Paraneoplastic Syndromes Associated with Lung Cancer (ectopic Cushing’s syndrome, SIADH, hypercalcemia of malignancy,Lambert-Eaton myasthenic syndrome (LEMS), paraneoplastic limbic encephalitis, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, dermatomyositis)

What every physician needs to know:

Lung cancer symptoms usually arise from the direct effects of tumor on the lungs or contiguous structures by compression, obstruction, or invasion of other organs. However, another important form of clinical presentation is paraneoplastic syndromes. Paraneoplastic syndromes are defined as symptoms and signs distant to the primary tumor site and unrelated to local effects or metastasis. They are mediated by endocrine and immune mechanisms.

Paraneoplastic syndromes occur in approximately 10-20% of patients with lung cancer, affect all organ systems but occur most commonly in the endocrine, neurologic, dermatologic and hematologic systems. Though both main types of lung cancer – small cell lung cancer (SCLC, about 15% of cases) and non-small cell lung cancer (NSCLC, around 85% of cases, including adenocarcinoma, squamous cell carcinoma and large cell carcinoma) – have been associated with paraneoplastic syndromes, they more commonly occur in association with small-cell lung cancer which shares a neuroendocrine lineage.

Manifestations of Paraneoplastic Syndromes:

Are you sure your patient has a paraneoplastic syndrome associated with lung cancer? What should you expect to find?

Ectopic Cushing's Syndrome (ECS)

Ectopic Cushing syndrome is typically caused by production of ACTH by non-pituitary tissue leading to hypercortisolism. However, rare reports of Cushing syndrome due to ectopic production CRH (corticotropic releasing hormone) and POMC (pro-opiomelanocortin) also exist. Symptoms and signs are typical of other causes of Cushing syndrome and include centripetal weight gain/truncal obesity, facial plethora, pathologic striae, dorsocervical fat pad enlargement, proximal muscle weakness hyperpigmentation, psychosis, and confusion. Hypokalemia and other electrolyte abnormalities may also occur, particularly in cases with marked hypercortisolism. The magnitude of cortisol production, progression of the underlying cancer, and patient vulnerability determine the severity of symptoms. Subclinical presentation of ECS in lung cancer (SCLC) has been reported and is defined as elevation of cortisol that does not demonstrate normal suppression after administration of exogenous steroids in the absence of overt clinical signs and symptoms of Cushing syndrome. ECS caused by small cell lung cancer (SCLC), or other aggressive tumors, may have an atypical presentation with muscle wasting and weight loss instead of classical sings of hypercortisolism such as moon facies and weight gain.

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Euvolemia, hyponatremia, low plasma osmolality and inappropriately concentrated urine not due to hypothyroidism or adrenal insufficiency are the classical findings of SIADH. The majority of patients are asymptomatic and symptoms generally develop when serum sodium falls below 125 mmol/L. The severity of symptoms is related to the rate of sodium decline, the level of serum sodium, and the age of patients. Symptoms and clinical manifestations present along a spectrum based on severity and rate of hyponatremia onset and include fatigue, anorexia, nausea, headache, generalized weakness, altered mental status, lethargy, confusion, seizures, coma, and even death.

Hypercalcemia of malignancy

Squamous cell carcinoma is the most common type of cancer associated with hypercalcemia.

Bone pain, malaise, fatigue, polyuria, polydipsia, constipation, nausea, vomiting, and confusion correlate with mild to moderate hypercalcemia (>10.5 mg/dL), while confusion, coma, bradycardia, heart block, and death present with severe hypercalcemia (>14 mg/dL). Hypercalcemia less commonly can cause pancreatitis. Baseline kidney function, volume status, underlying neurologic conditions, amount and speed of development of hypercalcemia determine the severity of the patient’s symptoms.

HCM is diagnosed based on the presence of elevated calcium in the setting of suppressed parathyroid hormone (PTH) and elevated parathyroid-related peptide (PTHRP), which is the hormone that causes this paraneoplastic syndrome.

