Rheumatic diseases associated with tumors. Paraneoplastic syndromes in rheumatology practice Paraneoplastic syndrome in rheumatology

For citation: Svetlova M.S. Rheumatic paraneoplastic syndromes // BC. 2014. No. 7. S. 496

Paraneoplastic arthritis refers to paraneoplastic reactions - non-oncological diseases and syndromes that occur in the body under the influence of tumor growth. Moreover, this growth does not occur due to the direct local action of neoplasm or its metastases on organs and tissues or the side effects of chemotherapy and concomitant infections, but as a result of influence on metabolism, immune, endocrine and other body systems.

In general, one or another paraneoplastic syndrome is diagnosed in 7-10% of patients with malignant neoplasms. The connection of malignant neoplasms with paraneoplastic reaction is confirmed by the rapid regression or complete disappearance of the latter after radical removal of the tumor and the reappearance of the same rheumatic symptoms with recurrence of neoplasm or metastasis.

Paraneoplastic rheumatic reactions occur mainly with low-grade malignant neoplasms of epithelial origin (cancer of various localization) and tumor lesions of the immune system (thymoma, lymphoma). Rheumatic paraneoplastic syndromes (RPNS) often coexist with other organ and systemic paraneoplastic manifestations. Most often, RPNS accompanies bronchogenic lung cancer, breast cancer, nephrocarcinoma, ovarian, prostate, and uterus cancer, less often - cancer of the esophagus, pancreas, testicles, and adrenal glands.

In different patients, the same RPNS may be a sign of a tumor of different localization and unequal morphological structure, and, conversely, with tumors of the same localization and similar morphological structure, there may be similar rheumatic manifestations. Moreover, in the same patient successively occurring throughout life (metachronous) tumors of different localization can cause different RPNS. Recurrent and metastasizing tumors are characterized by the same type of rheumatic symptoms and the original tumor.

The neoplastic process can cause both acute and chronic inflammatory reactions with pathological changes in the connective tissue and blood vessels in various organs and systems. The spectrum of RPNS is the most diverse - from local (in the form of arthralgia, arthritis) to a systemic inflammatory response. In some cases, they develop simultaneously with neoplastic transformation, in others - against the background of an already existing tumor process, sometimes precede the onset of its local symptoms for several months and even years.

In the pathogenesis of paraneoplastic reactions may be involved:

• immune reactions;
• direct toxic effect of tumor substances;
• metabolic disturbances caused by a tumor: hypercalcemia, hyperuricemia, consumption by a growing tumor of the components necessary for the normal functioning and structural integrity of healthy tissues;
• ectopic production of hormones and hormone-like substances, such as adrenocorticotropic or antidiuretic hormone, releasing factor, growth hormone, parathyroid hormone, insulin-like growth factor, erythropoietin;
• activation of a latent viral infection, the role of which is not excluded in the development of rheumatic inflammatory reactions in patients with malignant neoplasms.

It is believed that most RPNS are based on hyperergic immunoinflammatory reactions of reaginic, immunocomplex or autoimmune type to metastasizing malignant cells or "foreign" tumor antigens entering the bloodstream, possibly cross-reacting with antigens of normal tissues. In addition, the formation of neoantigens in normal tissues under the influence of circulating neoplasm metabolic products may play a role in the development of paraneoplastic immune inflammation. It is believed that the nature of RPNS is determined both by the antigenic properties of the tumor and by the individual immune responses of the patient, in particular, genetically determined or acquired imbalance of the main parts of the immune system. The participation of immune reactions in the development of RPNS is confirmed by their presence not only in visceral cancer, but also in neoplasms of the immune system, in particular in thymoma, lymphocytic leukemia, hairy cell (T-cell) leukemia, lymphoma, lymphosarcoma, lymphogranulomatosis and paraproteinemic hemoblastoses.

The role of common etiological factors and genetic predisposition in the development of rheumatic diseases and neoplastic process, at least tumor diseases of the immune system, is also discussed, which is supported by data on the transformation of Sjögren's syndrome into B-cell lymphoma.

A certain role in the development of RPNS is probably played by the direct action of biologically active substances secreted by tumor cells. It is believed that immunological changes in the body may be at the earliest stage of malignant tissue transformation, when the neoplasm, due to its small size, is not yet determined during the study. Malignant tumors have been described in patients who have suffered from chronic rheumatic inflammatory diseases for many years, for example, rheumatoid arthritis or systemic connective tissue diseases. It is believed that these cases could be associated with long-term prior immunosuppressive therapy, fibrosis and epithelial organ remodeling as a result of rheumatic inflammation, as well as a genetic predisposition to both types of diseases.

In addition, it is probably important to increase the life expectancy of patients with chronic inflammatory rheumatic diseases in the conditions of modern adequate therapy: patients live to the “cancer age”, and a malignant tumor occurs as a second disease. However, there are cases when the symptoms of a rheumatic disease that existed for a long time before the development of a malignant tumor disappeared after its radical removal.

The clinical manifestations of RPNS are very diverse. Joint damage in cancer patients is sometimes manifested only by persistent arthralgia, which in some cases is combined with tendonitis, ossalgia and myalgia. In other cases, manifest arthritis occurs, the mechanism of development of which and the clinical picture in different patients may be different.

Arthritis due to immune synovitis is more common. In this case, the clinical picture of the articular syndrome may resemble that of rheumatoid arthritis, reactive arthritis. In the first case, a symmetrical polyarthritis of the small joints of the hands and feet develops, in the second, an asymmetric oligo- or monoarthritis of the large joints, mainly of the lower extremities. In some patients, rheumatoid nodules and rheumatoid factor in the blood serum are observed, and with a protracted course of arthritis, erosive changes in the articular surfaces of the epiphyses. Occasionally, RPNS occurs with spinal lesions of the type of ankylosing spondylitis. Inflammatory changes in the joints, including early manifestations of a malignant neoplasm, are accompanied by general intoxication, an increase in ESR, and an increase in acute phase parameters.

In some malignant neoplasms, along with paraneoplastic arthritis, Marie-Bamberger syndrome (hypertrophic osteoarthropathy) may develop. The main manifestation of this syndrome is a kind of deformation of the fingers of both hands in the form of drumsticks due to thickening of the terminal phalanges. There are also changes in the nails in the form of watch glasses: they become dull, take the form of a hemisphere. The combination of both signs is called the "fingers of Hippocrates."

Along with the fingers of Hippocrates, periostitis of the end sections of the long tubular bones (often the forearms and lower legs), as well as the bones of the feet and hands, appears. In places of periosteal changes, pronounced ossalgia or arthralgia and local palpation soreness can be observed, and on x-ray examination - a double cortical layer (symptom of "tram rails").

In most cases, the cause of paraneoplastic Marie-Bamberger syndrome is lung cancer, less often other intrathoracic tumors, in particular benign neoplasms of the lungs: pleural mesothelioma, teratoma, mediastinal lipoma. Occasionally, the syndrome occurs in gastrointestinal cancer, lymphoma and lymphogranulomatosis with metastases to the lymph nodes of the mediastinum. Sometimes hypertrophic osteoarthropathy is the only manifestation of RPNS. At the same time, in addition to the main syndrome, symptoms of general intoxication, increasing emaciation, a significant increase in ESR are observed.

In some patients, paraneoplastic arthritis is combined with aponeurositis - a nodular thickening of the palmar aponeurosis and painful flexion contracture of the fingers, resembling that of systemic scleroderma. Similarity with systemic scleroderma is also given by the presence of Raynaud's syndrome, typical for this disease.

Cancer of the apex of the lung (Pancost's tumor), less often malignant tumors of other localization can lead to the development of the "shoulder-hand" syndrome (reflex sympathetic dystrophy or algoneurodystrophy), which is characterized by acute unilateral humeroscapular periarthritis in combination with vasomotor and trophic changes in the hand on the side of the lesion .

