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A. Types

  1. Systemic Symptoms
  2. Hematologic and Immunologic Abnormalities
  3. Hormonally Mediated Abnormalities
  4. Cutaneous Syndromes
  5. Neurologic Disorders

B. Systemic Symptoms

  1. Inflammatory Mediators Rsponsible [13]
    1. Interleukins: IL1, IL6
    2. Tumor Necrosis Factors: mainly TNF-alpha, some TNF-ß (lymphotoxin)
    3. Interferons: role unclear
    4. Other mediators including prostaglandins, leukotrienes, neutrotransmitters
    5. Autoantibodies
  2. Common relatively early in course of lymphomas
  3. Later in course of solid tumors
  4. Symptoms include: fever, night sweats, weight loss
  5. Cachexia [20]
    1. Likely caused by elevated levels of inflammatory mediators
    2. Redistribution of body's protein content
  6. Nonbacterial Endocarditis [10]
    1. Formation of vegetations on heart valves with frequent embolization
    2. May be associated with DIC (see below)
    3. Symptoms may mimic endocarditis and thromboembolic stroke
    4. Full systemic picture may ensue
    5. Usually with mucin producing adenocarcinomas (ovarian, pancreatic, others)
    6. Also foud with melanoma, hematologic cancers, non-malignant conditions
    7. Mitral valve is most frequently involved; aortic valve next
  7. Pulmonary Tumor Embolism [26]
    1. Presentation similar to more common thromboembolic PE
    2. Incidence ~15% amongst patients with solid tumors
    3. Breat,stomach, lung, and liver cancers most often reported
    4. Consider in any patient with cancer who presents with acute dyspnea

C. Hematologic and Immunologic Abnormalities

  1. Erythrocytosis
    1. Due to overproduction of erythropoietin
    2. Most common with hypernephroma (renal carcinoma)
    3. May be seen in hepatoma, uterine myoma, cerebellar hemangioma
  2. Anemia
    1. Antibody - commonly with chronic lymphocytic lymphoma, ovarian cancer, leukemia
    2. Microangiopathic Destruction - stomach, prostate, breast, lung, pancreas, colon cancers
    3. Pure Red Cell Aplasia - chronic lymphocytic leukemia
    4. Iron Deficiency
  3. Iron Deficiency
    1. Usually occult gastrointestinal neoplasm (right sided colon cancer)
    2. Genitourinary Cancers
    3. Head and neck cancers
  4. Leukemoid Reaction
    1. Very high neutrophil counts (normal cells), often >20-25K/µL
    2. Usually with gastrointestinal adenocarcinomas
    3. Preterminal event in most cases
  5. Leukopenia - leukemia, lymphoma, marrow infilatration
  6. Thrombocytosis
    1. Many tumor types, myeloproliferative syndrome, lung cancer, lymphoma
    2. Likely related to IL-6 production by tumor or, more likely, in response to it [13]
  7. Thrombocytopenia - many tumor types, bone marrow invasion
  8. Prolonged Bleeding
    1. Several unrelated abnormalities can cause prolonged bleeding
    2. Usually found with plasma cell dyscrasias, prostate cancer (fibrinolysin secretion)
    3. Myeloma, Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia
    4. Acquired von Willebrand Disease, usually due to antibodies, may increase bleeding [12]
  9. Disseminated Intravascular Coagulopathy (DIC)
    1. Many tumors, especially pancreatic and prostate
    2. Probably due to endothelial cell dysfunction related to tumor cell products
  10. Hypercoagulability (Thrombophilia)
    1. Trousseau Syndrome - migratory thrombophlebitis (see below)
    2. Deep Vein Thrombosis (DVT; see below)
    3. Polycythemia Vera also occurs (~12 fold risk for any cancer diagnosis) [14]
    4. Hypercoagulability is related to acquired resistance to anti-clotting factors
    5. Acquired resistance to protein C appears to be the most common finding [22]
    6. May also be related to endothelial cell dysfunction with loss of anti-clotting functions
    7. Anti-phospholipid antibody related thrombosis may also occur
  11. DVT [4,14]
    1. Presence of DVT is >3 fold risk for cancer overall
    2. DVT presentation is also >5 fold risk for having liver, pancreas, ovary, brain cancers, and for Hodgkin lymphoma
    3. DVT is a common presentation of patients with polycythemia vera
    4. Any kind of cancer associated with 6.7X increased risk for DVT [4]
    5. Hematologic malignancy associated with 28X increased DVT risk [4]
    6. In all Swedish patients with DVT, risk for cancer 10 years after the event was 30% above the mean
    7. Cancers diagnosed in association with DVT has poorer prognosis than without DVT [21]
    8. Cancer in patients with germline prothrombotic mutations (Factor V Leiden or prothrombin 20210A mutation) increases DVT risk >12X overall [4]
    9. Acquired protein C resistance (not related to Factor V Leiden) is most common [22]
  12. Non-bacterial endocarditis - hematologic, mucinous adenocarcinomas, melanoma [10]
  13. Vasculitis
    1. Nonblanchable, palpable purpura and nodules
    2. Leukemia: Hairy Cell and Chronic Myelogenous
    3. Lymphoma, Myeloma, Myelodysplastic Syndromes
    4. Probably due to immune complex formation related to anti-tumor immune response
    5. Immune complexes bind to endothelium stimulating inflammation
  14. Systemic Infections
    1. Bacterial - increased susceptbility with leukemia, lymphoma, myeloma, others
    2. Encapsulated Organisms - chronic lymphocytic leukemia, myeloma
    3. Salmonella bacteremia - lymphomas, gastrointestinal neoplasms (microperforations)
    4. Atypical organisms (mycobacteria, fungi, viral) - lymphomas, leukemias, others
    5. Many of these problems related to reduced Ig levels and/or splenic dysfunction
  15. Good's Syndrome
    1. Immunodeficiency associated with thymoma; occurs in ~10%
    2. May occur even after thymoma resection
    3. Includes both cellular and humoral immune abnormalities with low Ig and lymphopenia
    4. Hypogammaglobullinemia occurs in ~10% of thymoma patients
    5. May present with opportunistic infection; serum Ig levels should always be assessed
    6. Chronic sinus infections, bronchiectasis, pneumonia, infectious diarrhea may occur
    7. Treatment of hypogammaglobulinemia with intravenous Ig (IVIg) as needed
    8. Pneumocystis prophylaxis (and other opportunistic infections) with TMP/SMX