Lambert-Eaton Myasthenic Syndrome (LEMS)

LEMS is a rare autoimmune disorder of the neuromuscular junction and may precede the diagnosis of lung cancer. Progressive proximal, lower greater than upper extremity weakness is nearly always the initial symptom. Other symptoms include fatigue, myalgias, and areflexia. Autonomic symptoms are present in about half of the cases, while xerostomia and ptosis are present in about 25 percent. Constipation and erectile dysfunction may precede motor symptoms.

The syndrome lacks ocular involvement and rarely affects the respiratory musculature. On physical examination, proximal lower and upper extremity weakness, augmentation of strength during the first seconds of a maximum effort, and absent deep tendon reflexes may be found.

Paraneoplastic Limbic Encephalitis (PLE)

Limbic encephalitis (LE) affects the medial temporal lobe of the brain and has numerous causes including infection, autoimmune diseases or cancer.

Paraneoplastic limbic encephalitis (PLE) is indistinguishable from PLE due to other causes but is usually a part of multifocal encephalomyelitis, and rarely a solitary syndrome. PLE is characterized by acute to subacute onset of short-term memory deficits with preservation of other cognitive function. Clinical features also include depression, personality change or irritability; partial complex or motor seizures involving the face and extremities; gustatory and olfactory hallucinations; hyperphagia, drowsiness, hyperthermia, and pituitary hormonal deficits; and asymmetric loss of sensation in the extremities (hands more than legs).

Anti-neuronal antibody may be helpful in identifying the source of cancer. Anti-Hu antibodies are frequently noted in SCLC. Anti CV2/CRMP5 antibodies may also be present and are associated with other symptoms such as sensorimotor neuropathy, cerebellar ataxia, chorea, uveitis and optic neuritis.

Helpful criteria for PLE include:

A well-matched symptoms and signs

Presentation preceding cancer diagnosis by less than 4 years

Absence of direct complications of cancer such as:

Metastasis, infection, metabolic complication, nutritional deficits, cerebrovascular disorder or side effects of treatment

Presence of at least one of the following criteria:

Inflammatory changes in CSF

MRI findings (brain atrophy on T1, or unilateral/bilateral temporal lobe abnormalities on T2)

EEG findings (unilateral/bilateral abnormal EEG of temporal lobes, slow- or sharp-wave activity

Paraneoplastic cerebellar degeneration (PCD)

Paraneoplastic cerebellar degeneration is another type of paraneoplastic neurological syndrome and is linked with production of onconeural antibodies in approximately 60% of cases. Neurologic symptoms, source of cancer and the types of antibodies are highly correlated. This syndrome is more commonly associated with ovarian and breast cancer but is also reported in patients with SCLC. Patients with PCD and Hu antibodies usually manifest diffuse encephalomyelitis.

The onset of PCD is often subacute with progression over weeks to months and may precede tumor diagnosis. Symptoms include dizziness and nausea, ataxia of the limbs and midline, nystagmus, dysarthria, tremors, blurry vision, diplopia, and dysphagia. Mild memory and cognitive deficits and affective symptoms occur in up to 20 percent of patients (cerebellar cognitive affective syndrome).

Physical examination shows signs of cerebellar dysfunction, loss of coordination of unilateral onset, and progression to equal involvement of both sides and severe ataxia involving arms and legs. Midline cerebellar dysfunction (inability to stand without assistance), speech (progressive dysarthria), and nystagmus (horizontal or vertical, opsoclonus and ocular dysmetria) are also symptoms.

Helpful criteria to diagnose PCD include: development of severe pancerebellar syndrome in < 12 weeks, the absence of accelerated cerebellar atrophy more than that associated with normal and difficulties with usual daily activities.