In addition to paraneoplastic arthritis of immune origin, patients with malignant neoplasms may develop mono- or oligoarthritis due to metastatic damage to the synovial membrane by tumor cells or secondary gout against the background of hyperuricemia as a result of rapid tumor decay under the influence of cytostatics.

In some patients with oncological diseases, along with joint damage, extra-articular paraneoplastic rheumatic manifestations are observed: fever of the wrong type, not amenable to antibiotic and glucocorticoid therapy, lymphadenopathy, hepato- and splenomegaly, effusion serositis (pleurisy, pericarditis), myopathy, peripheral neuropathy, encephalopathy, nodular erythema, recurrent urticaria, hemorrhagic rash, panniculitis, Stevens-Jones syndrome, mucosal lesions, a pronounced increase in ESR, hypergammaglobulinemia, an increase in the level of circulating immune complexes in the blood, the presence of antinuclear antibodies, LE cells, rheumatoid factor, anemia, leukopenia and thrombocytopenia.

Diagnosis of paraneoplastic arthritis and other RNS is often difficult. At the same time, certain signs detected in patients with rheumatic symptoms and syndromes should cause alertness in the oncologist. These signs include:

• the occurrence of rheumatic pathology in persons over 50 years of age, i.e., at a later age than is typical for most rheumatic diseases, or, on the contrary, the appearance at a young age of signs of Horton's disease, polymyalgia rheumatica, characteristic of the elderly and old people;
• lack of sexual demorphism, typical for many rheumatic diseases;
• acute or subacute arthritis;
• discrepancy between the severity of arthritis and the general severe condition of the patient and high rates of activity of the inflammatory process;
• fever resistant to treatment with antibacterial and anti-inflammatory drugs;
• the absence of individual clinical and laboratory signs typical of a particular rheumatic disease;
• the persistent course of arthritis, often ahead of the clinical manifestation of a malignant formation;
• the appearance of new symptoms that are not characteristic of this rheumatic disease, due to local growth of the tumor or the development of its metastases.

When questioning the patient, it is important to pay attention to possible anorexia, aversion to meat food, progressive weight loss, persistent pain in the abdomen, bones, melena, vomiting of blood or "coffee grounds", paroxysmal excruciating cough, hemoptysis, bloody discharge from the vagina, hematuria, indication in a history of cancer, radiation and chemotherapy carried out for this reason.

An essential role in the diagnosis is played by a full-fledged objective examination, as well as the results of instrumental and laboratory tests.

It should be borne in mind that cancer patients sometimes have lesions of internal organs of non-rheumatic origin: bronchospastic syndrome, non-infectious endocarditis of the heart valves, thromboembolism of the pulmonary artery branches, recurrent migratory thrombophlebitis, nephrotic syndrome, thrombocytopenic purpura. In some cases, more often with tumors of the lung and kidney, there are signs of ectopic hormonal activity of tumors, in particular acromegaly, gynecomastia, galactorrhea, Itsenko-Cushing's syndrome. There may also be paraneoplastic dermatosis, the occurrence of which in people older than 40 years in most cases indicates the presence of a malignant neoplasm. These dermatoses include:

• black acanthosis;
• annular erythema of Gammel;
• acrokeratosis Base;
• hypertrichosis of vellus hair;
• acquired ichthyosis;
• erythema annulare Darya.

Metastatic bone marrow damage, especially against the background of cancer intoxication, can lead to hypoplastic anemia, often in combination with leukopenia and thrombocytopenia.

Thus, RPNS is an urgent problem that requires attention from the doctor to the patient, knowledge of the clinic, and the ability to diagnose rheumatic paraneoplastic manifestations.

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Paraneoplastic syndrome is a clinical picture of the disease, in which the patient has systemic manifestations of a malignant disease that occurs without metastases. This syndrome is caused by the action of certain substances synthesized by the tumor formation.

Paraneoplastic syndromes are also called paraneoplasias, they represent a very heterogeneous group of diseases that develop in the body under the influence of oncological changes, but are not the result of the action of a specific malignant formation on certain organs and tissues. These disorders appear as a result of its conditional influence on metabolic processes and other body functions.

Paraneoplastic syndrome and pathological anatomy are closely related.

Criteria

There are the following criteria:

1. Parallel development and simultaneous existence of oncological and non-oncological diseases.
2. The disappearance of symptoms of a benign disorder after the use of radical surgical procedures to remove a malignant neoplasm, or effective radiation treatment and chemotherapy.
3. The resumption of paraneoplastic syndrome with the appearance of tumor metastases, or with a relapse of this disease.
4. Correlation of both processes.

The first scientific descriptions of the connection between non-oncological diseases and malignant neoplasms appeared more than a century ago, and the researchers who first described them are the French general practitioner Trousseau and the Austrian dermatologist Gebra. However, the modern doctrine of such medical phenomena is one of the youngest in the field of oncological science and literature. There are still a lot of unresolved questions in it, which concern not only the mechanism of paraneoplasia, but also which diseases can be classified as paraneoplastic. Nevertheless, in modern medicine, it is very important for practicing oncologists to know the possibilities of combining certain diseases with each other, which, one way or another, can be associated with the presence of a malignant tumor in the body.

Research data and practice are important not only for this reason. It is known that paraneoplastic syndromes tend to develop at any of the stages of the oncological process, but most often at later ones. These diseases can be disguised as benign lesions, under which the earliest forms of oncological diseases are hidden. Moreover, sometimes there are cases of manifestation of such syndromes, which are the very first signs of malignant tumors. From this follows their special diagnostic value. The very term "paraneoplastic disease" in modern literature is considered not entirely accurate, since such ailments do not accompany malignant neoplasms, but are caused by them.

There are no specific and clear data on how often paraneoplastic syndrome occurs in oncology, however, judging by the data of medical studies, this frequency can vary from 15 to 70% or more with the progression of the tumor process. Now oncological medicine knows more than 70 varieties of malignant tumors, and this list is growing every year, and more and more information about paraneoplasia is becoming.

In the endocrine system

Paraneoplasia of endocrine origin includes diseases such as hypercortisolism, often associated with oncological diseases that develop in the human lungs, as well as tumor processes in the pancreas, abdominal organs, and digestion. These ailments are predominantly male patients. In such cases, the development of paraneoplastic disorders can be regarded as follows: the cells of some tumors have a high hormone-producing activity, and an excess or, conversely, a deficiency of a certain hormone causes the development of endocrinological disorders. The mechanism of hypoglycemia, which in most cases accompanies oncological processes, has the same structure.

These syndromes in endocrinology are often observed in the development of lung and bronchial cancer, some forms of which, for example, intercellular, have a high ability to produce hormones of an ectopic nature.

There are also paraneoplastic ophthalmic syndromes.

Diseases of the circulatory system

This type of injury is quite rare. These include some forms of anemia, in which malignant tumors, which are often accompanied by proliferation of lymphatic tissue, provoke the death of a large number of red blood cells using an autoimmune mechanism. One of the forms of paraneoplastic syndrome in oncology of this category is polycythemia, which is extremely rare. It can accompany tumor processes in the kidneys. This disease can also occur due to too high production of erythropoietin.

The most common phenomenon among paraneoplastic syndromes in pediatric oncology of the hematopoietic system is a violation of blood clotting. For example, multiple thromboses of an immigrating nature. Approximately 5-10% of all cases of venous thrombosis are believed to be similar paraneoplastic diseases. Especially in cases where they occur in a place of unusual localization, for example, in the occipital veins or on the hands.

Paraneoplastic syndrome in neurology

These diseases are most often found in oncological lesions of the lungs, mainly in men, and manifest themselves in the form of neuromuscular disorders. These include, for example, peripheral neuritis. Somewhat less often, lesions of the central nervous system are observed in the form of a certain degeneration of neurons, as well as white matter.

