82 Experimental Oncology 37, 82–88, 2015 (June) Exp Oncol 2015 REVIEWS 37, 2, 82–88 THE CONCEPTUAL AND CLINICAL PROBLEMS OF IN ONCOLOGY AND INTERNAL MEDICINE B.T. Bilynsky1,*, M.B. Dzhus2, R.I. Litvinyak3 1Danylo Halytsky Lviv National Medical University, Lviv 79010, Ukraine 2O.O. Bogomolets National Medical University, Kyiv 01601, Ukraine 3Lviv State Oncological Regional Treatment and Diagnostic Center, Lviv 79031, Ukraine

Symptomatology of oncological diseases consists not only of local symptoms caused by the primary malignancy or its metastases, but also by general systemic signs that are not directly connected with the tumor. These symptoms are mostly associated with auto- immunity or endocrine influences. In many cases, the source of paraneoplastic syndromes (PNS) is unknown. Nearly 15% of on- cological patients demonstrate these syndromes but it is diagnosed much more rarely. The survey of the numerous PNS is offered. The significance of the PNS differs for oncologists and other physicians who encounter it in their practice. The reason of those differences, as well as the connection between PNS and cancer toxicity is discussed. The experience of antitoxic therapy (hemo- sorption, lymphosorption, enterosorption) used in our clinic in the previous years is overviewed. Key Words: cancer, diagnosis, paraneoplastic syndromes, tumor toxicosis.

Tumors usually produce symptoms by invasion, ences of the tumor. Over 600 PNS have already been obstruction and bulk mass on the primary localization described so far (Table). of neoplasm and their regional or distant metastases. Table1. Most common PNS In addition, tumors can produce signs at a distance Syndrome Clinical signs from their localization. These are the so-called para- group neoplastic syndromes (PNS) [1, 2]. Cutane- maligna These syndromes are not a direct effect of the tu- ous Bazex paraneoplastic acrocheratosis mor or its metastases. They are caused by substances Acquired hypertrichosis lanuginose produced by tumor and distributed by circulation. Necrolytic migratory erythema These substances act on the target organs and result Leser-Trélat Sign Paraneoplastic pemphigus in clinical picture named PNS. Most of these substan- ces are polypeptide hormones, autoantibodies, growth Sweet syndrome factors, cytokines, hormones and their precursors. Palmoplantar keratoderma The ethiology and pathogenesis of a number of PNS Neurolo- are unknown till now (e.g. acanthosis nigricans) and gical Subacute cerebellar degeneration require additional investigations [3]. Opsoclonus-myoclonus Over the last years, many of these tumor-se- Optic neuritis Cancer associated retinopathy creted proteins have been described. The PNS may Subacute sensory neuronopathy be the first sign of a malignancy and we can use it for Guillain — Barre’ syndrome early cancer detection. PNS does not predict the result Chronic gastrointestinal pseudo-obstruction Myasthenia gravis of treatment of the underlying malignancy [4]. Lambert — Eaton myasthenic syndrome Thus, proteins secreted in PNS may be used as tu- Necrotising myelopathy mor markers. Different PNS caused by diverse reasons Endocrine SIADH Hypercalcemia (hormonal, immunological etc.) demonstrate various Cushing syndrome treatment results. A successful treatment of the tumor Hypoglycemia usually leads to disappearance of the PNS. In many Hemato- Eosinophilia logic Granulocytosis cases, the underlying tumor cannot be treated, but Pure red cell aplasia symptoms and complications of the PNS can be suc- Thrombocytosis cessfully managed by nonspecific means which were Thrombocytopenia tried in our institution (Lviv Oncological Center) several Anemia Coagulopathies (thrombophlebitis, thromboembolism, disse- years ago [5]. minated intravascular coagulation — DIC) It is believed that appearance of PNS is connected Rheuma- Paraneoplastic polyarthritis with endocrine, immunological or metabolic influ- tologic Remitting seronegative symmetrical synovitis with pitting edema Polymyalgia rheumatica Palmar fasciitis Submitted: March 5, 2015. Multicentric reticulohistiocytosis *Correspondence: E-mail: [email protected] Tumor-induced osteomalacia Abbreviations used: aPL — antiphospholipid antibodies; CLL — Vasculitis chronic lymphocytic leukemia; DIC — disseminated intravascular Renal Glomerulonephritis coagulation; PNS — paraneoplastic syndromes. Nephrotic syndrome Experimental Oncology 37, 82–88, 2015 (June) 83

