Paraneoplastic syndromes

ALSO KNOWN AS: Paraneoplastic disorders

RELATED CONDITIONS: Cushing syndrome, Lambert-Eaton myasthenic syndrome (LEMS), dermatomyositis-polymyositis, malignant carcinoid syndrome, leukemoid reaction, disseminated intravascular coagulation (DIC), syndrome of inappropriate antidiuretic hormone (SIADH)

DEFINITION: Paraneoplastic syndromes are a large group of clinical symptoms that may arise from the presence of a malignancy. While these symptoms can be considered distinct clinical entities in themselves, they are an indirect result of the primary neoplastic entity's biochemical by-products.

Risk factors: The risk factors for developing one or more paraneoplastic syndromes depend on a family history of malignant cancer and the primary tumor type. For instance, specific tumors, such as small-cell lung carcinoma, are associated with a higher predilection for Cushing syndrome due to adrenocorticaltropic hormone (ACTH) secretion.

Etiology and the disease process: The origin of most paraneoplastic syndromes is generally attributed to the unabated production of different types of chemical messengers by tumor cells. These chemicals include cytokines, hormones, and their precursors, autoantibodies, enzymes, and fetal proteins. The corresponding effect of these substances on metabolic, biochemical, and physiologic pathways can be observed clinically. Because these substances circulate through the body, the primary site of the tumor may be distant from the organ systems involved. Similarly, a paraneoplastic syndrome alone may herald the presence of malignancy bearing a poor prognosis.

Incidence: The incidence of paraneoplastic syndromes is estimated to be between 2 and 20 percent in patients with malignant cancer. However, these reported numbers may be lower than the actual incidence as these syndromes can masquerade as nonmalignant diseases on manifestation and thus are poorly accounted for.

Symptoms: Symptoms of paraneoplastic syndromes are very broad and may initially occur as nonspecific complaints such as an unexplained, persisting fever, noninduced loss of appetite, and involuntary weight loss. More specific symptoms point to an affected organ system, although the may remain unknown. Vague joint and muscle pain may be associated with bone joint thickening or connective tissue proliferation (scleroderma or amyloidosis). Weakness, diarrhea, and mental status changes can be attributed to electrolyte imbalances of sodium, potassium, and phosphorus; acid-base disorders caused by adrenocorticotropic hormone, antidiuretic hormone, or intestinal hormone secretion; kidney damage; or malabsorption of nutrients. Bleeding from underproduction or overactivation and depletion of coagulation components (disseminated intravascular coagulation, cryoglobulinemia), migratory sites of spontaneous intravascular clotting, or abnormal excesses of or deficits in red blood cells or white blood cell subtypes (anemia, erythrocytosis, thrombocytosis) may also be present. Itching is the most common skin complaint of cancer patients. Other skin lesions may appear and include loss or excess of hair (alopecia, hypertrichosis), stress-induced flushing, scalelike changes (ichthyosis), shingles (herpes zoster), and black pigmentation of the skin (acanthosis nigricans, dermic melanosis). Cushingoid symptoms (fatigue, lethargy, psychosis, buffalo hump, hypertension, purple striae, central obesity) are suggestive of excess ACTH-like molecule secretion. Muscular weakness around the pelvic girdle and scapular areas that improves throughout the day and decreased tendon reflexes are characteristic of Lambert-Eaton syndrome (LEMS).

Screening and diagnosis: There is no specific screening for paraneoplastic syndromes, as they depend on the underlying cause. However, blood tests, imaging, spinal taps, and laboratory studies are essential in establishing their presence. Establishing the etiology of a paraneoplastic syndrome depends on the clinical and confirmatory investigation of a suspected neoplasm through a combination of laboratory, imaging, and pathology studies of specimens. Bleeding disorders can often be assessed with blood tests such as complete blood counts, as well as assessments of platelet function, platelet factors, and clotting mechanisms. Multistep diagnostics such as the dexamethasone suppression test can be used to rule out a pituitary cause of Cushingoid symptoms by measuring ACTH and cortisol levels in response to low and high doses of dexamethasone if a twenty-four-hour screening for urine cortisol before testing is positive. Despite these investigations, a definitive “diagnosis” is established only once the primary tumor is located and biopsied, if not excised. A decrease in antidiuretic hormone secretion by the tumor is often resistant to changes in serum levels by withholding water intake.

Autoantibodies such as anti-Hu, anti-Ri, and antibodies against amphiphysin are present in some patients exhibiting neurologic symptoms and syndromes such as neuronopathy, encephalitis, opsoclonus/myoclonus syndrome, and stiff-person syndrome. Cancer-associated autoantibodies, such as the antineuronal Ma2, are seen in testicular cancer.

Treatment and therapy: Treatment and therapy are directed toward tumor detection and elimination. Depending on the type of tumor found, this may involve a combination of surgical, chemotherapeutic, and radiologic interventions. Treatment of the paraneoplastic disease itself will often fail if the location of the primary tumor is not established.

Immunosuppression may help in cases with an immune-mediated etiology. Agents used include cyclosporine, antithymocyte globulin, and prednisone.

Prognosis, prevention, and outcomes: Prognosis is widely variable and depends on the clinical presentation of the paraneoplastic disease. For example, disseminated intravascular coagulation may indicate a poor prognosis, while less life-threatening diseases fare better. Generally, treatment of the tumor results in resolution of the paraneoplastic disease. However, the severity of the specific disease may prolong recovery. There are no preventive measures.

Bibliography

Darnell, Robert B., and Jerome B. Posner. Paraneoplastic Syndromes. New York: Oxford UP, 2011.

Graber, Jerome J. “Paraneoplastic Neurologic Syndromes.” Continuum (Minneapolis, Minn.), vol. 29.6, 2023, pp. 1779-1808, doi:10.1212/CON.0000000000001357.

Kelloff, Gary, Ernest T. Hawk, and Caroline C. Sigman, editors. Cancer Chemoprevention. 2 vols., Totowa: Humana, 2005.

Montgomery, Hugh, Neil Goldsack, and Richard Marshall. My First MRCP Book. London: Remedica, 2003.

“Paraneoplastic Syndromes.” National Institute of Neurological Disorders and Stroke, www.ninds.nih.gov/health-information/disorders/paraneoplastic-syndromes. Accessed 28 June 2024.

“Paraneoplastic Syndromes: Symptoms, Types & Treatment.” Cleveland Clinic, 6 Sept. 2022, my.clevelandclinic.org/health/diseases/17938-paraneoplastic-syndromes. Accessed 28 June 2024.

Rose, Noel R., and Ian R. Mackay. The Autoimmune Diseases. 5th ed., Amsterdam: Elsevier/Academic, 2014.

Thapa, Bicky. “Paraneoplastic Syndromes - StatPearls.” NCBI, 31 Mar. 2023, www.ncbi.nlm.nih.gov/books/NBK507890. Accessed 28 June 2024.