In addition to peripheral neuritis, paraneoplastic diseases are very rarely diagnosed during the life of patients, and their true nature is determined already during the autopsy.

Paraneoplastic diseases of the muscular system

These diseases, with the exception of neuromyopathy, manifest as myopathies, myositis and myasthenia gravis, which lead to muscle atrophy. Prostigmin stops increasing muscle mass. Muscle pains are practically absent, there is also a stop of tendon reflexes. Paraneoplastic myopathy occurs in practice much more often than is commonly thought.

A characteristic paraneoplastic syndrome in the muscle system is also myasthenia gravis, which mainly affects the muscles of the pelvis, as well as the human torso. Polymyositis can be observed, which, as a rule, is accompanied by a variety of damage to the skin.

Consider paraneoplastic syndrome in rheumatology.

Joint damage

Such disorders in the human body manifest themselves much more often than others in the form of hypertrophic osteoarthropathy, when the fingers are predominantly affected. This paraneoplastic syndrome is characterized by a strong thickening of the fingers, and it is observed in people suffering from oncological diseases of a bronchogenic nature, as well as tumors of the pleura. This violation in most cases can be accompanied by gynecomastia.

Lymphatic system lesions

Such disorders in the system of lymph nodes are detected, as a rule, during histological studies of biopsy or autopsy materials. They manifest themselves in the form of the development of tuberculoid structures that do not have signs of caseous necrosis in the lymph nodes with any type of cancer of the internal organs. This histological structure may be characteristic of a disease such as sarcoidosis, which is also called Besnier-Beck-Schaumann disease. Paraneoplastic syndrome is common in lung cancer. Such disorders in the body's lymphatic system were previously considered random combinations of two unrelated diseases - oncology and sarcoidosis. Disturbances in the work of the lymph nodes were found, as a rule, during studies to identify the presence of metastasizing formations in cancer of the lungs, cervix, etc. To date, such violations are considered to be a paraneoplastic disease.

For skin lesions

Cutaneous paraneoplastic syndromes are very diverse, since the skin is the organ where their manifestations are most often localized. One of the most common and studied diseases of this nature is acanthosis nigricans, a specific chronic dermatosis, the clinical picture of which is characterized by the presence of papillomatous thickenings, as well as skin indurations with hyperpigmentation and hyperkeratosis, localized mainly in the area of ​​the axillary cavities and on the back of the head. The lion's share of patients with this disease is diagnosed with oncology of the pancreas or stomach, sometimes the lungs. In women, these ailments can be a sign of the development of ovarian and breast cancer.

It is very important to note that the majority of patients with acanthosis nigricans have a clinical picture of the development of some tumor processes, but initially such patients turn to dermatologists. Thus, the diagnosis of a typical chronic dermatosis in an adult by this specialist dictates the urgent need for a careful examination for oncological diseases. If the results of such diagnostics gave negative results, such patients should still be under dispensary observation in an oncological institution for a long period.

The next most common is paraneoplastic syndrome, which manifests itself in the form of a skin disease such as dermatomyositis. In patients who have been diagnosed with this disease, which belongs to the group of collagenoses, tumor processes are detected 6-8 times more often than in other people. Oncological diseases that can cause this disease are sarcoma and cancer of various internal organs, lymphoma, leukemia.

With other skin diseases known to medicine, described in science as paraneoplastic, the frequency of their combination with oncological formations is much lower than in cases with dermatomyositis and acanthosis nigricans.

Unclassifiable forms

Such violations are very diverse. They, as a rule, do not manifest themselves in the form of lesions of the internal organs of a person. Symptoms of paraneoplastic syndrome in this case can be:

• various fevers of unusual origin, especially in patients with metastases;
• weight loss in the presence of a negative nitrogen balance, which is due to the decay products of a malignant tumor;
• pain in cases where there is no direct connection between the tumor and the surrounding nerve endings;
• some mental disorders, etc.

Pathogenesis

This aspect, as well as the mechanism of long-term action of malignant formation, is not well understood in order to draw conclusions. It is believed that such symptoms, if we consider their connection with oncological ailments, are diseases of a secondary nature, and in order for them to begin to develop, it is necessary to change the internal background of the body. When these prerequisites arise, most likely, a wide variety of factors are involved, for example, cachexia, hormone-producing tumor tissue, autoimmunization of the body, trophic disorders, and many others.

Nevertheless, there are special genetically determined complexes of symptoms, one of the manifestations of which is an oncological neoplasm. An example here is a variety of which are known by the names of the authors who described them. For example, the Peutz-Touraine-Jeghers syndrome, which manifests itself in the form of hyperpigmentation of the skin of the fingers, as well as around the natural openings on the body, as well as generalized intestinal polyposis.

Main classification

Despite the fact that there is no single and clear classification of these syndromes, some researchers in the field of medicine still systematized their main manifestations. These include:

• Metabolic and endocrine diseases (hypercalcemia, carcinoid syndrome, hypertrophic osteoarthropathy, hyperuricemia, cryofibrinogenemia, Itsenko-Cushing's syndrome, Acantosis nigricans, increased ADH excretion, carcinoid syndrome, etc.).
• Endothelial diseases (thromboendocarditis and migrating thrombosis, as well as phlebitis). Allergic and autoimmune disorders of a secondary nature (systemic lupus erythematosus, Hashimoto's autoimmune thyroiditis, dermatomyositis, nephrotic syndrome, rheumatoid arthritis, hemorrhagic vasculitis, thrombocytopenic purpura, scleroderma, anaphylactic shock, urticaria, hemolytic anemia).
• CNS lesions, as well as neuromuscular diseases (dementia, psychosis, Eaton-Lambert syndrome, and others).
• Others (celiac disease, etc.).

Some diseases of a rheumatological nature may be associated with an increased risk of developing oncological pathologies. However, paraneoplastic processes often manifest themselves in the form of rheumatological diseases. Thus, when diagnosing the health status of such patients, specialists should adhere to the principles of increased vigilance due to the possible oncological nature of these disorders.

Diagnostics

In order to qualitatively and adequately diagnose the nature of the origin of a particular paraneoplastic disease, there is a certain list of specific laboratory tests of the patient's blood that will help to establish the cause of such disorders and rank them among the number of oncological changes in the human body.

These studies are special diagnostic tumor markers:

• for the mammary gland: CA-15-3, M20, M22, CEA, MUCI;
• for the uterus, as well as the cervix: M22, M20, CEA;
• testicles in men: CEA, hCG, AFP;
• ovaries in women: CA 125, AFP, CA 724, hCG, M22, CEA, M20;
• for the bladder: H/F, CYFRA 21-1;
• for the prostate gland: prostatic phosphatase, PSA total, PSA free;
• for the thyroid gland: calcitonin, thyroglobulin, CEA;
• for lungs and bronchi: NSE, NEA, CYFRA 21-1, M22, CA 72-4, M20;
• for the stomach and esophagus: CA 72-4, CA 19-9, CEA;
• for the liver: AFP, SA 19-9, CEA.

There is a popular diagnostic method - immunoblot. Antibodies in paraneoplastic syndromes (antineuronal) are immunoglobulins, they are active against tumor tissue neurons and protein antigens in the cytoplasm. This group includes antibodies Yo-1 (PCA1), Hu (ANNA-1), CV2, Ri (ANNA-2), Ma2, amphiphysin.

In neurology and oncology, analysis is often used, it is indispensable in the diagnosis of paraneoplastic neurological diseases, it helps to establish the presence of paraneoplastic encephalomyelitis, sensory neuropathy, progressive cerebellar degeneration, paraneoplastic myoclonus and ataxia, and muscle stiffness syndrome. The biomaterial is blood serum, which is taken from a vein. Normally, the result should be negative.