Paraneoplastic opsoclonus-myoclonus syndrome (POMS)

Paraneoplastic opsoclonus-myoclonus syndrome is characterized by an involuntary dyskinesia which is arrhythmic, disorganized, with different directions (horizontal, vertical and torsional elements) and usually comes with limbic/truncal myoclonic jerks, tremor, cerebellar ataxia and encephalopathy. It may be accompanied by involuntary rapid conjugate eye movement and dysarthria. Symptoms can precede diagnosis of malignancy.

Dermatomyositis (DM)

The pathognomonic heliotrope rash (purplish plaques on the upper eyelids); erythematous rash on the face, neck, back, chest, and shoulders; and Gottron’s papules (erythematous to violaceous papules often associated with scale over the phalangeal joints) may occur prior to onset of the myopathy also characteristic of DM. Other symptoms include systemic manifestations (fever and weight loss), proximal upper and lower extremity muscle weakness; dysphagia; heart and lung disorders (arrhythmia and respiratory failure), Raynaud’s phenomena and myalgia.

Beware: there are other diseases that can mimic a paraneoplastic syndrome associated with lung cancer:

Ectopic Cushing's Syndrome

Cushing’s syndrome due to other causes may mimic ECS and include endogenous Cushing syndrome due to adrenal adenoma, adrenal carcinoma, nodular adrenal hyperplasia, or due to use of exogenous glucocorticoids. Ectopic Cushing syndrome due to ACTH or CRH secretion not related to lung cancer may be due to bronchial carcinoid tumors, due to thymic or pancreatic neuroendocrine tumors, medullary thyroid cancer, pheochromocytoma, prostatic cancer.

SIADH

Though SIADH is strictly defined as a clinically euvolemic disorder, hypervolemic disorders including heart failure, nephrotic syndrome, and cirrhosis may also present with hyponatremia that may confuse diagnosis. Mannitol and glycine infusion (typically in the setting of neurosurgical and urologic disease respectively), as well as hyperglycemia may cause hyponatremia not due to SIADH. Severe hypothyroidism and primary adrenal insufficiency may also cause symptoms, signs and laboratory changes indistinguishable from those associated with SIADH and must therefore be excluded prior to assigning diagnosis. SCLC can induce ectopic release of ADH and cause SIADH. Numerous medications can also cause hyponatremia, such as Carbamazepine, Sodium valproate, Opiates, Non-steroidal anti-in?ammatory drugs (NSAIDs), Melphalan, Imatinib, Cyclophosphamide, Cisplatin, Ifosfamide, Vincristine, Vinorelbin, Vinblastine, Methotrexate, Interferon-alpha and Interferon-gamma.

Hypercalcemia of malignancy

Any cause of hypercalcemia may be confused with HCM. The most common include primary hyperparathyroidism which is typically sporadic but may include a familial form, and hyperparathyroidism associated with multiple endocrine neoplasia type I or II. Tertiary hyperparathyroidism due to chronic kidney failure typically only occurs in the clinical setting of end-stage renal failure patients. Parathyroid carcinoma is uncommon but accounts for 1-5% of cases with PTH-dependent hypercalcemia. Ectopic secretion of PTH by other neuroendocrine tumors is rare but is also reported.

There are numerous causes of non-PTH dependent hypercalcemia. These are far less common but may be more challenging to exclude. These include granulomatous diseases due to sarcoid, berylliosis, tuberculosis and other causes; Hodgkin’s lymphoma; and even inflammatory bowel diseases that all typically cause hypercalcemia by exuberant 1-hydroxylation of vitamin D. Other primary malignancy may produce PTHrP that potently causes hypercalcemia and include head and neck squamous cell cancers, renal cell tumors. A far less common cause of non-PTH dependent hypercalcemia associated with malignancy is direct tumoral osteolysis that liberates calcium by direct destruction of bone. Examples include multiple myeloma and breast cancer. Medications such as thiazide, lithium, vitamin A, or calcium antacids intoxication; and disorders such as hyperthyroidism, adrenal insufficiency, acromegaly, and pheochromocytoma; and prolonged immobility all cause hypercalcemia through PTH-independent mechanisms as well.