Syndrome gastrointestinal abnormalities. I (here — B. Bilyn- Clinical signs group sky) remember a clinical case when during a clinical Others Cachexia patient round I, being a young docent, diagnosed Fatigue Fever gastric cancer due to the presence of black spots Lactic acidosis on the patient’s face (acanthosis nigricans), which Hypouricemia was evaluated by my colleagues as melanoma [8, 10]. Their number is constantly increasing, but Vascular abnormalities belong to dermatological it is disputable whether all of them can be evaluated appearances. Episodic reddening of the face and neck as PNS. True PNS satisfy two main criteria: strong as- lasting a few minutes is associated with the carcinoid sociation of suspected PNS with malignancy and their syndrome, leukemia, medullary carcinoma of the thy- parallel course [3]. roid, renal cell carcinoma, systemic mastocytosis, and pheochromocytoma. Multifocal migratory thrombo- PARANEOPLASTIC CUTANEOUS phlebitis (antiphospholipid syndrome) is associated SYNDROMES with numerous malignancies, most commonly with For clinicians these syndromes can be of diagnostic gastrointestinal, but also lung, prostate, ovary tumors, value. The attitude of different medical experts to this leukemias and lymphomas. It is related to hyperco- phenomenon differs: dermatologists observe PNS agulable state accompanying the advanced cancer. or similar syndromes in skin diseases. Most important A cordlike thrombophlebitis on the thoracic wall for is to establish a differential diagnosis between der- (Mondor’s disease) may be associated with breast mal PNS and plural dermatosis. Cutaneous manifesta- cancer. Pruritus may be the initial feature of an occult tions of distant cancer are more frequent than other malignancy or a clinical manifestation of a previously similar appearances, and an especially wide variety diagnosed tumor. There are other numerous additional of skin syndromes is associated with malignancies [6]. hereditary disorders associated with cutaneous mani- These are first of all keratinization disorders. The most festations of malignancy [3, 6]. important PNS of this kind is acanthosis nigricans. Dermatologic PNS include also a number of en- It is characterized by grey-brown hyperpigmented docrine and metabolic lesions (systematic modular velvety plaques that often affect the neck, flexor are- panniculitis or subcutaneous fat necrosis, hyperpig- as, and anogenital region. It is typically associated mentation by Addison syndrome), telangiectasia, and with adenocarcinomas of the gastrointestinal tract, scleroderma-like changes in carcinoid syndrome, and predominantly with gastric cancer, but can be as- others [7, 8]. sociated with other adenocarcinomas (lung, breast, Bullous disorders, mostly paraneoplastic pemphi- ovarian, and even hematologic malignancies) [7]. gus usually occur in the presence of B-cell lympho- In addition, keratinization disorders are represented proliferative disorders — lymphomas, chronic lympho- by tripe palms, usually associated with lung or gastric cytic leukemia (CLL), Castleman’s disease, thymoma, cancers, acquired ichtiosis (associated with Hodg- Waldenstöm’s macroglobulinemia, and spindle cell kin’s and other lymphomas, multiple myeloma, Ka- neoplasms. Dermatologic PNS can be represented posi’s sarcoma). Palmar hyperkeratosis is associated by colagen-vascular diseases, disorders of hair, and with esophageal, breast, and ovarian carcinomas [8]. some skin neoplasms associated with internal malig- It is relevant to name several other cutaneous nancy. To the latter belong such autosomal-dominant PNS connected with different tumors: acrokeratosis syndromes as Muir — Torre syndrome (numerous paraneoplastica (Bazex’ syndrome), associated with sebaceous gland neoplasms), Cowden’s syndrome squamous cell carcinoma of the esophagus, head and (multiple hamartomas), Gardner’s syndrome (hun- neck or lung tumors. It precedes the tumor in 60% dreds of adenomatous colorectal polyps and nume- of cases. Exfoliative dermatitis may be associated rous epidermal cysts and soft tissue