In paraneoplastic syndrome, PDF is increased. Also, thromboembolic complications often lead to the death of cancer patients. The presence of chronic thrombohemorrhagic syndrome in the laboratory is diagnosed on the basis of an increased concentration of fibrinogen (2-2.5 times higher than normal), PDF (4-4.5 times higher than standard values), and increased platelet aggregation is also noted.

For the correct diagnosis of paraneoplastic and oncological processes in the human body, it is necessary to initially exclude the presence of autoimmune failures that can occur with pathologies of the nervous system.

Autoimmune markers include:

• SRP (qual.), RF (qual.);
• SRP (col.);
• AT to single strand DNA;
• ASLO;
• anti-ENA
• LE cells;
• Anti-MCV (citrulline);
• AT to native DNA and others.

How else is paraneoplastic syndromes determined in the clinic of internal diseases?

Additional diagnostic criteria

Confirmed symptoms:

• Classic neurological syndromes with the presence of oncological formation, which was diagnosed no later than 5 years after the development of this symptomatology.
• Non-classical syndromes that may disappear, or their severity significantly decreases after anti-cancer therapy, however, in this case, it should be revealed that the neurological deficit is not prone to self-remission.
• Non-classical syndromes with malignant tumor processes and with the detection of antibodies to neurons.
• Neurological syndromes of undifferentiated nature without malignant tumors.

Probability of occurrence

Possible cases of the development of this kind of syndromes:

1. Classical diseases with high risks of having a malignant tumor without the formation of antibodies to neurons. Paraneoplastic syndrome in cancer occurs quite often.
2. Without detection of oncological processes, but with the presence of such antibodies.
3. Paraneoplastic disorders of a non-classical nature with the presence of an oncological tumor diagnosed no later than two years after the discovery of neurological symptoms, without the presence of antibodies to neurons.

Almost 75% of patients who have been diagnosed with paraneoplastic orientation syndromes are diagnosed with the first signs of malignant processes in the body. In 80% of such people, positive results are detected when screening for the presence of cancer. The bulk of neoplasms of this nature are detected by radiological examination of organs located in the chest area, as well as in the abdominal cavity and small pelvis using computed tomography and PET methods.

Treatment of paraneoplastic syndrome

Therapy consists primarily in the treatment of the original cancerous tumor. Sometimes it is necessary to prescribe additional medications that suppress the immune processes that provoked the syndrome.

Medicines are used in combination with chemotherapy. The following drugs are relevant today:

• a group of corticosteroids ("Prednisolone");
• immunosuppressive agents such as "Cyclophosphamide", "Azathioprine";
• neuromuscular conduction stimulants such as "Pyridostigmine";
• anticonvulsants such as carbamazepine.

We reviewed the main types of paraneoplastic syndromes.

● There is not a single more or less significant pathophysiological phenomenon in the body in which the joints would not hurt Diterikhs M. M.

Rheumatology "overlap" oncology "Common" viruses VIRUSES Hepatitis B (HBV) and C (HCV) RHEUMATOLOGY ONCOLOGY ST: polyarteritis nodosa and Liver cancer others, cryoglobulinemia B-cell lymphoma Epstein-Barr virus (HHV Systemic diseases Burkitt's lymphoma-4) (SLE, SJS, SS) Lymphogranulomatosis Nasopharyngeal cancer Cytomegalovirus SLE, SJS, SS (?) Herpes virus type 8 Kaposi's sarcoma virus (HHV -8) study model Induced immunity Lymphoproliferative pathology Parvovirus B 19 Arthritis Oncohematological diseases Retrovirus 5 (HRV -5) SLE, SS, etc. Leukemias, lymphomas, sacromas T-lymphotropic virus SS, polymyositis, alveolitis, RA T-cell lymphoma type 1 (HTLV-1) (?)

Rheumatology «overlap» oncology General factors LECTURE PROBLEM OF ASSOCIATION OF RHEUMATIC AND ONCOLOGICAL DISEASES (pathogenetic and clinical aspects) N. G. Guseva GU Institute of Rheumatology, Russian Academy of Medical Sciences, Moscow PRACTICAL RHEUMATOLOGY № 4, 2004

Rheumatology "overlap" oncology Chemical factors ● Carcinogens (industrial, domestic, environmental) ● "Rheumatogenic" agents in plastic surgery and cosmetology ● Drug-induced SLE (procainamide, isoniazid, hydralazine, etanercept, infliximab, sulfasalazine) ● Induced SJS (bleomycin, topotecan) ● Acute polyarthritis (tamoxifen - estradiol inhibitor)

"Postchemotherapeutic rheumatism" Development of symptoms 2-16 months after chemotherapy (cyclophosphamide, methotrexate, fluoracil, etc.). ● ● ● myalgia arthralgia periarticular changes tenosynovitis less often - scleroderma and lupus-like diseases.

Trastuzumab (Herceptin) recombinant humanized monoclonal antibodies Musculoskeletal and connective tissue disorders: very common - arthralgia, muscle stiffness, myalgia; often - arthritis, back pain, ossalgia, muscle spasms, pain in the neck, pain in the limbs.

Rheumatology "overlap" oncology Immunological factors Autoantigens ● ● oncoproteins tumor suppressor proliferative other antigens. !!! Activation of autoimmune mechanisms in patients with malignant diseases is the basis for the development of rheumatic paraneoplastic syndromes and diseases.

Definition Paraneoplastic syndrome (PNS) - clinical and laboratory disorders that occur in malignant tumors and are caused by nonspecific reactions from various organs and systems or ectopic production of biologically active substances by the tumor.

Chronologically, PNS can ● precede the appearance of local symptoms of a malignant tumor (sometimes by several years) ● occur simultaneously with them ● develop after the establishment of the tumor process (1-2 years) or appears with a relapse of neoplasm N. B. ! PNS are not directly related to tumor volume and the number of metastases

What kind of tumors ● It is rheumatic PNS - with poorly differentiated neoplasms of epithelial origin ● ● ● ● Bronchogenic lung cancer Breast cancer Ovaries Uterus Prostate gland Stomach Large intestine Nephrocarcinoma

Classification of PNS (Laurie Yu. I. et al., 1972) ● Metabolic and endocrine disorders of GOA, hypercalcemia, hyperuricemia, acantosis nigricans, carcinoid syndrome, hyperfibrinogenemia, cryofibrinogenemia, Itsenko-Cushing's syndrome, hypoglycemia, increased excretion of ADH ● Vascular / endothelial disorders migratory thrombophlebitis, thromboendocarditis

Classification of PNS (Lorie Yu. I. et al., 1972) ● Secondary autoimmune and allergic syndromes dermatomyositis scleroderma SLE RA autoimmune thyroiditis Hashimoto hemolytic anemia thrombocytopenic purpura hemorrhagic vasculitis nephrotic syndrome urticaria anaphylactic shock

Classification of the PNS (Laurie Y. I. et al., 1972) ● Central nervous system and neuromuscular disorders Psychosis, dementia, Eaton-Lambert syndrome, acute demyelination of the cerebral cortex or spinal cord, peripheral sensory or sensory-motor neuropathy ● Other effusion pericarditis, celiac disease

Pathogenetic mechanisms of PNS Hormonal Production of bioactive substances and hormones by tumor cells Decreased sensitivity of target tissues to hormonal effects Disruption of endocrine regulation. Immune The similarity of tumor antigens and healthy tissues causes a reaction of humoral and cellular immunity, contributing to the development of autoimmune changes. Biochemical Tumor tissue is a "trap" for metabolites (nitrogen, glucose, lipids, vitamins, etc.). Changes the biochemical metabolism in the body, depleting the resources of healthy tissues and their functional activity. Genetic More than 200 hereditary syndromes are known to predispose to the development of neoplastic processes.