D. Hormonally Mediated Syndromes

  1. Hypercalcemia [11,24]
    1. Usually caused by secretion of parathyroid hormone related peptides (PTHRP)
    2. Called "Humoral Hypercalcemia of Malignancy"
    3. Commonly seen with squamous cell cancers of many organs, renal, ovarian, breast, uterine
    4. Local osteolytic hypercalcemia with breast cancer, myeloma, lymphoma
    5. Non-Hodgkin's (NHL) and hodgkin's lymphomas may secrete PTHRP at high levels [5,24]
    6. Lymphomas and some hepatomas hydroxylate vitamin D to active forms leading to hypercalcemia
    7. Ectopic PTH overproduction also seen in very small minority of cases
    8. Elevated PTHRP (and calcium levels) associated with increased mortality [1]
    9. Expression of RANKL or augmentation of RANKL/OPG ratio increases osteoclasts [29]
    10. Osteoclast activation leads to bone disease and/or hypercalcemia of malignancy
  2. Hyponatremia
    1. Usually due to antidiuretic hormone (ADH) secreting tumors
    2. Carcinomas, especially in the lung, and lymphomas (SIADH)
    3. Increased intracerebral pressure will also lead to increased ADH secretion
  3. Diarrhea
    1. Tumors of the GI tract secreting vasoactive intestinal polypeptide (VIP)
    2. Commonly found with pancreatic carcinoid tumors and bronchogenic cancers
    3. Also as part of typical carcinoid syndrome, with flushing, diarrhea, asthma
    4. Colonic polyps (neoplastic or benign) can produce diarrhea as well
    5. Pancreatic carcinoma with duct obstruction leads to steatorrhea/diarrhea
  4. Cushing's Syndrome
    1. Usually by ectopic secretion of adrenocorticotropic hormone (ACTH)
    2. Typically by neuroendocrine tumors, especially small cell lung carcinoma, and thymic Ca
    3. Will also produce metabolic alkalosis and hypokalemia
  5. Peptic Ulceration
    1. Gastrin or secretin release from carcinoid tumors and gastrinomas
    2. Diarrhea is part of this syndrome, called Zollinger-Ellison Syndrome (ZES)
    3. Patients develop muliple duodenal ulcers in 1st-3rd parts of duodenum
  6. Hypertension
    1. Neuroendocrine tumors - pheochromocytoma and other neurogenic tumors
    2. Renin production by Renal Carcinoma
  7. Hyperthryoidism
    1. Ectopic TSH production - rare in pituitary adenomas
    2. High levels of human chorionic gonadotropin (HCG) can bind and stimulate TSH receptors
    3. Commonly found in choriocarcinoma, placental tumor, embryonal testicular carcinoma