tumors), and with lymphomas and rarely with solid tumors (lung, Gorlin-Goltz syndrome (multiple basal cell carcinomas liver, prostate) [9]. with numerous bony abnormalities and a strong pre- Disorders of cutaneous discolonation and de- disposition for malignancy) [3, 9, 10]. positation (melanosis, plain xantomas, vitiligo, and leucoderma) are also considered to be PNS associated PARANEOPLASTIC NEUROLOGICAL with different malignancies. Neuroplastic dermatoses SYNDROMES constitute an interesting group. Sweet’s syndrome Neurologic manifestations of PNS are close presents with acute onset: fever, neutrophilia and to the dermatologic ones, and often have some com- appearance of cutaneous plaques on the face, neck, mon signs and etiological display with the skin syn- and upper extremities. Association with malignancies dromes [11]. occurs in 20% of cases. The other dermatologic PNS Neurological symptoms that are not related is pyroderma gangrenous appears as a form nonhea- to the direct effect of malignancies on the neurologic ling ulcers with a necrotic base. system are defined as PNS. These syndromes include Pyoderma gangrenosum is associated with he- dermatomyositis, Lambert — Eaton myasthenic syn- matological malignancies, inlcluding cutaneous drome, subacute cerebellar degeneration, subacute T-cell lymphomas, gastric carcinomas, and other sensory neuropathy, opsoclonus-myoclonus, sensory 84 Experimental Oncology 37, 82–88, 2015 (June) motor peripheral neuropathy, encephalomyelitis, and cases hypocalcemia is life threatening, especially if not many others [11, 15]. Such neurologic disorders recognized and untreated [3, 16, 17]. as PNS are associated with different malignancies Tumor induced osteomalatia is a rare PNS charac- in 10–60% of cases. Paraneoplastic disorders are terized by hypophosphatemia and very low circulating also a rare cause in vision loss in cancer patients [12]. concentrations of vitamin D3. The majority of neo- A number of antineural antibodies appear in the case plasms causing this syndrome are benign, but this PNS of PNS and cancers. That is why neurologists have can coexist with lung carcinoma, multiple myelomas, to be interested in recognition of the PNS, which would and prostate cancer. Patients present with bone pain, lead to the correct determination of diagnosis and ap- phosphaturia, renal glucosuria, hypophosphatemia, plication of an adequate treatment [12, 27]. normocalcemia, low level of 1,25 dihydroxyvitamin D3, and increased alkaline phosphatase level [18]. PARANEOPLASTIC ENDOCRINE Mesenchemal tumors and hepatic carcinomas are SYNDROMES mostly responsible for hypoglycemia as a PNS. Insu- Once a PNS is diagnosed, an appropriate systemic lomas also frequently produce hypoglycemia. Gas- evaluation for a neoplasm is to be undertaken. The ma- trointestinal stromal tumors, lymphomas and adrenal jority of PNS are connected with endocrinological carcinomas may also be associated with this PNS. Pa- disorders. In their practice, the experts in endocrino- tients may have typical signs of hypoglycemia inclu- logy encounter such clinical cases that are frequently ding generalized neurologic abnormalities. The causes associated with a wide variety of common cancers. of paraneoplastic hypoglycemia include production A number of PNS are associated with secretion of nonsuppressible insulin-like GF-1 and GF-2, hy- of several hormones and hormone-like substances. permetabolism of glucose, production of substances The most widespread of them are ACTH (Cushing stimulating ectopic insulin release, production of he- syndrome), antidiuretic hormone, insulin-like growth patic glucose inhibitor, insulin binding by a monoclonal factor, erythropoietin, growth factor realizing hormone, protein, insulin receptor proliferation or — rarely — parathormone-like protein, etc. [13, 28]. ectopic insulin production [4, 11]. The following tumors are associated with ectopic We can make a conclusion that in many cases adrenocorticotropic hormone: small cell lung carci- endocrinologists have common problems with on- noma, bronchial carcinoid, thymic carcinomas, tumors cologists and clinical errors may happen in some of pancreas, pheochromocytoma, medullary cancer unexpected circumstances, when a PNS is