Sections

Presentation

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,^{[16, 17]}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. Paraneoplastic syndromes are usually divided into the following categories:

Miscellaneous (nonspecific)
Rheumatologic
Renal
Gastrointestinal
Hematologic
Cutaneous
Endocrine
Neurologic/neuromuscular

Miscellaneous (nonspecific) syndromes

Fever, dysgeusia, anorexia, and cachexia are included in this category. Fever is frequently associated with the following:

Lymphomas ^[18]
Acute leukemias
Sarcomas
Renal cell carcinomas (Grawitz tumors)
Digestive tract malignancies (including liver cancer)

Rheumatologic syndromes

Paraneoplastic arthropathies arise as rheumatic polyarthritis or polymyalgia, particularly in patients with myelomas; lymphomas; acute leukemia; malignant histiocytosis; and tumors of the colon, pancreas, prostate, and CNS.^[19]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 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 syndromes

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^[20]).

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 syndromes

Watery diarrhea^[21]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 and F2) that lead to malabsorption and, consequently, unavailability of nutrients.

These alterations also can be observed in patients with any of the following:

Melanomas
Myelomas
Ovarian tumors
Pineal body tumors
Lung metastases

Hematologic syndromes

Symptoms related to erythrocytosis or anemia,^[21]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)^{[22, 23]}occurring in at least two sites. Leukemoid reactions, characterized by the presence of immature white blood cells 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, stomach, or pancreas. Cryoglobulinemia may occur in patients with lung cancer or pleural mesothelioma.

Cutaneous syndromes

Itching is the most frequent paraneoplastic cutaneous manifestation. Herpes zoster, ichthyosis,^[24]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 abdominal cancers, especially gastric neoplasms and adenocarcinomas.^[25]

Endocrine syndromes

Endocrine symptoms related to paraneoplastic syndromes usually resemble the more common endocrine disorders. 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.^{[26, 27, 6, 28]}Many tumors (eg, small cell cancer of the lung) can produce Cushing syndrome via ectopic production of ACTH or ACTH-like molecules.

Syndrome of inappropriate antidiuretic hormone (SIADH) is the most common paraneoplastic endocrine syndrome associated with small cell lung cancer (SCLC). Reports range from 10-45% of patients developing SIADH during their illness.^[29]

Neurologic/neuromuscular syndromes

Neuromuscular disorders related to cancers are included among the paraneoplastic syndromes. Such disorders affect 6% of all patients with cancer and are prevalent in ovarian and pulmonary cancers. Neuromuscular symptoms may mimic common neurologic conditions.

Myasthenia gravis^[30]is the most common paraneoplastic syndrome in patients with thymoma,^[31]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.^[32]Rarely, hypogammaglobulinemia and pure red cell aplasia occur as paraneoplastic syndromes in patients with thymoma.^[31]

Lambert-Eaton myasthenic syndrome (LEMS) 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. In 40-70% of cases, LEMS is associated with cancer, most commonly small cell lung cancer (SCLC).^[29]LEMS seems to result from interference with the release of acetylcholine due to immunologic attack against the presynaptic voltage-gated calcium channel.

Opsoclonus-myoclonus syndrome^[33]usually affects children younger than 4 years. It is associated with hypotonia, ataxia, and irritability. One in two patients has neuroblastoma.

Paraneoplastic limbic encephalitis^[34]is characterized by depression, seizures,^[35]irritability, and short-term memory loss. The neurologic symptoms develop rapidly and can resemble dementia. Paraneoplastic limbic encephalitis is most commonly associated with SCLC.^[36]

Encephalitis resulting from antibodies against the N-methyl-D-aspartate (NMDA) receptor may occur in patients with ovarian teratoma, many of whom are younger women; rarely, anti-NMDA-receptor encephalitis develops in patients with testicular teratoma or SCLC.^{[37, 38, 39]}Involvement of NMDA receptors in the hippocampus may result in prodromal flulike symptoms, psychiatric disturbance progressing to coma, movement disorders, autonomic instability, and respiratory failure.^[40]

Paraneoplastic encephalomyelitis is characterized by a complex of symptoms arising 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,^[41]breast cancer,^[42]SCLC,^[29]and ovarian cancer; it may occur in association with prostate carcinoma.^[43]

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.