Lambert-Eaton Myasthenic Syndrome

Mimics of LEMS include Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, dermatomyositis/polymyositis, inclusion body myositis, myasthenia gravis, neuropathy, myotonic dystrophy type 2, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, and their associated malignancies (non-small-cell lung cancer, lymphosarcoma, malignant thymoma, breast cancer, gastric cancer, colon cancer, prostate cancer, bladder cancer, renal cell carcinoma, and gallbladder cancer).

Paraneoplastic Limbic Encephalitis

Conditions that may be confused with PLE include intracranial metastasis, metabolic abnormalities, viral encephalitis, rapidly developing dementia, cerebrovascular events, adverse events from chemotherapy or radiation-induced encephalopathy, and Wernicke-Korsakoff syndrome.

Paraneoplastic cerebellar degeneration

Symptoms resembling PCD may occur due to cerebellar hemorrhage, cerebral venous thrombosis, cavernous sinus syndromes, demyelinating disease, vitamin deficiencies, neurologic sarcoidosis, lupus cerebritis, alcohol-induced cerebellar degeneration, late-onset spinocerebellar ataxia, olivopontocerebellar degeneration, meningioma, meningeal carcinomatosis, multiple sclerosis, and prion-related diseases.

Paraneoplastic opsoclonus-myoclonus

Other diseases or conditions that can mimic paraneoplastic opsoclonus-myoclonus include cerebrovascular disease, meningoencephalitis, and cerebral mass lesions.

Dermatomyositis

Cutaneous manifestations of numerous systemic diseases may be confused with dermatomyositis and include HIV infection, seborrheic dermatitis, systemic lupus erythematosus, lichen planus, polymorphous light eruption, psoriasis, atopic or contact dermatitis, and side effects of certain medications (glucocorticoids, statins, antimalarials, antipsychotics, colchicine, alcohol, cocaine, hydroxyurea, clofibrate, NSAID, and certain antiretrovirals).

How frequent are paraneoplastic syndromes associated with lung cancer?

Ectopic Cushing's Syndrome

Ectopic Cushing Syndrome is the second most common paraneoplastic syndrome in SCLC patients after SIADH. ECS occurs in 1-5 % of the patients with SCLC but account for up to 50% of all ECS cases. Carcinoid tumors (30–46% ECS cases), small cell lung cancer (8–20% ECS cases), and pulmonary tumorlets and non-small-cell lung carcinoma (2% of cases) explain the remainder.

SIADH

The incidence of clinical SIADH among patients with lung cancer is 7-16% depending on the definitions used. The incidence of hyponatremia is higher in patients with small cell lung cancer than non-SCLC patients (SCLC 14.2% vs NSCLC 2.7%). Approximately 25% of patients with small lung cancer (SCLC) develop hyponatremia and 60% of these cases is due to SIADH, other causes included hypervolemia (congestive heart failure), using diuretic (especially thiazide), or other medications (antidepressants and chemotherapeutic agents).

Hypercalcemia of malignancy

Hypercalcemia of malignancy occurs in 2-6% at presentation and 8-12% during the course of the lung cancer particularly with squamous cell carcinoma (up to 23% of cases).

PTHrP mediated hypercalcemia of malignancy explains up to 76% of cases. Direct tumoral osteolysis leading to hypercalcemia mediated by local factors including IL-1, IL-6, IL-11, PGE, TGF-α, TGF-β, and TNF-β occurs in 20% of all cancers (mainly breast, multiple myeloma and lymphoma). Rare cases of hypercalcemia due to ectopic PTH secretion in the lung cancer patients have been reported. Hypercalcemia due to 1-hydroxylation of vitamin D, which occurs frequently in lymphoma has not been reported due to lung cancer.