evaluated of the thyroid, gastrointestinal carcinoid, adenocarci- as a hormonal disease. noma, etc. [13, 14]. Clinical features of inappropriate antidiuretic hor- PARANEOPLASTIC HEMATOLOGIC mone production syndrome consist of combination SYNDROMES of water retention and secondary solute loss which Many PNS of different origin show some hemato- leads to the fall of plasma sodium concentration. logic manifestation. They include the following. As a rule, the patients have normal volume status, Erythrocytosis is mostly associated with renal hypothermia with hypoosmolality, elevated renal ex- cell carcinoma. The elevated serum erythropoietin cretion of sodium, and urine osmolality greater than is the chief reason of this PNS. Hepatoma is the next plasma osmolality. Most common clinical symptoms most common malignancy leading to erythrocytosis. in these patients are caused by central nervous sys- The elevation of serum erythropoietin is also the rea- tem toxicity. Patients complain of fatigue, anorexia, son of the development of erythrocytosis. Other headaches, and altered mental status. Further, with tumors may be also accompanied by erythrocytosis. the progress of the syndrome the delirium, confu- They include the following neoplasms: Wilms’ tumor, sion, and seizures develop. The syndrome may cause hemangiomas, cerebellar hemangioblastoma, sarco- a coma, and in rare cases result in death. Most patients mas, uterine fibrosis, and adrenal tumors [18]. have minimal symptoms and during routine laboratory There are obvious cases of polycythemia con- evaluation are diagnosed with hyponatremia [2, 11, 19]. nected with arterial desaturation associated with Tumors associated with bone metastases (breast, hemoglobinopathies, carboxyhemoglobinemia, and prostate, lung cancers) lead to hypocalcemia. Those chronic hypoxic states [19]. patients have increased skeletal avidity for calcium. The anemias are typical for many kinds of tumors, Hypocalcemia can also occur in patients, whose tu- especially at advanced stages. They are normo- mors secrete calcitonin (medullary thyroid carcinoma, cytic normochromic or hypochromic, connected with breast cancer, colorectal cancer, lung cancer, carci- chronic diseases, with bone marrow invasion, se- noid). Hypocalcemia has many clinical manifestations. condary to cytostatic therapy and radiation treatment. It can be asymptomatic, in some cases it demonstrates Normochromic normocytic anemia in cancer patients significant symptoms associated with neuromuscular is a common PNS. irritability and cardiovascular changes: peripheral and Paraneoplastic anemia is characterized by low perioral paresthesia, cramps, tetany, seizures, bron- serum iron levels, normal or increased ferritin levels, chospasm, laryngospasm, anxiety, confusion, cardiac normal iron stores, and low serum erythropoietin level. arrhythmias, and congestive cardic failure. In extreme Pure red cell aplasia is a rare cause of anemia in cancer Experimental Oncology 37, 82–88, 2015 (June) 85 patients. It can be associated with thymoma and hy- to thrombotic or hemorrhagic complications and may pogammaglobulinemia. This PNS may also be associ- occur with or without DIC. Nonbacterial endocarditis ated with different lymphoid malignancies. It is rarely should be suspected in cancer patients with ischemic caused by solid tumors. Warm antibody hemolytic embolic events and is most commonly seen with anemia is most commonly associated with lympho- adenocarcinomas of the lung and pancreas [20, 21]. mas. Cold agglutinin disease is most connected with Waldenström’s macroglobulinemia and lymphomas. PARANEOPLASTIC RENAL SYNDROMES Autoimmune hemolytic anemia may be associated Renal manifestations often accompany several with solid tumors, such as ovarian, lung, breast, gas- kinds of malignancy. In 22% of cases membranous trointestinal and renal cancers. nephropathy has been clearly associated with a malig- DIC can follow the microangiopathic hemolytic nancy. Most common malignancies in this connection anemia in metastatic carcinomas [20]. are lung, colon, and stomach carcinomas. As a PNS, microangiopathic hemolytic anemia may Nephrosis-ranged proteinuria, hypertension respond to effective anticancer therapy. The mecha- and microscopic