Paraneoplastic Syndromes Clinical Presentation

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History
Paraneoplastic syndromes most commonly occur in patients not known to have cancer, as well as in those with
active cancer and those in remission after treatment. A complete history and physical examination findings can
suggest neoplasia. Persons with a family history of malignancies (eg, breast,[7, 8] colon) may be at increased risk
and should be screened for cancer. Nonspecific syndromes can precede the clinical manifestations of the tumor,
and this occurrence is a negative prognostic factor.
Because of their complexity and variety, the clinical presentations of these syndromes may vary greatly. Usually,
paraneoplastic syndromes are divided into the following categories: (1) miscellaneous (nonspecific), (2)
rheumatologic, (3) renal, (4) gastrointestinal, (5) hematologic, (6) cutaneous, (7) endocrine, and (8) neuromuscular.
Miscellaneous (nonspecific)
Fever, dysgeusia, anorexia, and cachexia are included in this category.
Fever is frequently associated with lymphomas,[9] acute leukemias, sarcomas, renal cell carcinomas
(Grawitz tumors), and digestive malignancies (including the liver).
Rheumatologic
Paraneoplastic arthropathies arise as rheumatic polyarthritis[10] or polymyalgia, particularly in
patients with myelomas; lymphomas; acute leukemia; malignant histiocytosis; and tumors of the
colon, pancreas, prostate, and CNS.
Hypertrophic osteoarthropathy may be observed in patients with lung cancers, pleural mesothelioma,
or phrenic neurilemmoma.
Scleroderma may precede direct evidence of tumor
The widespread form is typical of malignancies of the breast, uterus, and lung (both alveolar
and bronchial forms).
The localized form is characteristic of carcinoids and of lung tumors (bronchoalveolar forms).
Systemic lupus erythematosus (SLE) may develop in patients with lymphomas or cancers of the
lung, breast, or gonads.
Secondary amyloidosis of the connective tissues is a rare presentation in patients with myeloma,
renal carcinoma, and lymphomas.
Renal
Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more than 20
mEq per 24 hours, may develop in patients with tumors that secrete adrenocorticotropic hormone
(ACTH) or ACTH-like substances. It occurs in 50% of individuals with ACTH-secreting tumors of the
lung (ie, small cell lung cancer[11] ).
Hypokalemia, hyponatremia or hypernatremia, hyperphosphatemia, and alkalosis or acidosis may
result from other types of tumors that produce ACTH, antidiuretic hormone (ADH), or gut hormones
(see Endocrine and neuromuscular, below).
Nephrotic syndrome is observed, although infrequently, in patients who have Hodgkin lymphoma
(HL); non-Hodgkin lymphoma (NHL); leukemias; melanomas; or malignancies of lung, thyroid, colon,
breast, ovary, or pancreatic head.
Secondary amyloidosis of the kidneys, heart, or CNS may rarely be a presenting feature in patients
with myeloma, renal carcinoma, or lymphomas. The clinical picture of secondary amyloidosis is
related to renal and cardiac injuries.
Gastrointestinal
Watery diarrhea[12] accompanied by an electrolyte imbalance leads to asthenia, confusion, and
exhaustion.
These problems are typical of patients with proctosigmoid tumors (both benign and malignant) and of
medullary thyroid carcinomas (MTCs) that produce several prostaglandins (PGs; especially PG E2
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and F2) that lead to malabsorption and, consequently, unavailability of nutrients.

