapy, hormonotherapy, and/or palliative care).
Treatment efficiency decreases as cancer progresses:
- the most efficient therapies are those applied to limited lesions (like those detected through organised screening): surgery and radiotherapy are then very efficient,
- Localised but more developed cancers can be the origin of silent metastases, which cannot be detected using standard clinical methods. In order to diminish the risk of metastasis, adjuvant treatments are proposed (chemotherapy or hormonotherapy), in complement to local treatment,
- Generalised cancers are generally not treated with a curative intention and only a palliative and temporary beneficial effect is obtained (except for tumours which are very sensitive to chemotherapy or hormonotherapy).
Malignant tumour | Clinical cancer | Metastatic cancer | |||||||||||||||||||||||||||||||||||||||
Tumour development and metastases Cellular divisions Local tumour development necessitates a great number of cellular divisions. The initial cancerous cells are stem cells , which give birth to clones.
A stem cell divides giving birth to two daughter cells: some are identical to their mother cells, others will differentiate (differentiation). Many daughter cells will die without offspring. By measuring perpendicular diameters either of human skin tumours or palpable lymph nodes, or of nodes or tumours observed on radiological images, or by measuring the incorporation of radioactive nucleotide in tumour DNA, we can calculate an approximate mean doubling time. For most human tumours, this doubling time is around 50 to 60 days. Thus, for most of its natural history, a human tumour divides itself (for at least 30 to 40 doublings), without any clinical symptoms, and without any possibility of diagnosis by the physician. One billion tumour cells represent an approximate tumour volume of 1 cm3.
When the tumour becomes visible or palpable, its apparent growth slows down (probably because of insufficient nutriments brought by surrounding vessels). A further 15 to 30 doublings will give way to an immense tumour which will kill its host. Cellular differentiation Cancers reproduce more or less precisely the normal structure of the tissue from which they originate. The degree of differentiation (or grading) generally has an important prognostic value. Usually, the more undifferentiated a cancer looks, the higher its proliferative potential, and the worse its prognosis. The main factors observed during de-differentiation are :
We will describe later the various classifications which have been elaborated according to the type of cancer or the histological grading. Precise measurable grades, with as little subjective criteria as possible, are essential in order to obtain reproducible classifications. These histological grades are very important for the definition of therapeutic protocols according to the cancer’s potential evolution. Local invasionOne of the major characteristics of cancer is the capacity of cancer cells to progressively invade neighbouring tissue. They divert for their benefit, either directly or by stimulating neighbouring normal cells, the usual mechanisms which allow normal modifications and modulations of connective tissue. They loose their mutual cohesion (normally dependant on surface proteins) and invade the neighbouring tissues. The breach and crossing of the basal membrane of the epithelium constitute the formal criteria to distinguish invasive cancers from in situ cancers.
Progressively, the precise border between the normal tissue and the cancerous lesion fades. For this reason, in order to completely remove the tumour, the surgeon will be obliged to concede a security margin, around the tumour, within the healthy tissue, and to offer the patient what we call a carcinologically correct surgical exeresis. Tumour invasion preferentially follows less resistant zones: organ capsules, nerve sheaths and small vessels. Usually, resistant tissues are: cartilage, arteries, nerves, tendons and aponevroses. When the tumour invades the vascular wall, haemorrhages become a usual clinical symptom, with major risk of massive haemorrhagic ruptures. When nerves are invaded, the patient becomes painful and paralyses may occur. When cancer cells invade the bone, they destroy its structure, either by direct contact or by stimulation of neighbouring osteoclasts. In some cases, this destruction is compensated by an osteoblastic bone synthesis (which explains the dense bone metastases of breast or prostate cancer). Bone invasion provokes persistent and intense pain, and possibly hypercalcemia (which remains rare considering the great frequency of bone metastases). Angiogenesis In order to survive, the cancerous tumour has to stimulate the creation of new blood vessels, a process called angiogenesis. However, this neo-angiogenesis may be insufficient and necrosis (cell death) can occur at the centre of the tumour, possibly with calcifications. The necrotic tumour will rapidly become superinfected, leading to dreadful smells. The identification, during angiographies (radiographies with injection of a contrast agent), of new vessels presenting a more or less anarchical architecture constitutes an important diagnostic factor. These new vessels are also fragile and bleed easily: haemorrhages, therefore, frequently constitute a revealing symptom. On the other hand, normal mesenchymatous cells are stimulated (fibroblast, connective tissue cells), and build what is called a 'stromal reaction' further accompanying the development of cancer.
The importance of angiogenesis can now be measured using antibodies to Factor VIII with immuno-histochemistry. The greater the vascularisation of a tumour, the greater the risk of tumour cells escaping and generating distant metastases, and therefore presenting the worst prognosis. Furthermore, a highly vascularised tumour may be an additional difficulty for the surgeon (for instance: osseous metastases of kidney cancer have a very rich vascularisation and haemostasis may be very difficult). The tumour may also bleed from its surface (like in placental choriocarcinoma). Lymphatic metastases Lymphatic invasion The lymphatic drainage of normal tissues explains the rapid invasion by tumour cells as soon as they reach the lymph wall. The cancer cells are carried away by the lymphatic flow towards the cortical sinus of the first lymph nodes. When the abnormal cells reach the node, a specific reaction is often observed, called non specific chronic lymphadenitis. In [2], the cancer cells lead to a lymphoid reaction and are destroyed. In [5], on the contrary, the cancer cells multiply and totally invade the lymph node, giving it a typical neoplasic aspect (hard, painless, fixed node). This fixation to neighbouring tissue is due to the invasion of the node capsule [6]. The cancer cells can then migrate towards the next lymph node, giving birth to carcinomatous lymphangitis either following the normal flow [7] or against the current. [8] These lesions explain the lymphatic stase and oedema.The presence of lymphatic invasion on surgical resection specimens or, even worse, the presence of invaded lymph nodes are typical of an aggressive tumour. They are correlated with poor prognosis and prompt oncologists to prescribe adjuvant treatment (radiotherapy and/or hormonotherapy-chemotherapy). Pathologic nodes An intermediate step is the presence of a left supraclavicar lymph node (or Troisier's ganglion), representing the last stop before cells reach the general circulation, and signifying the general diffusion of cancerous lesions. The following scheme illustrates the situation of the major satellite nodes.