E. Musculoskeletal Symptoms

  1. Arthropathy
    1. Leukemia - asymmetric oligoarthritis, hemarthrosis possible; direct infiltrates [32]
    2. Lymphoma - similar to rheumatoid arthritis
    3. Prostate and Pancreatic Cancers - similar to rheumatoid arthritis
    4. Hypertrophic Pulmonary Osteoarthropathy - clubbing; intrathoracic tumors
  2. Tumor Induced Osteopenia (see above) [11]
    1. Local effects - osteolytic cancers
    2. Hypercalcemia of malignancy - due to ectopic PTHRP production
  3. Tumor Induced Osteomalacia [30]
    1. Rare disorder of hypophosphatemia due to excessive urinary phosphate losses
    2. Serum hypophosphatemia leads to osteomalacia
    3. Usually associated with benign tumors of mesenchymal origin
    4. These tumors produce "phosphatonin", a hormone which causes renal phosphate wasting
    5. Phosphatonin is likely FGF-23 (fibroblast growth factor 23)
    6. Phosphatonin is highly expressed in tumors that cause osteomalacia
    7. Symptoms include bone pain, low serum phosphate levels
    8. Octreotide (somatostatin analog) can reverse urinary phosphate loss and osteomalacia
    9. Removal of tumor also abolishes osteomalacia
    10. Oral phosphate 1-4gm/day and calcitriol 1-3µg/d are usually given
    11. Calcitriol increases phosphate absorption and replenishes low levels
  4. Gout
    1. High cell turnover
    2. Hemopoietic tumors, myeloma
  5. Myositis
    1. Dermatomyositis - 5-10% of patients >40 years old will develop neoplasm
    2. Polymyositis - less frequently associated with carcinoma
    3. Carcinomatous (Necrotizing) Myopathy - proximal muscles; often bronchogenic carcinoma
    4. Myotonia
  6. Amyloidosis
    1. Amyloid deposits in synovium
    2. Large joints with peri-articular involvement
    3. Carpal Tunnel Syndrome and Chronic Tenosynovitis
    4. May present with macroglossia and/or renal dysfunction
    5. Most commonly seen in multiple myeloma, renal cell cancers, Hodgkin Lymphoma
  7. Myasthenic Syndromes (see below) [6]
  8. Bone metastases are due to local direct or hormonal effects [28]