hematuria characterize the syn- nism of most PN anemias remains unknown. drome. Immune complexes are thought to play a role Granulocytosis with elevation of white blood in malignancy-associated glomerular disease. The re- cell count without infection or leukemia is common sponsible antigens include fetal antigens, autologous in neoplasms as one of the PNS. Usually, tumors that nontumor antigens, tumor-associated antigens, and are accompanied by granulocytosis include Hodg- viral antigens [4]. kin’s lymphoma, different other lymphomas, and a va- Other glomerular diseases include membrano- riety of solid tumors such as stomach, lung, pancreatic, proliferative glomerulonephritis and minimal-change brain cancers, and malignant melanoma. The common disease. Hodgkin’s lymphoma is the cause of most mechanism associated with granulocytosis is produc- cases of minimal-change disease with lympho- tion of growth factors by the tumor. proliferative disorders, pancreatic carcinoma, and Granulocytopenia may appeare as a PNS. Except mesothelioma. Approximately 10–15% of cases under the influence of chemotherapy, radiation therapy precede the lymphoma and 40–50% manifest after or tumor infiltration of bone marrow, the tumors can the tumor is diagnosed. There is a parallel relationship rarely produce a factor that would suppress granu- between the activity of the lymphoma and the degree lopoieses by interfering with many growth factors. of proteinuria. There are several reports about antibodies against Other cancer-associated glomerulopathies in- granulocytes in patients with Hodgkin’s lymphoma. clude focal and segmental glomerulosclerosis with Neutropenia associated with large granular lympho- CLL, T-cell non-Hodgkin’s lymphomas, and acute cytic leukemia and lymphoma may be caused by im- myelo genous leukemia. Immunoglobulin A nephropa- mune dysregulation of T-cells. In some cases, thrombophlebitis represents thy is associated with lung, head, and neck cancer, an incident of PNS. Oncological patients have a hy- pancreatic cancer, mycosis fungoides, and liposar- percoagulable state. An association between venous coma. Membranoproliferative glomerulonephritis thrombosis and malignancy was first suggested is connected with chronic lymphoblastic leukemia, by Trousseau in 1865. Clinical thromboembolism Burkitt’s and other lymphomas, hairy cell leukemia, occurs in 11% of cancer patients and is the second and malignant melanoma [3]. leading cause of death in patients with overt malig- Thus, the nephrologists have to do with different nant diseases. Clearly, cancer related thrombosis has PNS that need to be differentiated from non-oncologi- a complex of features including different imbalances cal renal diseases and vice versa. Internists encounter of coagulation and fibrinolysis. Several studies of pa- the PNS more often than other specialists. In internal tients with venous thromboembolism suggest a higher medicine clinics classic PNS is encountered in 90% incidence of malignancy diagnosed within the first of patients with PNS, the endocrine and metabolic syn- 6 months after presentation of thrombosis. dromes in 7–10%, the rheumatoid-like — in 25–62%, Several paraneoplastic coagulopathies associated the cardiovascular — in up to 50%, dermatological — with cancer have been reported too. It concerns such in 14–63%, neurological — in 1%, gastrointestinal localizations of malignancy as gastric and adrenal syndromes — in 12–22%, hematological — in 35–55% carcinomas, leukemias and lymphomas [2, 21]. of patients. Consequently, the internists have to re- Acquired hemophilia (factor VIII antibodies) has member about the possibility of PNS in their patients. been reported in patients with solid tumors, parapro- teinemias and lymphoproliferative disorders. Overt DIC PARANEOPLASTIC RHEUMATOLOGIC occurs in 7% of patients with solid tumors (primarily SYNDROMES adenocarcinomas). Eosinophilia, basophilia, thrombo- Rheumatologists are of special importance among cytosis, thrombocytopenia, and thrombophlebitis also other representatives of medical professions. In their belong to hematologic manifestations of PNS [22]. practice, rheumatologists often encounter the so- Hematologic manifestations of cancer include called “masks” — typical for rheumatological disorders also nonbacterial thrombotic endocarditis. It may lead but sometimes present as a part of PNS. 86 Experimental Oncology 37, 82–88, 2015 (June)

