Paraneoplastic syndromes

The term "paraneoplastic" was first used by the French scientists Guichard and Vignon in 1949 to describe the multiple nerve deficits in a patient with cervical carcinoma in a pathophysiological context of her malignant disease.

Paraneoplastic syndromes are a heterogeneous group of different symptom complexes which are not directly caused by the tumor itself or by its metastases, but which are causally or formally genetically linked to the presence of the tumor.

The pathological paraneoplastic symptoms are caused, on the one hand, as a result of changes in the surrounding microenvironment of the tumor (by paracrine secreted mediators and hormones), and on the other hand, by humoral tumor products that influence other organs. They appear as skin, muscle, joint and bone changes as well as neuronal or gastrointestinal changes.

The clinically perceivable paraneoplastic symptomatology is specific only in a few cases. It is (by definition) not linked to the location of the tumor or its metastases, but often correlates in its severity with the course of the tumor disease. Paraneoplastic syndromes manifest themselves before or during tumor disease, but may also precede it for a long time. Thus, they play an important role as indicators for the early detection of an underlying malignant disease, especially with regard to the possibly still curative treatment of a primarius. Paraneoplastic symptoms may also regress after removal of the primarius and its metastases or after successful chemotherapy and radiotherapy.

Most commonly, paraneoplastic syndromes occur in:

• Lung carcinoma, especially small cell lung carcinoma.
• Renal cell carcinoma
• Hepatocellular carcinoma
• Leukemias
• Lymphomas
• Multiple myeloma
• Breast carcinoma
• Ovarian cancer
• Neuronal tumors
• Gastric carcinoma
• Pancreatic cancer

Paraneoplastic syndromes are described in about 8-20% of patients with malignant tumors, with the scattering being due to a differently stringent definition of paraneoplastic syndromes. In addition, the clinical differentiation of symptoms from adverse drug reactions(ADRs) is not infrequently difficult.

The cause of many paraneoplasias is unclear. Presumably, mutations during tumorigenesis alter not only the proliferation metabolism but also the performance metabolism of the cancer cell. As a consequence, biologically active substances are synthesized, causing pathological symptoms, including general symptoms such as fever, night sweats, weight loss and cachexia.

Furthermore, paraneoplastic syndromes are caused by ectopic production of (peptide) hormones and hormone-like acting polypeptides as well as growth factors with the involvement of mutated oncogenes and suppressor genes.

Immunologic phenomena, e.g., by formation of antibodies, may also be responsible for the development of paraneoplastic syndromes. This is especially the case in neurological and dermatological syndromes (vasculitides, dermatomyosis, hypertrichoses, etc.). Furthermore, tumor-induced disturbances of organ functions (e.g. liver or kidney dysfunction) may cause paraneoplastic symptoms.

Often (but not always) parallelism can be observed between clinical symptoms and tumor events. Thus, clinical symptoms may improve or disappear completely after treatment or removal of the tumor. A recurrence of the initiating tumor can (but does not necessarily have to) lead to a recurrence of the paraneoplastic symptoms. However, this axiom is not always given. Thus, it appears that paraneoplastic-induced autoimmunologic diseases, such as paraneoplastic dermatomyositis or paraneoplastic pemphigus, may persist even after removal or treatment of the primarius.

Paraneoplastic syndromes occur as hematogenous, endocrine, immunological/allergic or inflammatory disorders and manifest themselves preferentially in the skin, hematopoietic system, musculature, joints, skeleton, central nervous system, eyes, gastrointesztinal tract. Basically, "general paraneoplastic syndromes" can be distinguished from "organ-related paraneoplastic syndromes":

General paraneoplastic symptoms

Patients with tumor diseases often suffer from general paraneoplastic accompanying symptoms such as:

• Fever
• Night sweats
• Anorexia
• cachexia.

These symptoms may be caused by release of cytokines involved in inflammatory responses or tumor-associated immune responses, or by mediators related to tumor cell demise, such as TNF-alpha. Alterations in liver function and steroid production may also contribute to these common paraneoplastic symptoms.