F. Neurological Syndromes [6,7]

  1. Direct mass effects in brain or on spinal cord are not considered paraneoplastic
  2. Neurologic syndromes also occur because of chemotherapy or radiotherapy
  3. Overall incidence of true neurological paraneopastic syndromes is ~1%
    1. Lung cancer is most commonly associated (~3%)
    2. Immune dyscrasias also often have a neurologic component
    3. Production of autoantibodies to neuronal components is often found
  4. Classification (Table 1, Ref [6])
    1. Brain and Cranial Nerves
    2. Spinal Cord
    3. Dorsal Root Ganglia - sensory neuropathy
    4. Peripheral Nerves
    5. Neuromuscular Junction
    6. Muscle (see above)
  5. Brain and Cranial Nerve Syndromes
    1. Limbic Encephalopathy or Encephalomyelitis
    2. Brain Stem Encephalitis
    3. Paraneoplastic Sensory Neuropathy
    4. Paraneoplastic Cerebellar Degeneration (see below)
    5. Opsoclonus-Myoclonus Autonomic Dysfunction
    6. Ocular: Cancer associated retinopathy, optic neuritis
    7. Chorea
    8. Parkinsonism
    9. Generally poor response to treatment of tumor
  6. Spinal Cord
    1. Necrotizing myelopathy
    2. Inflammatory myelitis
    3. Motor neuron disease (amyotrophic lateral sclerosis)
    4. Subacute Motor Neuropathy
    5. Stiff-Person Syndrome
    6. Cauda equina syndrome usually due to direct mass effects
    7. Generally poor response to treatment of tumor
  7. Peripheral Nerves
    1. Autonomic neuropathy
    2. Guillain-Barre Syndrome
    3. Brachial Neuritis
    4. Chronic sensorimotor neuropathy - anti-MAG Abs, Waldenstrom's Macroglobulinemia
    5. Vasculitic neuropathy
    6. Neuromyotonia - associated with anti-VGKC (potassium channels), thymoma, SCLC
    7. Generally good response to treatment of tumor ± immunosuppression
  8. Neuromuscular Junction
    1. Eaton-Lambert Myasthenic Syndrome
    2. Myasthenia Gravis
  9. Paraneoplastic Cerebellar Degeneration (PCD) [3]
    1. Truncal and appendicular ataxia
    2. Dysarthria
    3. Nystagmus
    4. Most often mediated by anti-Yo autoantibody against perkinje cells
    5. Anti-Yo Abs associated with breast, ovarian > lung carcinomas
    6. Hodgkin's Lymphoma also causes cerebeller degeneration associated with anti-Tr Abs
    7. Anti-mGluR1 (metabotropic glutamate receptor) also found with Hodgkin's Lymphoma
    8. Anti-Zic4 Antibodies associate dwith small-cell lung cancer
    9. Other autoantibodies sometimes associated with PCD: anti-VGCC, anti-Hu (ANNA-1), anti-Ri (ANNA-2), anti-CV2/CRMP5, anti-Ma, anti-amphiphysin Abs [3]
    10. May respond to immunoadsorption on Protein A column
  10. Brainstem Encephalomyelitis [9]
    1. Presents as sensory neuropathy in ~80% of cases
    2. May include elements of autonomic neuropathy and/or ganglionopathy
    3. Small cell lung cancer (SCLC) associated with 80% of cases of paraneoplastic encephalitis
    4. SCLC associated encephalitis due to anti-Hu (ANNA-1) antibody in >50% of cases
    5. Hu is a series of 4 antigens expressed by both neurons and SCLC
    6. Anti-Ma1 Abs found with lung cancers
    7. Anti-Ma2 Abs may be found with testicular cancer (brain/testes antigen) [17]
  11. Eaton-Lambert Syndrome [15]
    1. Typically associated with bronchogenic cancers, especially small cell lung carcinoma
    2. Due to various auto-Abs which prevent acetylcholine release or function
    3. Release of acetylcholine is voltage-gated calcium channel dependent
    4. Antibodies to the P/Q type of calcium channel are found in ~50-95% of cases [6]
    5. Anti-VGCC (presynaptic neuromuscular junction) also found
    6. Up to 13% of patients have anti-AChR or anti-striational auto-Abs [6]
    7. Muscles typically strengthen with use
    8. Cholinesterase inhibitors may improve symptoms (similar to myasthenia gravis)
    9. DAP may also be effective
  12. Myasthenia Gravis (MG)
    1. Associated with thymoma in ~30% of cases
    2. Anti-acetylcholine receptor (AChR) Abs block post-synaptic neurotransmitter function
    3. Majority of patients with thymoma and MG will have striational auto-Abs
    4. Muscles weaken with use
  13. Autoimmune Autonomic Neuropathy [19]
    1. Paraneoplastic form and idiopathic forms of autoimmune autonomic neuropathy exist
    2. Panautonomic failure develops over days to weeks (subacute)
    3. Monophasic with slow and incomplete recovery
    4. Sympathetic failure manifested with orthostatic hypotension and anhidrosis
    5. Parasympathetic failure manifested with GI dysmotility and abnormal pupillary responses
    6. Ganglioic acetylcholine receptor antibodies are found in ~40% of cases
    7. Antibody levels show some correlation with level of disease
  14. Both T and B lymphocytes are involved in dysregulation