Lambert-Eaton Myasthenic Syndrome

LEMS is the most common neurological paraneoplastic syndrome in small cell lung cancer (SCLC). Annual incidence of LEMS is 0.6 case per million, and prevalence is 2.8 cases per million in the US. Paraneoplastic LEMS is almost always associated with SCLC. However, LEMS associated with NSCLC is also reported. Small cell lung cancer (SCLC) is associated with up to 60% of LEMS cases. The incidence of LEMS is 3% in SCLC patients.

Paraneoplastic Limbic Encephalitis

This is a rare disorder. Sixty percent of all PLE cases are paraneoplastic. PLE is most commonly associated with SCLC in almost 50% of the cases. However, it can be seen with NSCLC (10%), such as adenocarcinoma, and squamous cell carcinoma.

Paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration occurs in 25% of paraneoplastic neurological syndromes, more commonly in women. It is associated with anti-Hu antibodies in small-cell lung cancer.

Paraneoplastic opsoclonus-myoclonus

POMS is a very rare disorder that occurs most frequently in older patients with lung cancer.

Dermatomyositis

Patients with dermatomyositis have a10-fold increase in overall cancer risk and a 31-fold increase in lung cancer specifically–particularly SCLC. Lung cancer is responsible for 17.4% cases of cancer-associated DM. However, DM remains a rare disease and occurs in only 5.9% of patients with lung cancer.

Which individuals are at greatest risk of developing a paraneoplastic syndrome associated with lung cancer?

Ectopic Cushing's Syndrome

Patients with SCLC or carcinoid tumor are at higher risk of developing ECS due to lung tumor. Small-cell lung carcinoma and atypical bronchial carcinoid tumors have the worst prognosis.

SIADH

Those with small-cell lung carcinoma are at greatest risk, although SIADH can also be seen in carcinoid tumors.

Hypercalcemia of malignancy

Those at greatest risk of hypercalcemia are those with non-small-cell lung cancer, particularly the squamous cell variety.

Lambert-Eaton Myasthenic Syndrome

SCLC is the most frequent malignancy associated with LEMS.

Paraneoplastic Limbic Encephalitis

Patients with small-cell lung cancer are at greater risk. They are usually poorly responsive to treatment.

Paraneoplastic cerebellar degeneration

Those with small-cell lung cancer are at greater risk.

Paraneoplastic opsoclonus-myoclonus

Those with small-cell lung cancer are at greatest risk, although the condition can also be seen in other malignancies (breast, uterus, bladder, thyroid, and pancreatic cancers).

Dermatomyositis

The risk of cancer is markedly elevated during the first year of diagnosis of myositis. Older people have higher risk of malignancy. In western countries lung cancer is commonly linked to DM. Although the current data are mixed regarding the indicators of prognosis or predictor of malignancy in DM, age, ESR, cutaneous rash, skin lesion (skin necrosis, periungueal erythema, ulceration), neoplastic markers and dysphagia are reported as helpful markers to evaluate the presence of associated malignancy. Cutaneous necrosis, heliotrope erythema, dysphagia, dyspnea, muscle weakness, arthralgia, and positive anti-155/140 antibodies are considered as risk factors for cancer. Protective factors against malignancy include Raynaud’s phenomenon, interstitial lung disease, arthritis, refractory to therapy, fever, positive anti Jo-1 antibody, positive ENA antibodies and high titer of antinuclear antibody.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Ectopic Cushing's Syndrome

The following tests are useful for initial screening, and at least 2 abnormal tests or replicates are most convincing. The use oral, inhaled and topical exogenous glucocorticoids must be discontinued prior to testing or may cause false positive results:

Elevated twenty-four-hour urine-free cortisol (≥ two measurements, above upper limit of reference range)

Elevated late night salivary cortisol (two measurements, above upper limit of reference range)

1 mg overnight dexamethasone suppression test (normal 8AM plasma cortisol concentration is below 1.8 µg/dl (50 nmol/L) after overnight dexamethasone)