Paraneoplastic articular (PNS) and related syndromes ● Tumor-associated arthritis (rheumatoid-like, ankylosing Sp. A) ● Palmar fasciitis, contractures ● Migrant tendovaginitis ● Hyperuricemia and gouty arthritis ● Hypercalcemic arthropathy ● Hypertrophic osteoarthropathy ● Steatonecrotic polyarthritis ● Shoulder-hand syndrome, algodystrophy (reflex sympathetic dystrophy) ● Panniculitis, polymyalgia rheumatica

Features of paraneoplastic articular syndrome Variable More often asymmetric lesion of 1-3 joints Severe joint deformity is not typical Prevalence of exudative changes in small and large (knee) joints ● Arthritis in combination with tendinitis, myalgia, ossalgia ● A combination of several PNS with various clinical and laboratory manifestations is possible, which complicates the diagnosis and timely recognition of the tumor. ● Inconsistency of the severity of the condition with inflammatory changes in the joints ● ●

Features of pain in paraneoplastic articular syndrome ● Predominance of pain intensity over other manifestations of the articular syndrome ● Pain is poorly relieved ● Constant, aggravated by movement ● In some cases, stiffness is possible (less than 30 minutes) ● Persistent arthralgia, resistant to standard therapy ● Ossalgia, myalgia (polymyalgia )

Features of PNS: response to therapy ● Resistant to treatment with GCs, NSAIDs ● May weaken or disappear during tumor treatment (surgical removal, chemotherapy) - 78.5% ● Reappear with relapse or metastasis.

Laboratory changes ● ● A sharp increase in ESR, anemia, RF in 15% ANCA, ANA (26%) Antiphospholipid antibodies

Hypertrophic osteoarthropathy 22-30% - lung cancer: mesothelioma - 50-60%, bronchogenic cancer - 10-20%

Hypertrophic osteoarthropathy ● Radiographically periosteal overlays around the diaphysis. ● GOA of tumor origin develops relatively quickly with a pronounced pain syndrome. ● There may be an isolated thickening of the nail phalanges in the form of "drum sticks", ● Due to the development of connective tissue elements, swelling of soft tissues and periosteum ● Patients with isolated "drum sticks" syndrome are not characterized by damage to the interphalangeal joints.

Rheumatoid-like arthritis Associated with lymphoproliferative processes (lymphoma, myeloma, leukemia), cancer of the lung, gastrointestinal tract, prostate.

Rheumatoid-like arthritis ● ● ● asymmetric mono-, oligo- or polyarthritis; lack of expression of the inflammatory reaction of the joints; no deformation; compaction of periarticular tissues; absence of rheumatoid nodules and RF in the blood; absence of pathological changes on radiographs of bones and joints; ● refractoriness to anti-inflammatory therapy; ● the effectiveness of antitumor treatment, which is accompanied by positive dynamics of the articular syndrome.

Clinical example Paraneoplastic articular syndrome in Hodgkin's lymphoma ● Patient Sh., ml. sergeant, drafted 05.2014 ● June 2015 - edema of both feet and n / 3 lower legs, difficulty in moving in the ankle joints, T 37.8 C. Hospitalized with a diagnosis of pneumonia. ● Inspection dif. d-z with debut RA, Sp. A ● Antibacterial therapy, NSAIDs - preservation of edema, subfebrile condition, prescription of GC - no complete answer ● Re-hospitalization 09.2015 - lymphadenopathy of the cervical lymph nodes. Biopsy. Histological examination of the cervical lymph node from 21.09.15: lymphogranulomatosis, nodular sclerosis ● Final diagnosis: Hodgkin's lymphoma, a variant of nodular sclerosis.

Spondyloarthropathies ● In the elderly, regardless of gender ● Asymmetric lesions of the hip joints are characteristic. ● In esophageal carcinoma and Hodgkin's disease, the rhizomelic form of ankylosing spondylitis may develop. .

Leukemias and paraneoplastic articular syndrome ● In 4% of adults, the first manifestations of leukemia are articular syndrome ● Manifested by symmetrical or migrating polyarthritis, ossalgia, back pain of the type of radiculopathy. ● Articular manifestations are the result of leukemic infiltration of the synovial membrane, hemorrhages in the joint or periarticular tissues.

Clinical example: acute lymphocytic leukemia and Sp. A ● Man, 18 years old ● For 4 months - complaints of pain in the lower back and left knee joint ● Pain persisted throughout the day and at night, without morning stiffness. Rest did not bring relief. Over time, the pain became unbearable ● Heredity according to Sp. Not aggravated ● NSAIDs (15mg/day) had no effect ONCOLOGY LETTERS 11: 1143 -1145, 2016

Clinical example: acute lymphocytic leukemia and Sp. A ● MRI - moderate bilateral erosive sacroiliitis ● No effect from NSAIDs ● Objectively T 38 C, splenomegaly ● ANA, ANCA, RF, HLA-B 27 - negative. ONCOLOGY LETTERS 11:1143-1145, 2016

Paraneoplastic seronegative polyarthritis ● Dominant lesion of periarticular tissues ● Formation of contractures ● Increasing restriction of movements ● Predominantly in young and middle-aged women Lymphoproliferative diseases Ovarian cancer

Palmar fasciitis and polyarthritis syndrome - Systematic literature review of 100 cases B. Manger, G. Schett/Seminarsin. Arthritis and. Rheumatism] (2014)

Syndrome of palmar fasciitis and polyarthritis / ● Predominantly hand or generalized. ● Damage to the hands varies from diffuse edema to the development of typical Dupuytren's contractures. ● In this case, lesions of the shoulder, metacarpophalangeal and proximal interphalangeal joints, morning stiffness are observed. Fasciitis-panniculitis syndrome ● Edema, induration of the skin and underlying tissues, including deep layers of subcutaneous tissue and fascia, sometimes accompanied by eosinophilia. More often in women

Steatonecrotic polyarthritis ● More common in older men. ● Pseudo-gouty nature of the articular syndrome ● Rapid mono- or oligoarthritis in combination with non-purulent subcutaneous nodules that occur during relapses of fever. ● X-rays of bones and joints: microcysts due to necrosis of bone marrow fat.

Recurrent seronegative symmetrical synovitis with hand edema (RS 3 PE) ● Sudden onset ● Elderly men ● RF "-" ● Often fever, weight loss ● No effect of GCs

Hypercalcemic arthropathy ● breast, lung and kidney cancer. ● muscle pain and weakness, ossalgia, anorexia, arrhythmia, polyuria, fatigue, drowsiness. ● 20% of patients with hypercalcemia are asymptomatic.