G. Cutaneous Neoplastic and Paraneoplastic Syndromes

  1. Abnormal Pigment
    1. Acanthosis Nigricans - gastrointestinal and other visceral carcinomas
    2. Diffuse Hyperpigmentation - ACTH/MSH producing tumors (melanocyte stimulation)
    3. Cafe-au-lait Spots - Neurofibromatosis
    4. Xeroderma pigmentosa - squamous cancers of skin (autosomal recessive)
  2. Sweet's Syndrome [27]
    1. Acute febrile neutrophilic dermatosis
    2. Malignancy, infection, drug reaction, or autoimmune disease implicated
    3. Amongst maligancy, acute myelocytic leukemia (AML) most common
    4. Erythematous rash, sudden onset fever, neutrophilia; endomyocarditis may occur
    5. May also occur with G-CSF (Neupogen®) treatment
  3. Bullous Lesions [18]
    1. Erythema multiforme - leukemia, lymphoma, others
    2. Pemphigoid - melanoma, bronchial cancers, stomach, others
    3. Paraneoplastic Pemphigus
  4. Paraneoplastic Pemphigus [2,18,25]
    1. Autoimmune vesicular eruption usually associated with hematologic cancer
    2. B-Cell Non-Hodgkin's lymphoma most common, then chronic lymphocytic leukemia (CLL)
    3. Also associated with Castleman's disease, where tumor cell antigens stimulate pathogenic autoantibody formation [8]
    4. Less commonly seen with sarcoma, lung cancer, thymoma
    5. Painful mucous membrane ulcerations are often first manifestation
    6. Bilateral conjunctival blistering in >70%
    7. Skin lesions vary in shape and size, and may become confluent
    8. Erythematous maculopapular rash with bullous lesions developing
    9. Progressive respiratory failure with bronchiolitis obliterans can occur [16]
    10. Due to production of IgG autoAbs against both desmosome and hemidesmosome proteins
    11. Autoantibodies specific for desmogleins 3 and 1, and bullous pemphigoid antigens 1 and 2
    12. Additional autoantibodies to plakins and to 170K protein
    13. Nearly always fatal within 2 years when associated with malignant neoplasm
    14. Chemotherapy is not effective for reducing disease
    15. Glucocorticoids and/or mycophenolate mofitel may be beneficial
    16. Tumor removal is often beneficial, though mucosal lesions may take months to resolve [8]
  5. Purpura and Ecchymoses
    1. Thrombocytopenia from any cause
    2. May also occur with macroglobulinemia
  6. Puritis
    1. Hodgkin's Disease
    2. Polycythemia Vera
    3. Jaundice from any cause
  7. Pyoderma
    1. Frequently in patients with leukemia, lymphoma, myleoma, neutropenia (chemotherapy)
    2. Also found in patients with congenital abnormal granulocyte function
    3. Most commonly seen in setting of bone marrow transplant
  8. Dermatomyositis
    1. Risk ~4.5X increased over general population for development of neoplasm
    2. Cancer associated with 5-10% of cases in patients presenting after age 40 years
  9. Lichen Sclerosus et atrophicus
  10. Hypertrichosis (Hirsutism)
    1. Ovarian and adrenal Tumors
    2. Ectopic ACTH production - especially lung tumors
    3. Gonadotropin hyperexcretion
    4. Hypertrichosis lanuginosa acquisita (generalized fine hair growth) - common tumors
  11. Acquired Ichthyosis
    1. Small white to brown scales with free edge
    2. Mainly on trunk and extensor surfaces
    3. Mainly associated with Hodgkin's Disease
  12. Sign of Leser-Trelat
    1. Sudden increase in size and number of seborrheic keratoses
    2. Asscoiated with development of GI carcinomas and lymphomas, other tumors
  13. Tripe Palms
    1. Thickened velvet or moss texturned, skin ridging
    2. Occurs with lung and gastric cancers
  14. Thrombophlebitis [23]
    1. Migratory thromboses, formerly "Trousseau Syndrome"
    2. Associated with carcinomas, usually of the pancreas
    3. Multiple arterial thrombi leading to myocardial infarction and/or stroke may occur
  15. Vasculitis - see above

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