Two-day 2 mg dexamethasone suppression test (2 mg/day for 48 hours, cortisol > 1.8 µg/dl)
In the patients with possible cyclic Cushing and mild clinical features, serial urine free cortisol or late night salivary cortisol measurement is recommended
Ectopic Cushing syndrome is distinguished from adrenal Cushing syndrome based on the presence of an elevated serum ACTH level of at least 20 pg/mL

SIADH

Major criteria

Clinical euvolemia

Low serum sodium (<130 mEq/L)

Plasma hypoosmolality (Plasma osmolality < 275 mosmol/kg), with inappropriate urine concentration (Uosm > 100 mOsm/kg H2O, usually higher than serum)

Natriuresis UNa > 30 mEq/L with normal dietary salt and water intake (fractional excretion of Na [FENa] > 0.5%, depending on Na intake)

Normal kidney, adrenal, thyroid, pituitary, heart, and liver function

No recent use of diuretic medications
Minor criteria

Water restriction corrects hyponatremia

Normal saline (0.9% saline) infusion doesn’t correct hyponatremia

No signs of volume depletion or volume overload

Serum uric acid < 4 mg/dl

Serum urea < 21.6 mg/dl

Fractional excretion of Na >0.5%

Fractional excretion of urea >55%

Fractional excretion of uric acid >12%

Hypercalcemia of malignancy

Check serum calcium, phosphorus, renal function, and PTH
Humoral hypercalcemia of malignancy:

Low serum phosphorus

Suppressed PTH

Increased PTHrP (normal level < 2.0 pmol/l)

Rarely increased ectopic PTH and low PTHrP
Bone metastasis:

Normal serum PTHrP, suppressed PTH, and phosphorus levels

Increased alkaline phosphatase.
Other key “tip-off” findings:

Myeloma screen: if positive, multiple myeloma (usually hypercalcemia with normal alkaline phosphatase)

Marked elevation of 1,25-dihydroxyvitamin D in the setting of suppressed PTH and PTHrP: lymphoma, granulomatous disease, or inflammatory bowel diseases
Electrocardiogram findings: prolonged PR and QRS intervals, shortening of QT interval, bradycardia, and heart block are found on electrocardiogram.

Lambert-Eaton Myasthenic Syndrome (LEMS)

CPK: normal.
Antibodies to P/Q-type voltage gated calcium channels are present in 75-100 percent of LEMS with small-cell lung cancer and 50-90 percent of patients with LEMS without underlying cancer.
Antibodies to domain IV of the alpha-1A P/Q-VGCC subunit is in favor of non tumoral LEMS (38% positive in non tumoral LEMS, and 5% positive in patients with SCLC-LEMS).
A markedly positive edrophonium test typically favors myasthenia gravis, but is usually unnecessary. The test may be weakly positive in LEMS.
Among patients with an appropriate symptomatic presentation, anti SOX (Sry-like high mobility group box-proteins 1) antibodies may be positive in up to 64% of patients with paraneoplastic LEMS, and have a 95% specificity for differentiating between paraneoplastic and idiopathic LEMS in small-cell lung cancer.

Paraneoplastic Limbic Encephalitis

Cerebrospinal fluid analysis reveals moderate mononuclear pleocytosis, and increased proteins, intrathecal IgG and oligoclonal bands.
Antibody markers: Serum and CSF anti-neuronal antibodies. Anti-Hu antibodies are present in up to 80 percent of small-cell lung carcinoma-associated limbic encephalitis though these markers may also be detected in neuroblastoma and prostatic cancer. Anti-Ma2 and anti CV2 antibodies may also be identified in patients with lung cancer but also occur frequently testicular tumors, breast cancer, and are associated with hypotalamic and brainstem encephalitis. Anti CV2 (collapsin response mediator protein 5, or CRMP5) antibodies are associated with small cell lung cancer and malignant thymoma. Anti-amphiphysin is associated with stiff-person syndrome and may be seen in breast cancer and small-cell lung cancer.
The antibodies associated with immune-mediated limbic encephalitis and lung cancer include AMPAR (Autoimmune or paraneoplastic, SCLC), GABABR (Autoimmune or paraneoplastic, SCLC), GAD-65, ANNA1 (Hu, paraneoplastic, SCLC), ANNA 3 (paraneoplastic, SCLC), Amphiphysin (paraneoplastic, SCLC and breast), and CRMP-5 (paraneoplastic, SCLC or thymoma).