Metastasis histology Metastasis pathology: The structural pathology of metastases is not always identical to that of the originating tumour. We can distinguish:
In fact, when we can study the biological properties (genetic analysis for instance) of the metastatic cells, we find great variations from one metastatic site to another. In experimental animal tumours, metastasis localisation can be modified by genetic manipulations. Usefulness of immunohistochemistry techniquesWhen the metastasis reveals cancer or when it arises a long time after treatment of the primitive tumour (see next page on chronology), it is very important to try to link such a metastasis with a primitive tumour, in order to establish the most appropriate treatment.Immunohistochemistry is one of the current tools used for this purpose . Metastasis chronology From a clinical point of view, we can distinguish :
The chronology of metastases is very important for their treatment : In most cases, a metastasis cannot be cured and good palliative treatment (which can include surgery and/or radiotherapy and/or chemotherapy) should privilege the quality of life and be decided after an open discussion with the patient and his(her) family. Revealing metastasisThe next table is based on knowledge of the usual biology of tumours. When a metastasis reveals a cancer, we should try to find the originating tumour with as few tests as possible, since any test represents inconvenience for patients, and very few 'discoveries', although interesting for the physician, are of real use to the patient.However, all tumours can produce any kind of metastasis.
Searching for the originating cancer is of real use when an efficient therapy can be proposed in order to obtain good clinical remission whilst preserving quality of life. Treatment should not deteriorate quality of life: when finding such a revealing metastasis, the major problem for the physician is the announcement of the truth and the necessary open dialogue which should be established with the patient. Local treatment of the metastasis is generally necessary since it is symptomatic: pain, bleeding or solely visible tumour. Radiotherapy is very useful (pain, bleeding) delaying the necessary use of sedation treatment. General Reactions Anorexia: Anorexia is the lack or loss of appetite and interest in food.During the cancer process, anorexia can be induced in three different ways:
During cancer, anorexia may be due to cancer itself, its treatment or the psychological consequences of cancer (depression). Biological anomalies related to cancer are sometimes observed:
Most therapies do promote anorexia, at least during the first days:
Anorexia may also be the consequence of psychological disorders induced by cancer:
CachexiaCachexia or general state alteration including major weight loss is the consequence of both anorexia and evolution of the cancer process. Various factors have been incriminated:
The easiest way to measure cachexia is to weigh the patient although the weight loss may be masked by oedema or effusion (like ascites). A loss of 10% to 20% of normal weight can be observed in cancers of the stomach or the oesophagus. There is a clear correlation between the weight loss observed before treatment and poor cancer prognosis. Severe under nourishment may be observed during complicated treatment (such as radiotherapy for head and neck cancers or poorly tolerated chemotherapy). These therapies may have to be temporarily stopped in order to take corrective measures (such as hyperalimentation by nutritive components or IV feeding). Severe cachexia is frequently observed at the end of life. Major emaciation is due to the disappearance of all muscular and fat masses. The skin becomes very fragile like parchment, dentures become too big for the mouth, the patient becomes skeletal. In such a state of under nourishment, complications arise very quickly: a dry mouth further reduces feeding, the body support zones are the target of necrosis process (decubitus bedsore). Biologically, such cachexia induces an increased metabolism of lipids and proteins, anaemia (without any clear aetiology), hypo-albuminemia (further inducing oedema), hyponatremia. FeverFever is a very frequent symptom at the end of life in cancer patients. An infection should always be investigated (cf. chapter on emergencies), but generally is not proven (no germ). Some cancers specifically involve fever during their evolution (Hodgkin’s disease, acute leukaemia, kidney cancer, osteogenic sarcoma, atrial myxoma), with sweating episodes, probably related to cytokine production. More frequently, fever is observed with major tumour mass (almost the same mechanisms as for cachexia), with tumour necrosis (and the risk of anaerobic super infection). Major liver metastases are often complicated by a moderate fever which can be notably reduced by anti-inflammatory drugs like cortisone. Paraneoplastic syndromes Some general reactions to cancer may constitute its revealing symptom, or occur during its evolution. These paraneoplastic syndromes are systemic symptoms which appear (and disappear) with the tumour. Most of these syndromes are very rare although their list might seem long. These syndromes are among the best known and explored: they are the consequence of an ectopic secretion of a substance which mimics a hormone (or is the hormone itself). Its very elevated blood concentration explains the disappearance of the syndrome when the tumour is removed. Some are very classical:
Haematological disordersThey are very frequent and of various types:
Dermatological syndromesCancers can produce skin metastases (breast cancer, permeation nodules, tumour fistula) which should be diagnosed. Other dermatological syndromes include:
Neurological manifestationsMost neurological manifestations are in relation with a direct lesion by a metastasis.Some are claimed to be paraneoplastic:
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1 comment:
I’ve been thinking about writing a very comparable post over the last couple of weeks,
what is anisocytosis
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