History of cancer

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.

                                                (or) 

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. Stem cells Proliferating cells Differentiating cells Development of a tumour from a stem cell 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. Cellular multiplications and clinical symptoms 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 : Abnormally sized cell nuclei (anisocaryosis),, numerous and/or abnormal mitoses,  cells of different sizes (anisocytosis), disappearance of the specific characteristics of normal cells (such as hormone receptors, normal secretion products, differentiation markers),   multiplication and piling of cellular layers, disappearance of normal tissue morphology (epithelium, glandular tubules, and so on). 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 invasion One 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. 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. Diagram of tumour vascularisation . The tumour [1] periphery is well irrigated, but not the central part where necrosis occurs, [2] giving way to foul-smelling cellular death. The limit between the healthy tissue and the tumour is not clear [3]. An intermediately sized vessel irrigates the tumour and the adjacent region [4]. Multiple small anarchic vessels stem from this artery [5] : they can bleed, but bleeding is diffuse and generally not very abundant [6]. At the base of the necrotic zone, the artery can burst giving birth to major or cataclysmic haemorrhages [7]. 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   The most deleterious effect of cancer is the development of metastases. This development is the logical consequence of the local invasion process that we described earlier. The same mechanisms are used by the cancerous cells to invade lymphatic and blood vessels, thus allowing distant 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.   When the cancer cells leave the initial tumour, they are drained along the flow of adjacent lymphaticvessels towards a satellite lymph node [1]. In the node, many situations may arise: In [2], the cancer cells lead to a lymphoid reaction and are destroyed. In [3], the cancer cells stay in the node without any reaction (this is called a micro metastasis). Sometimes, [4], they flow across the satellite node without any specific reaction. 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 When cancer invasion of the lymphatic system progresses further, cancer cells reach the thoracic duct then the general blood circulation to produce various metastatic lesions (cf. following pages). 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.   Cervical nodes are most important for the classification and prognosis of head and neck cancers. Breast cancer nodes are situated either in the armpit (axillary nodes), inside the thorax (internal mammary nodes) or above the clavicle. For lung cancers, proximal nodes are the most significant. The same can be said for colon cancers. Pelvic cancers are drained by iliac nodes. However, for testicular cancers the draining nodes are in the lumbo-aortic region. Diagram of node invasion according to tumour localisation Distant metastases Distant metastases We have described in ''Cours de Cancérologie Fondamentale' (in French) the known biochemical mechanisms during the adhesion of cancer cells to the vascular wall, and their crossing through the endothelium. At least experimentally, the specificity of metastasis localisation seems to be linked to endothelial adhesion molecules, which are different from one organ to another. Mechanistic distribution of distant metastases The localisation of haematogenous metastases is not unique. It correlates, at least to a degree, with the venous drainage of the cancerous organ and the first capillary filter through which the cancer cells must circulate. Schematically, 'Walter's rules' distinguish 4 possible evolutions: pulmonary evolution Circulating cancer cells originating from lung cancer flow into the pulmonary veins, left heart and the general circulation, giving birth to ubiquitous metastases (bone, liver, brain, adrenal glands, skin, and so on).[1] liver evolution Circulating cancer cells originating from liver cancer or metastases flow towards the right heart by supra-hepatic veins and lung capillaries, where they form metastases. They can then cross over the pulmonary filter and proliferate throughout the entire body. [2] vena cava evolution Cancer cells are drained by the vena cava system and will firstly reach the lungs, then the whole body (cancer from pelvis, kidney). [3] portal vein evolution Cancer cells originating from cancer of the digestive system follow the portal system towards the liver which is the specific site of metastases for such tumours (colon, stomach, pancreas). Following this initial stage, we can observe hepatic and pulmonary type metastases. [4] In 1940, Batson theorised a venous plexus route by which tumours spread to the spine from prostate carcinoma thus explaining the great number of prostate metastases to vertebral bodies and the iliac bone. Genuine proof of such a mechanism has not been