Physical Examination

As with the history, physical examination findings in patients with paraneoplastic syndromes are divided into the following categories:

Miscellaneous (nonspecific)
Rheumatologic
Renal
Gastrointestinal
Hematologic
Cutaneous
Endocrine
Neurologic/neuromuscular

Miscellaneous (nonspecific) syndromes

Miscellaneous paraneoplastic findings include the following:

Fever generally occurs in the evening and is of a continual-remittent type
Dysgeusia manifests in a variety of ways, from ageusia to aversion to protein (in particular, meat proteins)
Anorexia is common among patients with neoplastic syndromes and is responsible, along with dysgeusia, for weight loss and even cachexia

Rheumatologic syndromes

Rheumatologic paraneoplastic syndromes include the following:

Hypertrophic osteoarthropathy
Polymyositis and dermatomyositis
Scleroderma
Systemic lupus erythematosus (SLE)

Hypertrophic osteoarthropathy presents as digital clubbing and painful swelling of the hip, wrist, and knee, accompanied by an articular effusion. The long bones may also be involved; in such cases, patients complain of pain and x-rays show a typical elevation (thickening and detachment) of the periosteum

Polymyositis and dermatomyositis may occur as paraneoplastic syndromes in patients with lymphomas or cancers of the lung, stomach, breast, or uterus.^[44]These syndromes are characterized clinically by asthenia, pain, and progressive hypertrophy of proximal muscles. Subsequent involvement of the skin manifests as violet-colored rashes of the face and hands.

A retrospective study by Fardet et al identified the following independent factors associated with an underlying malignancy in patients with dermatomyositis^[45]:

Age at diagnosis >52 years (hazard ratio [HR], 7.24; 95% confidence interval [CI], 2.35-22.31)
Rapid onset of skin and/or muscular symptoms (HR, 3.11; 95% CI, 1.07-9.02)
Presence of skin necrosis (HR, 3.84; 95% CI, 1.00-14.85) or periungual erythema (HR, 3.93; 95% CI, 1.16-13.24)
A low baseline level of complement factor C4 (HR, 2.74; 95% CI, 1.11-6.75)
However, a low baseline lymphocyte count (< 1500/mm ³) was associated with a lower likelihood of malignancy (HR, 0.33; 95% CI, 0.14-0.80)

For patients with paraneoplastic scleroderma or SLE, the clinical picture is characteristic of nonparaneoplastic conditions

Renal syndromes

Renal paraneoplastic findings include the following:

Urinary symptoms related to paraneoplastic disorders are characterized by edema resulting from hypoalbuminemia and proteinuria (>3 g/24 h)
Hypercholesterolemia may be present

Gastrointestinal syndromes

The clinical picture of paraneoplastic disorders affecting the gastrointestinal system is similar to that of nontropical sprue.

Hematologic syndromes

Thrombocytosis (>500,000 platelets/dL) can be observed in patients with cancer of the lung, breast, digestive organs, or reproductive organs. This thrombocytosis leads to the following two phenomena:

Migrating thrombophlebitis that is resistant to standard anticoagulant therapy and involves the arm veins, the inferior vena cava, and the jugular veins; it usually appears as oval formations along small and medium-size veins, accompanied by cutaneous necrosis.
Marantic (nonbacterial) endocarditis characterized by growths developing on the heart valves that may break off and form emboli

Cutaneous syndromes

Cutaneous paraneoplastic findings include the following:

Herpes zoster and alopecia presenting as part of a paraneoplastic syndrome are similar to their equivalent benign forms
Flushes appear that are similar to those related to benign conditions such as stress
Hypertrichosis is not different from the form it takes when related to an endocrine imbalance (usually, adrenal dysfunction); paraneoplastic hypertrichosis is characterized by a sudden appearance of wooly hair on the face and ears that disappears promptly after the tumor is removed
Ichthyosis, which in the early stages could mimic a benign dermatosis, is characterized by desquamation of the extensory surface of the limbs (resembles the scales of a fish, from the ancient Greek ichthus, meaning fish)
Patients with glucagonoma may have necrotizing migrating erythema (NME)^[46]resulting from erythematous and exfoliative injuries that differ from exfoliative erythrodermia; This is typical of leukemias and lymphomas and results in blushing and diffuse skin desquamation that affects cutaneous adnexa, which subsequently results in alopecia and nail fragility but which rarely is accompanied by fever, chills, and itching
Acanthosis nigricans and dermic melanosis are often pathognomonic for the presence of a malignancy