Organ-related paraneoplastic snydromes

Skin (Cutaneous Paraneoplastic Syndromes):

• The skin is a common projection organ for paraneoplastic symtpoms and syndromes (see Cutaneous Paraneoplastic Syndromes below). A distinction is made between a few obligate and a variety of facultativecutaneous paraneoplastic syn dromes. For example, pruritus is the most common cutaneous symptom in tumor patients (e.g., leukemia, Hodgkin's disease, myeloproliferative neoplasms, and lymphomas).

Endocrine (Endocrine paraneoplastic syndromes): They occur mainly in tumors that originate from endorkin active cells and consequently, synthesize ectopic hormones or hormone-like substances.

• Endogenous Cushing's syndrome due to ectopic (paraneoplastic) ACTH secretion (Note: A central Cushing's syndrome = Cushing's disease, due to a microadenoma of the anterior pituitary is not a paraneoplastic syndrome). Causally, paraneoplastic Cushing's syndrome is due to stimulated ACTH secretion by ectopically formed CRH in tumors, most commonly in bronchial carcinomas, C-cell carcinomas, protate carcinomas, and carcinoids. Clinical: Characteristic features of hypercortisolimus with increase in cortisol levels with hyperglycemia, hypokalemia, hypertension, truncal obesity and "full moon face".
• Acromegaly: Caused by ectopic, pathologic GHRH and GH secretion. Causes are carcinoids, bronchial, ovarian, mammary, thyroid, colon carcinomas, pancreatic islet cell tumors, phenochromocytomas, neuroblastomas. Clinical: Signs of acromegaly with arthralgias, amenorrhea, galactorrhea, impotence, hypertension and others.
• Hyperthyroidism: Caused by ectopic TRH and TSRH production. Caused by bladder mole and chorionic carcinoma. Clinical: Hyperthyroidism with tachycardia, weight loss, heat intolerance and others.
• Disturbances of water and electrolyte balance, including hyponatremia: these fumional disturbances may be the result of ectopic production of vasopressin and parathyroid hormones. Causes are often small cell and non-small cell lung carcinomas.
• Hypoglycemia syndromes: Hypoglycemia may be the result of insulin-like-growth-factor (IGF) I and II production (fibrosarcoma/hemangioblastoma), anabolic steroids with insulin action (adrenocortical carcinoma), excessive glucose consumption (pseudomyxoma), or tumor-induced hyperinsulinism (hepatocellular carcinoma).

• Hypertension: Hypertension may be parabenoplastic as a result of increased cortisol production (ACTH-secreting tumors).

• Hyperprolactinemia: Ectopic prolactin release due to breast carcinoma. Clinical: Decrease in libido in males and females. In women, hyperprolactinemia leads to secondary amenorrhea with anovulation, eyelid bido disorders, hirsutism, seborrhea. Galactorrhea may occur as an additional symptom. In men, this endocrinopathy leads to a decrease in testosterone levels. Libido disturbances, erectile dysfunction and a decrease in ejaculate volume occur. In addition, gynecomastia and rarely galactorrhea may occur.

• Other:
• Carcinoid paraneoplasia: ectopically produced serotonin by lung and pancreatic carcinoma.
• Parathyroid hormone-related protein (PTHrP): ectopically produced parathyroid hormone-related protein (PTHrP) by squamous cell carcinoma of lung, head and neck tumors, bladder tumors. PTHrP causes hypercalcemia and associated symptoms (polyuria, dehydration, constipation, muscle weakness).
• Calcitonin (formed by: breast carcinoma, small cell lung carcinoma, medullary thyroid carcinoma). Calcitonin causes serum calcium levels to drop, leading to muscle spasms and cardiac arrhythmias.
• Tumor necrosis factor (TNF) and interleukin-6 (formation by versch. Tumors lymphomas and leukemias, multiple endocrine neoplasms typeI,II,III). Clinical: Tumor cachexia

Gastrointestinal tract (Gastrointestinal paraneoplastic syndromes).