established. Other favourite sites However, these mechanistic explanations cannot clarify some very specific favourite sites for some tumours (for instance, prostate cancer metastases almost exclusively to the bone). These predilections are independent of lymphatic or blood drainage and rely on receptor mechanisms between cancer cells and endothelial cells. The knowledge of these preferential sites is very useful to define standard check-ups in order to detect most metastases without prescribing a superfluous number of radiological or biological tests. Primitive tumour Preferential sites of metastase Lung Breast Colon - Pancreas Prostate Thyroid Kidney Liver, Brain, Bone, Adrenal glands, Skin Bone, Lung, Pleura, Liver, Peritoneum Liver, Peritoneum Bone Bone, Lung Bone, Lung Bone metastases from prostate and breast cancers are often condensating lesions by stimulation of osteoblasts. On the spine, we can observe what is called an 'ivory vertebra'. Intra-cavitary metastases Some tumours will essentially develop at the tumour site (local evolution) or in a natural cavity: for instance, ovarian tumours and the peritoneal cavity, brain tumours and the meninges. However, with recent possibilities in inducing very long clinical remission of such tumours (by chemotherapy or radiotherapy), we now (but rarely) observe distant metastases of these lesions, originally known as 'locally evolving tumours': a brain metastasis of an ovarian cancer or a lung metastasis of a brain tumour).                                                                         Metastasis histology    Metastasis pathology:  The structural pathology of metastases is not always identical to that of the originating tumour. We can distinguish: identical structures, allowing simple diagnosis of the origin of a revealing metastasis (thyroid, kidney, prostate, etc.), less differentiated structures which only enable general non specific diagnosis of the origin of a revealing metastasis (adenocarcinoma, squamous cell carcinoma, etc.)  sometimes, but rarely, the metastasis is more differentiated than the originating tumour, totally different structures (i.e. embryonic tumours). 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 techniques When 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  Some cancers have a very limited local development but very rapidly engender metastases . On the contrary, other tumours may produce metastases years after complete clinical remission has been obtained at the originating site. From a clinical point of view, we can distinguish : Revealing metastases  10 to 15% of cancers are revealed by their metastases. The localisation of metastases often allows prediction of the originating tumour site (cf. next table). Synchronous metastases These metastases are discovered at the same time as the originating tumour either because they present clinical symptoms or because they are detected during the systematic check-up carried out before any local treatment. Delayed metastases Detected months or years after treatment of the originating tumour. Metastases are less and less frequent as time goes by. A late metastasis may be unique and be treated locally with prolonged survival.. The chronology of metastases is very important for their treatment : Cancer which is revealed by a metastasis or which already presents metastases at the time of discovery is very unlikely to be cured with contemporary therapeutic means (with a few exceptions for which chemotherapy is very active, such as placental choriocarcinomas, testicular tumours and ovarian carcinoma). Awareness of the primitive cancer may allow very efficient palliative treatment (like hormonotherapy for breast cancer, prostate cancer or iodine treatment for thyroid cancer), offering patients long clinical remission and good quality of life. Local treatment of the originating tumour might be beneficial for the patient, avoiding complications like pain or bleeding. When no such simple treatment is available, an open dialogue should be established between the patient and his/her carers before beginning any active therapy, that differs from the necessary palliative and symptomatic treatment. The occurrence of one unique metastasis, a long time after treatment of the initial tumour, offers the hope that this metastasis is genuinely unique (no other microscopic metastases). Local treatment of the metastasis may, therefore, offer long-term complete clinical remission with good quality of life. When such localised surgical or radiotherapy treatment is not feasible, new chemotherapy or hormonotherapy may also be very efficient. 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 metastasis The 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. Revealing metastasis Originiting tumour Liver Lung Bone Brain Colon, Pancreas, Stomach, Breast, Ovary, Lung Breast, Colon, Lung, Testicle, Sarcoma Breast, Prostate, Kidney, Thyroid, Lung Lung, Breast, Stomach 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:  premature satiety: the person is unable to eat more than a few mouthfuls,  nausea: the person feels like vomiting as soon as food arrives, loss of or change in sense of taste and smell: no food is pleasant to eat, the smell of meat, pork, ham becomes unpleasant. Due to this discomfort, the person is unable to prepare meals and forgets to eat. 