Acanthosis nigricans and dermic melanosis are similar but differ by location. Dermic melanosis is diffuse; acanthosis nigricans usually is accompanied by confluent papillomas and affects the oral, umbilical, axillary, and inguinal areas. Three types of acanthosis nigricans are described: benign, pseudoacanthosis, and malignant. Unlike the benign form, which tends to develop slowly, the malignant form is characterized by sudden onset of extensive lesions with rapid growth. Leser-Trélat sign consists of multiple seborrheic keratoses (black, brown, or tan), often pruritic, primarily on the thorax and dorsum.^[25]

Endocrine syndromes

This is a heterogeneous group of disorders characterized by clinical signs that vary greatly according to the specific disorder, as follows:

Patients with Cushing syndrome as part of a paraneoplastic syndrome appear similar to patients with Cushing disease, with the typical moon facies and obesity of the trunk; symptoms caused by human chorionic gonadotropin and urinary gonadotropin peptide are absent; gynecomastia may occur in males
Hyponatremia may occur in patients with tumors that produce hormones that affect water and electrolyte balance (ie, antidiuretic hormone [ADH])
Hypercalcemia mediated by the secretion of parathyroid hormone–related peptide has been reported in a variety of cancers, including gynecologic malignancies^{[47, 48]}
Hypoglycemia seems related to production of insulinlike growth factor (IGF)-1 and IGF-2

Neurologic/neuromuscular syndromes

One or more neurologic paraneoplastic syndromes may be present in patients with cancer, especially those suffering from lung cancer. Neuropathies may be sensory, motor, or mixed.

Sensory neuropathy, which usually affects only patients with lung cancer, originates from ganglionic degeneration, and its onset is characterized by paresthesias and tabeticlike pain, acute hyporeflexia with a reduction of proprioceptive sensitivity and ataxia (both static and dynamic), vibratory anesthesia, deafness, cutaneous hypoesthesia or anesthesia, dysgeusia, and dysosmia.

Mixed neuropathy may occur with several malignancies and has an extremely variable presentation, with motor or sensory symptoms either preceding the clinical onset of tumor disease or accompanying it. The spinal cord can be affected by either subacute necrotic myelitis or subacute myelitis. These conditions lead to a progressive flaccid paraplegia with areflexia, lack of sphincteric control, and anesthesia of the lower limbs.

A lateral amyotrophic syndrome (LAS) may occur, presenting as the typical muscular asthenia and atrophy, hyperreflexia with pyramidal fasciculations, and degeneration of the second motor neuron. This form of LAS differs from the nonparaneoplastic form because it includes sensory involvement (ie, proprioception and pallesthesia).

The cerebellum may be the site of subacute neuronal degeneration^[49]in patients with small cell carcinoma or breast or gynecologic tumors. Such degeneration presents clinically as cerebellar ataxia, dysarthria, and nystagmus. Dysphagia, palpebral ptosis, deafness, and a positive Babinski sign may also occur.

The cerebellum of patients with lung cancer also may be affected by encephalitis. In such cases, the clinical picture is characterized by convulsions, delirium, and a lack of long-term memory. In other patients, the pathological process involves the medulla (ie, encephalomyelitis).

In some patients with leukemias, lymphomas, or epithelial cancers, a rare degenerative process involving the semioval center may be observed. This degenerative process is characterized by convulsions, cerebellar ataxia, progressive dementia, aphasia, hemiparesis, hemihypoesthesia, dysphagia, and nystagmus. The process develops rapidly, leading to death within 6 months of onset.

Lambert-Eaton myasthenic syndrome (LEMS) is most often associated with small cell lung cancer (SCLC) and may also occur in patients with lymphomas; thymomas; or cancers of the pancreas, rectum, kidney, breast, prostate, or uterus. LEMS may resolve after surgical resection of the primary tumor but not after radiotherapy or chemotherapy.

Stiff-person syndrome can be an autoimmune phenomenon or a manifestation of cancers such as thymoma or lung cancer. It is characterized clinically by muscle stiffness of the trunk and limbs involving the abdominal and thoracolumbar paraspinal muscles, which leads to deformities such as lordosis, along with painful muscle spasms, which can be induced by a sudden noise, tactile stimulation, or emotional stress.^[50]

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