• Diarrhea: Following tumor-induced secretion of prostaglandins or of vasoactive intestinal peptide, watery diarrhea with subsequent dehydration and shifts in electrolyte balance may occur. Causes include pancreatic islet cell tumors (gastrinomas).
• Diarrhea+flush: Carcinoid tumors produce serotonin degradation products leading to flush symptoms, diarrhea, and respiratory distress.
• Chronic enteritis: mainly in lymphomas. They can lead to protein-losing enteropathy.

Blood-forming systems (Hematologic paraneoplastic syndromes): These include substances that are either produced by tumors or resemble physiologic growth factors or block normal endocrine signals for hematologic development. Furthermore, they include antibodies that cross-react with receptors or cell lines.

Hematopoiesis:

• Anemia: due to tumor infiltrates of bone marrow, blood loss, hemolysis due to heat and cold agglutinins; iron utilization disorders, iron deficiency, and others.
• Thymic tumors are increasingly associated with anemia/thrombocytopenia/leukopenia/hypogammoglobulinemia.
• Evans syndrome: Immune thrombocytopenia and Coombs-positive hemolytic anemias may complicate the course of lymphoid tumor disease and Hodgkin's lymphoma.
• Microangiopathic hemolytic anemia (MAHA), in gastric, breast, bronchial, prostate,ovarian, pancreatic, colon, hepatocellular carcinomas, etc. endothelial cell lesions with activation of platelets and plasmatic coagulation up to hemolytic uremic syndrome (HUS) or disseminated intravascular coagulation syndrome (DIC).
• Erythrocytosis (polyglobulia): Due to ectopic production of erythropoietin or erythropoietin-like substances, erythrocytosis may occur in various types of tumors, especially renal cell carcinomas,- and liver tumors, cerebellar hemangioblastomas, lung tumors, and others. Thromboembolic complications are rare.

Leukopoiesis:

• Granulocytosis due to ectopic production of hematopoietic cytokines (G-CSF, GM-CSF, interleukin-3, interleukin-6) in bronchial carcinomas, gatrointestinal tumors, ovarian carcinomas, tumors of the genitourinary tract. Dermatologically, Sweet syndrome may develop.
• Hematoeosinophilia with consecutive symptoms (see also Eosinophilia, Skin Changes).
• Leuko-/granulocyopenia: large granular lymphocyte(NK cell) syndrome

Thrombopoiesis:

• Thrombocytosis. Approximately 10-15% of all patients with thrombocytosis (>500/nl) have an underlying malignancy. Ectopic production of interleukin-6, possibly thrombopoietin in bronchial, pancreatic, gastrointestinal, breast, urogenital, ovarian, prostate crinomas and lymphomas.
• Tumor-associated hemophagocytic lymphohistiocytosis (HLH): a hyperinflammatory syndrome classified among the histiocytoses, caused by a massive, exuberant, sepsis-like, inflammatory response of the immune system with overwhelming activation of T lymphocytes and macrophages. It is about 30% tumor associated (hematopoietic malignancies).
• Hypercoagulopathy: with thromboembolic events in patients with versch.Malignomen (pancreatic carcinoma, lung carcinoma).

CNS- Brain/Cerebellum (Neurological paraneoplastic syndromes).