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: elevation of serum lactate, related to the tumour mass, ketosis due to fasting, hypercalcaemia (paraneoplastic syndrome or due to bone metastases), anatomical alterations and mechanical consequences related to cancer of the digestive tract: cancer of the oro-pharynx, oesophagus, stomach, pancreas, liver, peritoneum, abnormal secretion of bombesin (a neuropeptide produced by small cell lung carcinoma) or serotonin (produced by carcinoid tumours), elevation of serum tryptophane due to abnormal tumour metabolism, production by the tumour cells of cytokins like TNFα (Tumor Necrosis Factor α), IL1 (Interleukin-1) or IFN-γ (Interferon γ), which seem to possess a direct effect on the satiety centre of the brain (hypothalamus). Most therapies do promote anorexia, at least during the first days: taste modifications and alimentary difficulties after a surgical procedure, vomiting and nausea induced by radiotherapy, often associated with mucitis (lesion of the mucosae), dryness of digestive mucosae, such as the disappearance of salivary secretion, chemotherapy induced nausea, vomiting and mucitis. Anorexia may also be the consequence of psychological disorders induced by cancer: transitory loss of appetite after the announcement of the disease, psychotic depression favoured by cancer, with its major weight loss and necessitating anti-depressive treatments. Cachexia Cachexia 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: diversion of the normal metabolism by the growing tumour, mass effect of the tumour itself as well as secretion of cytokines with a necrotic effect (see above), direct effect on the digestive tract (sub-occlusions, absorption disorders), previous poor alimentation or under nourishment due to alcoholism and smoking, liver metastases (poor metabolism of normal nutriments). 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. Fever Fever 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. Endocrine manifestations 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: the ectopic secretion of β -HCG by placental choriocarcinoma and germinal tumours, of gonadal or extra-gonadal origin. This secretion may provoke mono- or bilateral breast gynecomastia, the ectopic secretion of PTH (para-thyroid hormone) during malignant hypercalcaemia of squamous head and neck cancer, or lung or oesophagus tumours, the ectopic secretion of ACTH (Cushing’s syndrome) accompanying small cell lung cancers, the ectopic secretion of ADH (Schwartz-Bartter's syndrome with hyponatremia and edema) accompanying small cell lung cancers, the ectopic secretion of GH (Growth Hormone: hypertrophic pulmonary osteoarthropathy or Bamberger-Marie's disease: mild arthralgia with typical digital clubbing) as seen in bronchogenic carcinoma, Haematological disorders They are very frequent and of various types: Erythrocytosis of renal tumours of various types and cerebellum hemangioblastomas which are often explained by erythropoietin ectopic secretion, Anaemias of various aetiologies blood loss by hemorrhage of the cancer itself, inflammatory syndrome, intra-vascular disseminated coagulation, auto-immune diseases during B lymphoid tumours, poor absorption of B12 vitamin and folic acid. Most anaemia during the terminal phase has no precise aetiology and is considered to be part of terminal cachexia. Leukocyte alterations : Pseudo-leukaemic reaction which might be a symptom of medullar invasion, Deregulation of secretion of growth factor GM-CSF, without medullar invasion. Thrombocytosis a well-known factor of any inflammatory syndrome in cancer, Thrombocytopenia occurring during intra-vascular disseminated coagulation, auto-immune purpura haemorrhagica during lympho-proliferative syndromes. Various coagulation disorders. Dermatological syndromes Cancers can produce skin metastases (breast cancer, permeation nodules, tumour fistula) which should be diagnosed. Other dermatological syndromes include: Dermatomyositis or polymyositis, which can occur in various kinds of cancer, with its typical lilac-coloured (heliotrope) erythema over the bridge of the nose, the orbital regions, cheeks, forehead, with lilac-coloured lines on the hand and around the nails. The muscular syndrome is more or less severe, and more important on proximal muscles. Treatment involves the treatment of the tumour and is completed by corticosteroids. Other paraneoplastic syndromes : Breast Paget's disease : eczema of the nipple, acquired ichtyosis during Hodgkin’s disease, acanthosis nigricans (hyperpigmentation seen on axilla et hyperkeratosis of skin folds) during digestive cancers, erythema gyratum repens, hypertrichosis lanuginosa acquisita (face hair during pulmonary and digestive cancers). Neurological manifestations Most neurological manifestations are in relation with a direct lesion by a metastasis. Some are claimed to be paraneoplastic: Cerebral disorders related to metabolic perturbations (hyponatraemia) Paraneoplastic Encephalomyelitis Subacute autonomic neuropathy Cerebellar ataxia Lambert-Eaton's myasthenic syndrome