The safety issue of basic and biological drugs ● In general, patients with RA and active malignancies should not be treated with DMARDs and GEBAs while they receive chemotherapy and radiotherapy. ● The decision on treatment is made jointly with the oncologist and the patient. ● If a malignant neoplasm occurs in a patient with RA, all DMARDs should be discontinued, with the exception of aminoquinoline drugs, gold salts and sulfasalazine. ● With current malignant neoplasms, it is not recommended to use GIBP www. rheumatologist. en

Algorithm of actions ● Thorough oncosearch, including targeted, taking into account the correspondence of the form of the articular syndrome to a certain oncological nosology, tumor markers ● No confirmed oncopathology - dynamic observation, repeated oncosearch Cancer

Inflammation is crucial for cancer development - Inflammation is crucial for cancer development Paraneoplastic syndrome - a rheumatologist's point of view Assoc. A. E. Buglova Department of Cardiology and Rheumatology Bel. MAPE 26 - 27. 05. 2016 - lll Eurasian Congress of Rheumatologists

Paraneoplastic syndrome develops in the presence of a malignant neoplasm, but is not associated with a direct effect of tumor cells on other tissues, is not due to the action of metastases, the presence of concomitant infection, nutritional deficiency, or treatment of the disease itself. Rheumatic diseases associated with malignant diseases are independent nosological forms of an autoimmune inflammatory nature that usually occur in the absence of neoplasms. However, in these rheumatic diseases, either a high risk of developing malignant diseases remains, or there is a primary malignant disease that cannot be detected at this stage. This category of diseases includes such systemic connective tissue diseases as dermatomyositis and Sjögren's disease.
Paraneoplastic syndrome may be due to several mechanisms. The tumor can cause dysfunction of various tissues by ectopic expression of hormonal factors. For example, hypercalcemia in tumors develops as a result of the ectopic expression of PTH-related proteins, which are somewhat different from PTH itself, but their physiological activity does not differ from the action of PTH itself. This results in increased bone resorption. At the same time, parathyroid proteins can contribute to the growth of the tumor itself and the development of osteolytic metastases. Most often, this mechanism is inherent in glandular carcinoma of the lungs and kidneys.
Another mechanism for the formation of paraneoplastic syndrome may be associated with tumor antigens, to which the human immune system reacts with the formation of autoantibodies, including antibodies to double-stranded DNA and antinuclear antibodies. Currently, more than 400 types of such antigens are known. In most cases, the clinical significance of these autoantibodies has not been established, but in some paraneoplastic conditions (paraneoplastic neurological degeneration), their role has been determined.
The paraneoplastic syndrome primarily includes myopathy and arthropathy, as well as various nonspecific clinical symptoms. Criteria for the definition of rheumatic paraneoplastic syndrome do not exist, however, certain symptoms may indicate the presence of a neoplastic process. Information on the prevalence of paraneoplastic syndrome in patients with malignant diseases, and especially in certain types of tumors, is not available. However, it is known that approximately 15% of patients admitted to the hospital for malignant disease had a paraneoplastic syndrome. Approximately 1/3 of patients paraneoplastic syndrome was due to hormonal dysfunction, in other cases, hematological, rheumatic and neurological disorders were observed. It is believed that certain manifestations of paraneoplastic syndrome in cancer patients can develop during the course of the disease in 50-75% of cases. Characteristics of rheumatic paraneoplastic syndrome are presented in Table. 14.1.
Dermatomyositis and polymyositis. Dermatomyositis, more rarely polymyositis, can be associated with a wide range of solid tumors, sarcomas, carcinomas, and lymphomas. In one Scandinavian study conducted in 2001, in which

Clinical characteristics
Association with neoplasm
laboratory
diagnostics
Other diagnostic methods

Dermatomyositis and polymyositis
Myasthenic syndrome (Eaton-Lambert)
Hypertrophic osteoarthropathy
Paracancrotic polyarthritis
Amyloidosis
Lupus-like syndrome
sympathetic
dystrophy:

1. type (shoulder-hand syndrome);
2. type (polyarthritis, palmar fasciitis)

Steadily progressive proximal muscle weakness; skin rash with dermatomyositis
Muscle weakness (most pronounced in the pelvic girdle and hips); diplopia, dysarthria, ptosis
Hypertrophy of fingers and toes; periostitis with ossalgia; arthralgia or frank arthritis with effusion
Asymmetric arthritis with a primary lesion of the joints of the lower extremities
Peripheral neuropathy: cutaneous purpura, subcutaneous nodules, scleroderma-like skin infiltration, arthropathy, carpal tunnel syndrome, cardiomyopathy
Raynaud's syndrome; pleurisy; pneumonitis; pericarditis; nonerosive polyarthritis

1. type: pain in the upper limbs, trophic skin changes;
2. type: the same; aggressive polyarthritis and palmar fasciitis

Equally common in various tumors
Small cell lung cancer
Lung adenocarcinoma, mesothelioma, lung metastases
breast cancer in women; in men, the predominant localization of the tumor was not revealed
Multiple myeloma. Waldenström macroglobulinemia, lymphomas and carcinoma
Ovarian adenocarcinoma, lymphoma, thymoma, myeloma, lung, colon, breast, testicular cancer

1. type: brain, lungs, uterus, mammary gland, esophagus
2. type: ovarian cancer, small cell lung cancer, pancreatic adenocarcinoma, chronic myeloid leukemia, malignant non-Hodgkin's lymphoma

Increase in creatine phosphokinase (CPK)
Increase in alkaline phosphatase. ESR
Absence of RF and ANA in blood serum
Antibodies to DNA
Electromyo
graphy;
muscle biopsy
Electromyo
graphy
Radiography of long tubular bones; skeletal scintigraphy
No specific radiological changes
Soft tissue biopsy
Radiography of the upper extremities (osteopenia);
scintigraphy
skeleton