Rheumatologic diseases and malignancies have These signs are common for a large number of ma- many common features — in ethiology, diagnostics, lignancies and some researchers argue that these and complications, including some PNS. symptoms characterize tumorous intoxication. The peculiarities of paraneoplastic rheumatic syn- PNS simulating autoimmune disorders are quite dromes are as follows: frequent in rheumatological practice. Relation between • chronological correlation with oncological dise- tumors and autoimmune processes is rather compli- ases; cated. Many factors take place in those relations. • frequent occurrence in elderly age; An allergic reaction often develops on the back- • asymmetric affection of joints; ground of tumors. • predominant involvement of lower limbs into Oncoantigens further sensitize the organism. This the process; leads to violation of immunologic tolerance to autoan- • abrupt in onset; tigens. Anticancer drugs also have influence on the im- • as a rule, absence of rheumatoid factors and rheu- munological state of the organism. As a result, many matoid nods; rheumatological signs appear also in cancer patients. • nonspecific alterations in synovial bioptates; Emergence and development of tumors is ac- • positive dynamics of PNS during the successful companied by metabolic changes in the organism treatment of malignancy; that lead to disturbance of protein, fat, carbohydrate • “rheumatological” symptoms recurrence caused metabolism, and to infringement of immune system. by metastases or local recurrence of the malig- Clinical signs of such events include weakness, tired- nancy. ness, hypodynamia, disturbance of sleep, weight loss, Rheumatologic PNS include: hypothermia, and several other symptoms. These • hyperytrophic osteoarthropathy (Marie — Bam- facts are defined as endogen intoxication syndrome berger syndrome); or tumor toxicosis. These phenomena are present • rheumatoid arthritis; in 70–80% of oncological patients [23]. • dermatomyositis; To compare PNS it is necessary to remember that • tendovaginitis migricans; the same signs can be evaluated as common symp- • scleroderma-like syndrome; toms of many PNS. • different types of vasculitis including panarteritis Reports on sorbtion appeared in oncological litera- nodosa and Wegener’s vasculitis; ture at the end of the previous century [24]. • lupus erythematosus; Rheumatoid arthritis or asymmetric polyarthritis • palmar hyperkeratosis; may occur with malignancy. • polychondritis and many other above-mentioned Joint manifestations regress on removal or control syndromes [2–4]. of the underlying malignancy in 48% of patients. About Malignization is often accompanied by autoimmune 80% of female patients with asymmetric polyarthritis processes that are followed by production of a variety and malignancy had breast cancer. Some 83% of pa- (nearly 400 kinds) of antibodies against the bright spec- tients with polymyalgia rheumatica are said to develop trum of antigens. Oncoproteins controlling the cellular growth and differentiation are best known among them. a malignancy within 3 months and some of these cases For example, 50% of patients with breast cancer repre- may represent arterial embolism of muscle through sent p185, some other proteins are associated with lung nonbacterial thrombotic endocarditis. Lymphomas cancer, ovaries and colon malignancies. Best known may be associated with systemic rheumatic disease. is p53 which prevents cancerogenese and teratogenous In Sjögren’s syndrome a spectrum of benign to ma- disorders. In the process of mutation, it loses the named lignant lymphoproliferations can be seen, but whether properties and is present in many tumors in such form. this is “at a distance from the tumor” remains to be de- Its specificity is nearly 96%, so it can serve as a test for termined [29]. early diagnosis in high-risk patients. The antigens con- Metastases to joints can simulate rheumatoid ar- nected with cell proliferation are present in every kind thritis and cytological examinations should be done of cancer in 2% of