• Peripheral neuropathy: Peripheral neuropathy is the most common neurologic paraneoplastic syndrome (usually distal sensorimotor polyneuropathy is present, resulting in mild sensorimotor weakness, sensory loss, and disappearance of distal reflexes).
• Subacute sensory neuropathy: This is a, rare, more specific form of peripheral neuropathy. There is degeneration of spinal ganglia with progressive sensory loss and ataxia, but only mild muscle weakness. These changes can lead to permanent disability. The autoantibody anti-Hu is found in some patients with lung tumors.
• Guillain-Barré syndrome, another increasing peripheral neuropathy, is a rare finding in the general population (rare in patients with Hodgkin lymphoma).
• Lambert-Eaton myasthenic syndrome (pseudomyasthenic syndrome) is an immune-mediated syndrome, similar to myasthenia gravis, affecting primarily distal and proximal skeletal muscle (presynaptic defect resulting from inadequate release of acetylcholine at nerve terminals). The syndrome is most common in small cell lung carcinoma (Oat cell-carcinoma).
• Subacute cerebellar degeneration causes progressive bilateral ataxia of the arms and legs, dysarthria, and occasionally vertigo and double vision. Neurologic signs may include dementia with or without brainstem signs, ophthalmoplegia, nystagmus, and positive Babinski signs with marked dysarthria and involvement of the arms. The autoantibody anti-Yo is found in the serum or cerebrospinal fluid of some patients, especially in women with breast or ovarian cancer.
• Opsoclonus (short, rapid, and irregular eye movements) is a rare cerebellar syndrome that can occur in association with childhood neuroblastoma. It is associated with cerebellar ataxia and myoclonias of the trunk and extremities. The circulating antibody anti-Ri may be detectable.
• Subacute motor neuropathy is a rare disease that results in painless weakness of the lower motor neurons of the upper and lower extremities. It is most commonly seen in patients with Hodgkin's lymphoma or other lymphomas. Degeneration of the anterior horn cells occurs. Spontaneous improvement usually occurs.
• Subacute necrotizing myelopathy is a rare syndrome in which rapidly progressive sensory and motor loss occurs in the white and gray matter of the spinal cord.
• Encephalitis can present as a paraneoplastic syndrome in various forms depending on the region of the brain affected. Global encephalitis is thought to be the cause of encephalopathy, which most commonly occurs in small cell lung carcinoma. Anti-Hu antibodies directed against RNA-binding proteins may be present in serum and CSF.
• Optic neuropathy

Kidney (Paraneoplastic Syndromes of the Kidney).

Glomerular disorders:

• Membranous glomerulonephritis: Patients with colon carcinoma, ovarian carcinoma, and lymphoma may develop membranous glomerulonephritis as a result of circulating immune complexes.
• Minimal-change glomerulopathy: it occurs much less frequently as a paraneoplastic syndrome. Associations with lymphoproliferative disorders, especially Hodgkin's disease, have been demonstrated.
• IgA nephropathy: In renal cell carcinoma, a frequent occurrence of IgA nephropathy is described in the surgical specimen of the affected kidney.

Tubulointerstitial disorders:

• Tubulointerstitial nephritis in multiple myeloma (myeloma kidney).
• Hypercalcemic nephropathy: Tumor-associated hypercalcemia due to multiple myeloma or solid tumors with skeletal metastases or endocrine-active tumors with ectopic production of parathyroid hormone or parathyroid peptides can cause hypercalcemic nephropathy
• Uric acid nephropathy: Acute uric acid nephropathy may occur in neoplasms with high cell turnover and is pathogenetically primarily due to precipitation in the collecting duct system.

Microvascular disease:

• Rarely, renal microvascular changes are also observed in the setting of tumor disease. Renal vasculitis may occur in association with hepatocellular carcinoma in hepatitis C infection with cryoglobulinemia, as well as associations with lung tumors and lymphoma.

Liver (Hepatogenic paraneoplastic syndromes).

• Cholestasis: Cholestasis is known to be a paraneoplastic syndrome in patients with malignant lymphohyperplastic disease and renal cell carcinoma.
• Vanishing bile duct syndrome (VDBS) occurs congenitally or acquired. Acquired causes include autoimmune reactions, primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), and medications. In addition, VDBS can be paraneoplastic in the setting of Hodgkin's lymphoma.

Immune system (autoimmune paraneoplastic syndromes; cf. Rheumatoid paraneoplastic syndromes).