more than 900 patients with dermato- or polymyositis were included, it was shown that the incidence of malignant disease in this group of patients was 32%. Thus, the relative risk of developing a tumor in dermatomyositis and polymyositis was 2.9 and 1.75, respectively, compared with the general population. A closer relationship between malignancy and dermatomyositis was found in men older than 50 years: more than 70% of male patients were diagnosed with neoplasm. It is also known that secondary paraneoplastic dermato- or polymyositis often develops in children. The relationship between these two diseases is not fully understood, and literature data are contradictory. So, the tumor may precede the onset of dermatomyositis, compete with it, or develop against it.
Myasthenic syndrome (Eaton-Lambert). This syndrome refers to autoimmune forms of pathology, its main manifestation is muscle weakness. Most often, myasthenic syndrome develops in patients with lung cancer, especially in small cell cancer. E. Lambert [et al.] (1956, 1965) discovered and described this syndrome in 6% of patients with small cell lung cancer and less than 1% of patients with other lung tumors.
Hypertrophic osteoarthropathy. There are primary and secondary hypertrophic osteoarthropathy. The primary form is not associated with any systemic disease. Among the secondary causes of hypertrophic osteoarthropathy, malignant tumors play a leading role. Most often, this syndrome develops in various lung tumors, especially in adenocarcinoma (in 12% of cases), as well as in lung diseases complicated by respiratory failure. The list of diseases accompanied by hypertrophic arthropathy includes mesothelioma, kidney metastases, lymphogranulomatosis, thymoma, esophageal leiomyoma, osteogenic sarcoma, fibrosarcoma, undifferentiated nasopharyngeal tumor. Hypertrophic arthropathy practically does not occur in small cell lung cancer. Clinically, this syndrome is manifested by thickening of the terminal phalanges of the fingers and toes due to local proliferation of the skin and bone tissue, which leads to the formation of the so-called "drumsticks", periostitis of tubular bones, oligo- or polysynovitis.
According to one hypothesis, the development of proliferative processes in the distal extremities is associated with the movement there of megakaryocytes capable of secreting growth factors that are normally inactivated in the lungs. More often arthropathy is accompanied by severe pain than deformity of the fingers. This syndrome is defined only in adults. The likelihood of a paraneoplastic process increases with the rapid progression of hypertrophic osteoarthropathy. Plain radiography of the hands and feet can confirm the diagnosis in the presence of periostitis in the distal phalanges, osteophytosis, and sometimes acroosteolysis. Successful treatment of malignant disease leads to remission of hypertrophic osteoarthropathy.
Paracancrotic polyarthritis. The development of asymmetric arthritis predominantly of the joints of the lower extremities in persons over 65 years of age should always be considered as a possible paraneoplastic symptom. If in men the predominant localization of the tumor is not described in the event of paracancrotic polyarthritis, then in women, cancer is diagnosed in 80% of cases.
mammary gland. The clinical picture of paracancrotic polyarthritis may correspond to the clinic of seronegative rheumatoid arthritis.
Amyloidosis. Approximately 15% of cases of amyloidosis are believed to be due to malignant diseases, among which lymphoproliferative diseases (myeloma, lymphomas) and carcinomas predominate. Thus, amyloidosis develops in 6-15% of patients with myeloma and Waldenström's macroglobulinemia, in 4% of patients with lymphogranulomatosis and in 1% of other non-Hodgkin's lymphomas. The following types of carcinomas are associated with amyloidosis: hypernephroma, cancer of the bladder, kidney, cervical canal, and biliary tract. The spectrum of clinical manifestations of amyloidosis associated with neoplasms includes peripheral neuropathy and mononeuropathy, weight loss, and restrictive cardiomyopathy. When examining the skin and mucous membranes, purpura, subcutaneous nodules, scleroderma-like infiltration of skin areas, and macroglossia can be detected. Arthropathy in amyloidosis has the following symptoms: predominantly large joints (shoulder, knee, wrist) are affected, soreness and stiffness of the joints are noted. Sometimes infiltration near the joint can be quite pronounced. Amyloidosis is also characterized by the development of carpal tunnel syndrome.
Arthropathy Jacques. Jacques arthropathy is a rapidly progressive, non-erosive arthropathy, leading to the development of limited deformities of predominantly small joints of the upper extremities and accompanied by pain syndrome of varying severity. Currently, there are descriptions of cases of the development of Jacques arthropathy in lung cancer, but most often it occurs in systemic lupus erythematosus.
Paraneoplastic lupus-like syndrome. The syndrome can develop in malignant diseases such as Hodgkin's lymphoma (lymphogranulomatosis), multiple myeloma, neoplasms of the lungs, colon, breast, ovaries, testicles. The syndrome includes polyserositis (pleurisy, pericarditis, pneumonitis), non-erosive polyarthritis, and antinuclear antibodies. The rapid development of serositis and Raynaud's syndrome is associated with ovarian adenocarcinoma.
Paraneoplastic scleroderma-like syndrome. Currently, there is no consensus that scleroderma should be classified as a paraneoplastic syndrome. In the literature, there are descriptions of cases of a combination of scleroderma and tumors such as adenocarcinoma and carcinoma. Despite the fact that the malignant disease was manifested by skin symptoms, signs of systemic sclerosis were detected in half of the cases.
There are also two syndromes in which patients have signs of skin lesions similar to scleroderma. These are POEMS syndrome and Werner's syndrome. POEMS syndrome is a rare form of plasmacytic dyscrasia associated with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and scleroderma. Werner's syndrome is an autosomal recessive disorder characterized by juvenile cataracts, scleroderma-like skin lesions, accelerated aging, and a high incidence of connective tissue neoplasms.
Necrotizing vasculitis. The development of necrotizing vasculitis occurs against the background of hemoblastoses (leukemia) and lymphomas. Most often affected
vessels of small or medium caliber. According to the predominant localization of vascular lesions, either skin purpura develops, or a skin ulcerative-necrotic process with multiple neuritis, an abdominal syndrome, as in polyarteritis nodosa. Sometimes neoplasm manifests itself as digital gangrene, the possible causes of which may be cryoglobulinemia, deposits of immune complexes in the vessel wall, hypercoagulability, and vascular embolization.
Nodular erythema. Erythema nodosum, as one of the variants of cutaneous vasculitis, is most often a manifestation of Hodgkin's and non-Hodgkin's lymphomas, as well as some hemoblastoses. Pancreatic carcinoma may be accompanied by skin panniculitis (infiltration around fat cells), which is clinically similar to erythema nodosum. Differential diagnosis is carried out only on the basis of histological examination.

Paraneoplastic syndrome is a set of clinical signs and laboratory indicators of oncopathology that are not associated with metastasis and growth of the primary tumor. Manifestations of the syndrome are due to disorders occurring in target organs. Pathology develops in response to the release of biologically active substances into the blood by cancer cells. This affects the organs of the endocrine and immune systems, skin, heart and blood vessels, nerve fibers, muscle tissue, kidneys, gastrointestinal tract.

Specific antibodies appear in the blood when a malignant tumor develops in the body. They cross-react with normal tissues and damage them, which also leads to the development of paraneoplasia. Antitumor immunity is formed, which has little effect on the course of an already developed tumor, but becomes the main cause of the development of this syndrome.

Paraneoplastic syndrome is manifested by disorders of various organs and systems and is secondary. It occurs mainly in the elderly, becomes a nonspecific marker of neoplasm and a frequent companion of lymphoma, lung, ovarian, and breast cancer. Paraneoplasia often interferes with the recognition of a true tumor, masking its manifestations. In some patients, clinical signs of paraneoplastic syndrome precede symptoms of malignancy. Sometimes they are years ahead of the manifestation of cancer. This is especially noticeable with skin manifestations, neurological disorders, polymyositis, and fever.

Paraneoplastic syndrome does not occur in all cancer patients. Only 15% of patients suffer from this pathology. In more rare cases, paraneoplastic syndrome develops with some benign tumors and non-tumor diseases: rheumatism, pulmonary pathology, heart disease, endocrinopathies.

For the first time they started talking about this disease at the end of the 19th century, and only in the middle of the 20th century the term "paraneoplasia" was officially approved. The variety of systemic manifestations and the involvement of almost all vital organs in the process are signs that create certain difficulties in the diagnosis of paraneoplastic reactions.

Classification

Etiopathogenetic classification:

• Endocrine paraneoplasia are divided into two main types: hypercortisolism in lung cancer and hyperthyroidism in cancer of the gastrointestinal tract. Hormone-producing tumor cells secrete biocompounds in excessive or insufficient amounts, which leads to the development of an endocrine symptom complex. Most often, endocrine paraneoplasia occurs in bronchial cancer with ectopic hormone production.
• Paraneoplastic syndrome with damage to the hematopoietic system- a rare thing. Common forms of pathology: anemia, polycythemia, vein thrombosis. Paraneoplasia is based on hyperplasia of lymphoid tissue with proliferation, natural destruction of red blood cells, secondary erythrocytosis, disruption of the hemostasis system.
• Neurological paraneoplasia occur in lung cancer in men and are manifested by peripheral neuritis or CNS damage.
• Paraneoplastic muscle lesions occur in the form of myopathy, myasthenia gravis, myositis and often lead first to their hypotrophy, and then to complete atrophy.
• Articular paraneoplasia: hypertrophic osteoarthropathy with lesions of the fingers is observed in bronchial cancer and tumors of the pleura.
• Paraneoplastic dermatological syndrome- the most common manifestation of cancer of the abdominal cavity and small pelvis. Patients develop chronic dermatosis and papillomatosis. Their skin in certain areas of the body thickens and hyperpigmented. Dermatomyositis is often combined with malignant skin diseases. This collagenosis occurs against the background of cancer or sarcoma of various organs, leukemia, lymphoma. Cases of black acanthosis of the skin, migrating erythema, acquired ichthyosis, pyoderma gangrenosum, herpes zoster, visceral polyposis, poikiloderma of the whole body are described.
• Gastrointestinal manifestations of cancer- protein-losing enteropathy, anorexia and cachexia.
• Unclassified paraneoplastic syndromes include: fever of unknown etiology, weight loss, pain syndrome, mental disorders.

various paraneoplasias

Brief classification of paraneoplasia according to the morphological principle:

1. Metabolic disorders - an increase in the concentration of calcium or fibrinogen in the blood.
2. Endocrine disorders - benign enlargement of the mammary glands in men.
3. Vascular disorders - the formation of parietal blood clots in the cavities of the heart, the migration of blood clots through the veins.
4. Autoimmune-allergic disorders - vasculitis, dermatomyositis, myocarditis, nephronephritis.
5. Neurological disorders - cerebellar degeneration, damage to peripheral nerves.
6. More rare forms are anemia, excessive hair growth, fat in the feces.