These alterations also can be observed in patients with melanomas, myelomas, ovarian tumors,
pineal body tumors, and lung metastases.
Hematologic
Symptoms related to erythrocytosis or anemia,[12] thrombocytosis, disseminated intravascular
coagulation (DIC), and leukemoid reactions may result from many types of cancers.
In some cases, symptoms result from migrating vascular thrombosis (ie, Trousseau syndrome)[13]
occurring in at least 2 sites.
Leukemoid reactions, characterized by the presence of immature WBCs in the bloodstream, are
usually accompanied by hypereosinophilia and itching. These reactions are typically observed in
patients with lymphomas or cancers of the lung, breast, or stomach.
Cryoglobulinemia may occur in patients with lung cancer or pleural mesothelioma.
Cutaneous[14]
Itching is the most frequent cutaneous manifestation in patients with cancer.
Herpes zoster, ichthyosis,[15] flushes, alopecia, or hypertrichosis also may be observed.
Acanthosis nigricans and dermic melanosis are characterized by a blackish pigmentation of the skin
and usually occur in patients with metastatic melanomas or pancreatic tumors.
Endocrine
Endocrine symptoms related to paraneoplastic syndromes usually resemble the more common
endocrine disorders (eg, Cushing syndrome). Neuromuscular symptoms may mimic common
neurological conditions (eg, dementia).
Cushing syndrome, accompanied by hypokalemia, very high plasma ACTH levels, and increased
serum and urine cortisol concentrations, is the most common example of an endocrine disorder
linked to a malignancy.[16, 17, 3, 18] This is related to the ectopic production of ACTH or ACTH-like
molecules from many tumors (eg, small cell cancer of the lung).
Neuromuscular
Neuromuscular disorders related to cancers are now included among the paraneoplastic syndromes.
Such disorders affect 6% of all patients with cancer and are prevalent in ovarian and pulmonary
cancers. Examples include the following:
Myasthenia gravis[19] is the most common paraneoplastic syndrome in patients with thymoma,
[20] a malignancy arising from epithelial cells of the thymus. Indeed, thymoma is the underlying
cause in approximately 10% to 15% of cases of myasthenia gravis.[21] Rarely,
hypogammaglobulinemia and pure red cell aplasia occur as paraneoplastic syndromes in
patients with thymoma.[20]
Lambert-Eaton myasthenic syndrome (LEMS), which manifests as asthenia of the scapular
and pelvic girdles and a reduction of tendon reflexes. LEMS sometimes can be accompanied
by xerostomia, sexual impotence, myopathy, and peripheral neuropathy. It is associated with
cancer 40-70% of the time, most commonly small cell lung cancer (SCLC). It seems to result
from interference with the release of acetylcholine due to immunologic attack against the
presynaptic voltage-gated calcium channel.
Opsoclonus-myoclonus syndrome[22] usually affects children younger than 4 years. It is
associated with hypotonia, ataxia, and irritability. One in two patients has neuroblastoma.
Paraneoplastic limbic encephalitis[23] is characterized by depression, seizures, irritability, and
short-term memory loss. The neurologic symptoms develop rapidly and can resesmble
dementia. Paraneoplastic limbic encephalitis is most commonly associated with SCLC.[24]
Paraneoplastic encephalomyelitis is characterized by a complex of symptoms derived from
brainstem encephalitis, limbic encephalitis, cerebellar degeneration, myelitis, and autonomic
dysfunction. Such neurologic deficits and signs seem to be related to an inflammatory
process involving multiple areas of the nervous system.
Paraneoplastic cerebellar degeneration causes gait difficulties, dizziness, nausea, and
diplopia, followed by ataxia, dysarthria, and dysphagia. Paraneoplastic cerebellar
degeneration is frequently associated with Hodgkin lymphoma,[25] breast cancer,[26] SCLC,
and ovarian cancer; it may occur in association with prostate carcinoma.[27]
Paraneoplastic sensory neuropathy affects lower and upper extremities and is characterized
by progressive sensory loss, either symmetric or asymmetric. It seems to be related to the
loss of the dorsal root ganglia with early involvement of major fibers responsible for detecting
vibration and position.

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Contributor Information and Disclosures

Author
Luigi Santacroce, MD Assistant Professor, Medical School, State University at Bari, Italy
Disclosure: Nothing to disclose.
Coauthor(s)
Laura Diomede University of Bari School of Medicine, Italy
Disclosure: Nothing to disclose.
Silvia Gagliardi, MD Consulting Staff, Department of Surgery, Medical Center Vita, Italy
Disclosure: Nothing to disclose.
Lodovico Balducci, MD Professor of Oncology and Medicine, University of South Florida College of Medicine;
Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Benjamin Movsas, MD Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology,
American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.
Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good
Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical
Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.
Chief Editor
Jules E Harris, MD Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona
College of Medicine, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research,
American Association for the Advancement of Science, American Association of Immunologists, American
Society of Hematology, and Central Society for Clinical Research
Disclosure: Nothing to disclose.

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