cases. in regard to joint effusions in cancer patients [30]. It is known that autoimmune rheumatological disor- Fever occurs frequently in cancer patients and ders are connected with a lot of antibodies — Ro, La, is usually caused by infection. In addition, there Sm, RNP, and others may be present in patients with exist other noninfectious causes, with which certain malignancies. A high level (22%) of antiphospholipid concerns are associated. Main associations are with antibodies (aPL) is detected in 3% of patients with Hodgkin’s lymphoma, myxomas, hypernephromas, malignancies as compared to healthy contingent. osteogenic sarcomas, and other tumors. Tumor- The risk of thrombosis triples in oncologic patients with associated fever is usually defined as “unexplained” aPL(+) in comparison with the patients with aPL(−). fever that coincides with tumor growth, disappears At the same time, a patient with aPL(+) has a higher promptly on tumor removal or control and reappears risk of cancer development. with tumor recurrence. When the fever persists, the tu- The so-called classic PNS which include fever, mor is a likely cause of it if other reasonable causes asthenia, cachexia, and anaemia are worth discussing. are excluded. In Hodgkin’s disease, fever is a bad Experimental Oncology 37, 82–88, 2015 (June) 87 prognostic sign. There are no data on the influence cal confirmation of malignancy interpret all present of fever associated with other tumors on prognosis. symptoms as a manifestation of cancer. The etiology of tumor-associated fever is con- According to estimations, PNS does not correlate nected with several “endogenous” pyrogens released with the stage of tumor or its prognosis. That is why by tumor cells [25, 26]. they stay outside the consideration of oncologists. Some malignant cells are able to stimulate The problem of tumor toxicosis (or immune- the production of “blocking antibodies” against complex disease corresponding to malignancies) was tumor antigens, for example, the production of im- discussed in special literature several decades ago. munoglobulins of A, E, and D classes which do not As a logical conclusion, a detoxication or deblocking activate the complement system and conjugates with treatment was proposed. Probably it could be rea- tumorous antigens building antigen-antibodies com- sonable to return to this idea in some patients with PNS. plex on the surface of cancer cell which can cause the so-called immune-complex syndrome similar CONCLUSIONS to PNS or tumor toxicosis [32]. 1. PNS are a heterogenous group of phenomena All of these pathologies are characterized by an ag- caused by malignancies influencing the endocrine and gregate of symptoms including weakness, tiredness, immune systems, metabolism, and other mechanisms, hypodynamia, sleep disorders, appetite loss, paleness, not all of which have been identified by now. hypothermia, and other symptoms. Some decades ago 2. Not all facts that are described as PNS cor- such complexes of metabolic and nonspecific clinical respond to the identification criteria for PNS. Some signs were evaluated as tumor toxicosis and a corre- of them are not influenced by radical treatment sponding treatment was proposed [33]. We investigated of the tumor, whereas such influence is postulated the possibilities of detoxication treatment, including as obligatory for PNS cases. hemosorption, lymphosorption, enterosorption, and 3. Some PNS are life-threatening and therefore others. We learned that in some cases not only does require active treatment. the sorption treatment give unexpectedly positive re- 4. Tumorous toxicosis or immune-complex dise- sults in regard to clinical course but sometimes also ase, which were widely discussed in the past decades, facilitates the reduction of the tumor [34]. are de facto a part of PNS and consequently their In particular, plasmapheresis was used in 4 patients respective treatment deserves attention. with lung cancer, and provided for lessening or even REFERENCES elimination of clinical symptoms influencing clini- 1. Pelosof LC, Gerber DE. Paraneoplastic syn- cal, biochemical and immunological manifestations dromes: an approach to diagnosis and treatment. 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