Etiology

The etiology of most paraneoplastic syndromes remains unknown. Etiological factors in the development of paraneoplasia:

• Release of biologically active substances into the blood by cancer cells.
• Formation of antibodies in response to oncoantigens.
• Genetically determined susceptibility to the development of autoimmune processes.

The reasons for the development of the main types of paraneoplastic syndrome:

1. Neurological paraneoplasias develop as a result of an attack by anti-cancer antibodies or T-lymphocytes and normal neurons.
2. Nonspecific syndromes in the form of fever are due to the production of pyrogens and liver dysfunction; taste disturbance is associated with a deficiency of certain trace elements in the body; cachexia - with the release of biological compounds into the blood.
3. The rheumatological syndrome is caused by the production of antinuclear antibodies and the expression of antigens.
4. Nephrological syndrome - deposition of the CEC in the nephrons of the kidneys with a violation of the process of filtration and reabsorption.
5. Gastrointestinal syndrome - the formation of substances that affect the motor and secretory functions of the digestive tract.
6. Hemosyndrome - hyperproduction of hematopoietin, a violation of its breakdown and excretion, a tendency to bleed due to various blood clotting disorders.
7. The dermatological syndrome is caused by hypereosinophilia and immunosuppression, which are present in every cancer patient.

Pathogenesis

There are two main mechanisms for the development of paraneoplastic syndrome. The first is associated with the secretion of hormones by cancer cells, and the second is associated with the formation of oncoantigens.

Pathogenetic links of paraneoplasia in glandular carcinoma of the lung or kidney:

• ectopic release of parathyroid hormone or proteins associated with it,
• hypocalcemia,
• rapid destruction of bones,
• increased tumor growth
• spread of metastases.

The oncogenic path of development of the syndrome is due to excessive production of autoantibodies. The clinical role of most antigens currently remains unknown.

The risk group includes:

1. persons over 40 years old,
2. patients whose systemic clinical signs are resistant to treatment,
3. patients whose laboratory parameters do not correspond to the clinical diagnosis,
4. individuals with rapidly progressive visceral pathology,
5. patients with a complicated family history of cancer development,
6. patients in whom the severity of clinical symptoms decreases as tumor intoxication increases.

Factors contributing to the development of paraneoplastic syndromes:

• change in the internal environment of the body,
• cachexia,
• the presence of hormone-producing tumor tissue,
• autoimmunization,
• trophic disorder,
• genetic predisposition.

Symptoms

Clinical signs of the disease develop in a short time: for several weeks or months. The symptomatology of the pathology depends on the type of paraneoplastic syndrome and the affected organ. Common symptoms of pathology include: loss of appetite, exhaustion, fever, malaise.

1. The main symptoms of paraneoplasia are myopathy and arthropathy.. In patients, myasthenia gravis gradually increases, skin rashes, eyelid drooping, double vision appear. In the hypertrophic form, the fingers and toes increase and hurt, arthralgia and myalgia occur, the joints of the extremities become asymmetric.
2. Neurological paraneoplastic syndrome manifested by typical neurological symptoms up to the development of dementia. When the cerebellum is damaged in patients, the gait and swallowing process are disturbed, dizziness, nausea, ataxia, and dysarthria occur. The syndrome can occur in the form of encephalitis, neuroses, dementia, encephalomyelopathy, ganglionitis, funicular myelosis.
3. Endocrine paraneoplasia manifested by the phenomena of hormonal imbalance and metabolic disorders. With lung cancer, patients develop a pathology that clinically resembles Itsenko-Cushing's syndrome. Hypercortisolism is accompanied by a violation of the basic metabolism, the development of immunodeficiency, the appearance of ecchymosis, myasthenia gravis, and sexual disorders. Patients develop hyperglycemia, hypertension, atypical obesity, hirsutism, the face becomes moon-shaped. They complain of muscle weakness and swelling. In the blood and urine, the concentration of corticosteroids increases. Hypersecretion of antidiuretic hormone and parathyroid hormones is manifested by hyponatremia and hypercalcemia, respectively. Patients develop weakness, lethargy and other signs of asthenia, dyspeptic symptoms and mental disorders, leading to clouding of consciousness and coma.
4. Signs of hematological syndrome are: normochromic anemia, leukocytosis with a shift of the formula to the left, agranulocytosis, thrombocytosis, DIC, leukemoid reaction, eosinophilia.
5. The main manifestations of the skin syndrome are: itching, excessive keratinization of the skin, hair loss or excessive growth, pigmentary and papillary dystrophy. The skin is affected mainly on the neck, in the armpits, on the hips. Patients complain of intense night sweats and pigmentary changes in the epidermis.
6. Rheumatological syndrome proceeds according to the type of polyarthritis, osteoarthropathy, deformation of the nail plates, polymyalgia. It is observed in patients with multiple myeloma, cancer of the blood and intestines. Cancer of the mediastinal and pelvic organs is accompanied by the development of autoimmune diseases of the connective tissue: lupus, amyloidosis, scleroderma.
7. Gastrointestinal syndromes manifested by nausea, vomiting, watery diarrhea, dehydration and asthenization of the body, clouding of consciousness.

The appearance of nonspecific syndromes in patients is regarded by oncologists as an unfavorable prognostic factor. In patients, body temperature rises, taste is disturbed, anorexia develops, and there is an aversion to familiar food and smells.

Video: an example of paraneoplastic neuromyotonia

Diagnostics

Diagnosis and treatment of paraneoplasia are carried out by oncologists, dermatologists, immunologists and other narrow specialists. They listen to the complaints of patients, collect an anamnesis of life and illness, examine and prescribe a number of additional diagnostic procedures.

Laboratory diagnostics consists in carrying out:

• hemograms,
• blood test for tumor markers,
• general urinalysis,
• liquor analysis.

Instrumental diagnostics allows you to find the location of the original tumor. For this, scintigraphy and various types of tomography are used: computer, positron emission, magnetic resonance. Biopsy and endoscopy are the most informative diagnostic methods for the localization of education in hollow organs.

Treatment

Treatment of paraneoplastic syndrome is aimed at eliminating the root cause of the pathology - the removal of the original cancerous tumor. To date, no specific therapy for paraneoplasia has been developed. All the efforts of doctors are aimed at eliminating the tumor process.

Conservative therapy consists in prescribing medications that suppress immune processes that contribute to the development of paraneoplasia. Treatment of immune disorders is carried out with the help of immunosuppression - by administering immunoglobulins, corticosteroids, other immunosuppressants or plasmapheresis to the patient. The most common and effective immunosuppressants are Cyclosporine, Metatrexate, and Thalidomide.

Additionally, the following groups of drugs are prescribed:

1. Glucocorticosteroids - "Prednisolone", "Betamethasone",
2. Stimulators of neuromuscular conduction - "Kalimin", "Mestinon",
3. Anticonvulsants - Finlepsin, Amizepin, Konvuleks,
4. Vitamin therapy.

Physiotherapy procedures prescribed by oncologists to patients: ultraviolet irradiation, diadynamic therapy, electrosleep, electrical muscle stimulation, ultrasonic exposure, electrophoretic administration of drugs into the body, hydrotherapy, magnet, balneotherapy.

Alternative treatment of paraneoplastic syndrome without traditional therapy is not effective. They only complement each other and are used only after visiting a doctor. Alternative treatment consists in regularly taking propolis tincture with honey; mixtures of aloe, honey, cognac and badger fat; decoction of cherry leaves. Phytotherapy of paraneoplasia - the use of infusions and decoctions of sage, yarrow, anise, plantain, elecampane, licorice, chamomile.

Paraneoplastic syndrome in oncology is a complication of cancer, which often leads to irreversible organ failure and often ends in death. Timely and high-quality treatment of the initial cancerous process makes the prognosis of the disease relatively favorable.

Video: about paraneoplastic syndromes and rheumatology