Rheumatic or rheumatoid diseases caused by autoimmune reactions can be an expression of paraneoplastic syndromes. These syndromes are rare, but represent an important differential diagnosis to classical rheumatologic and other rheumatologic accentuated syndromes (e.g. systemic scleroderma/dermatomyositis). Early recognition of the syndromes, if necessary with supplementary laboratory and examination findings, allows diagnosis of an underlying malignancy and, if necessary, curative therapy.

• Paraneoplastic Arthritis (PA): Paraneoplastic arthritis is particularly difficult to detect because, in addition to polyarthritis, positive rheumatoid factor is present in up to 23% and positive anti-citrullinated proteins (ACPAs) in 11% of patients (Kisacik B et al. 2014).
• Palmary fasciitis with polyarthritis (PFPAS): The rare PFPAS syndrome offers a clearly distinguishable presentation compared to paraneoplastic arthritis due to associated inflammation of the palmar/plantar fascia. Originally, palmar fasciitis-with-polyarthritis syndrome was associated with ovarian cancer (>50% of patients). However, it is now also associated with several other malignancies e.g. adenocarcinoma of the lung, non-small cell carcinoma of the lung (Okumura H et al. 2022; Manger B et al. 2014; Sheehy C et al. 2007).
• Pancreatic panniculitis with polyarthritis (PPP): PPP refers to a syndrome in which polyarthritis is associated with panniculitis resembling erythema nodosum. PPP often occurs in patients with pancreatitis and severely elevated lipase levels. In acinar cell carcinoma of the pancreas, PPP often occurs with high lipase levels. Here, PPP syndrome is associated with a poor prognosis (Zundler S et al. 2016).
• Remitting seronegative symmetrical synovitis with pitting edema (RS3PE): Clinically, RS3PE patients present with usually acute, bilateral, massive, pillow-like swelling of the dorsum of the hands and/or feet, with associated synovitis of the hand and finger joints (the rheumatologic components are often masked). Paraneoplastic RS3PE is present in approximately 30% of these patientsl (Li H et al. (2015).
• Tumor-induced osteomalacia (TIO): The syndrome is caused by rare mesenchymal osseous tumor entities (40%) or soft tissue tumors (55%), with about 8% being malignant.
• Hypertrophic osteoarthropathy (Marie-Bamberger) (HOA): This classic paraneoplasia is particularly caused by thoracic malignancies and especially bronchial carcinomas. Increased production of vascular endothelial growth factor (VEGF) results in differentiation of the periosteum into osteoblasts.
• Malignancy-associated myositis (CAM): Inflammatory myopathies (IIM) comprise a heterogeneous group of muscle diseases (Lundberg IE et al. 2017) and are associated with a variable risk of malignancy. The subgroup of dermatomyositides is associated with a markedly increased risk of malignancy, unlike the other IIMs, some of which are poorly defined (Qiang JK et al 2016). The malignancy risk of dermatomyositis patients with anti-TIF1γ is increased 27-fold (Trallero-Araguás E et al. (2012). TIF-1γ ubiquitinates the tumor suppressor gene p53, thereby downregulating it, leading to decreased apoptosis of tumor cells.
• Systemic scleroderma can develop in patients with hematologic tumors, such as chronic myelomonocytic leukemia, or tumors of the colon, pancreas, or prostate.
• Systemic scleroderma or systemic lupus erythematosus may also occur in patients with lung and gynecologic tumors.

Eyes (Ocular Paraneoplastic Syndromes): Circulating tumor proteins that resemble retinal proteins and thereby trigger an immune reaction against retinal tissue are probably the cause.

• CAR syndrome (Cancer-associated retinopathy): Association with small-cell lung carcinoma.
• MAR syndrome (melanoma-associatedretinopathy): Melanoma-induced immune response against retinal predominantly downstream of rods, so-called on-depolarizing bipolar cells.
• Diffuse uveal melanocytic proliferation: association with lung carcinomas.

The most successful treatment is control and gfls. removal of an underlying primarius , but some symptoms can also be controlled by certain drugs (e.g., cyproheptadine or somatostatin analogues in carcinoid syndromes, bisphosphonates and corticosteroids in hypercalcemia).

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