Paraneoplastic cerebellar degeneration (PCD)

Once suspected or once a diagnosis of subacute cerebellar degeneration is made, blood and CSF analysis for autoantibodies are warranted and can aid the determination of the underlying primary malignancy (e.g., anti-Hu antibodies in small cell lung cancer).
CSF mononuclear pleocytosis is seen in 75% of patients with PCD but may be normal. Elevated protein concentrations in CSF can be seen in most case, and in some cases oligoclonal bands (increased IgG) is detected.
Patients with small-cell lung cancer and PCD may show different onconeural antibodies such as, anti-VGCCs (voltage-gated calcium channels) antibodies (up to 41%) with or without associated LEMS, anti-Hu antibodies (antineuronal nuclear antibody, ANNA 1) in 23%, or less commonly antibodies against other onconeural antigens such as anti-CRMP5 or CV2 (collapsin-response mediator protein 5), antiamphiphysin, anti-PCA2 (purkinje cell cytoplasmic antibody type 2) or ANNA3.

Paraneoplastic opsoclonus-myoclonus

CSF sampling reveals elevated protein levels, lymphocytic pleocytosis, elevated IgG index, and oligoclonal bands.
ANNA-1/Anti-Hu antibodies associated with small cell lung cancer. ANNA-2/anti-Ri antibody was the most commonly reported antibody but more associated with breast cancer. Antineuronal nuclear antibodies (ANNA-1/Hu or ANNA-2/Ri) support the diagnosis of SCLC but are present in less than half of patients. However, ANNA-2/anti-Ri antibody can be seen in NSCLC.

Dermatomyositis

Serum CK, AST, ALT, LDH and aldolase levels are elevated.
Antinuclear antibodies (ANA); anti-Ro/SSA, anti-La/SSB, anti-ribonucleoprotein (RNP), and anti-Sm
Antibodies associated and specific for myositis:

Anti-Jo-1 and other anti-synthetase antibodies

Antibodies against the Mi2, SRP, PM/Scl, and Ku antigens
Erythrocyte sedimentation rate is elevated
TSH to rule out hypothyroidism

What imaging studies will be helpful in making or excluding the diagnosis of a paraneoplastic syndrome associated with lung cancer?

Ectopic Cushing’s Syndrome (ESC)

Chest-computed tomography scan will reveal mediastinal mass, pulmonary nodule or mass, endobronchial lesion or segmental/lobar collapse. Though MRI of the pituitary gland, with high level of cortisol makes Cushing disease as a source of cortisol unlikely, since ACTH secreting pituitary adenomas are often small, inferior petrosal sinus sampling is typically necessary to definitively distinguish between ectopic and pituitary Cushing syndrome. The probability of coexistent Cushing’s disease and ECS is extremely rare. Somatostatin receptors scintigraphy (SRS), positron emission tomography (PET), and/or endoscopic procedures are alternative options to localize the tumor.

SIADH

Malignancy, medications, pulmonary disease, and CNS disorders are common causes of SIADH. Clinical judgement plays a key role in determining the amount of biochemical and radiological investigations. Search for pulmonary malignancy with chest radiograph or computed tomography if no other primary cause is evident is recommended as SIADH could be the presenting symptom for lung cancer, particularly in smokers.

Hypercalcemia of malignancy

Chest imaging by radiograph or computed tomography will aid in evaluating for a pulmonary malignancy. Plain radiographs of sites of bony pain may reveal the presence of metastasis. A bone scan will evaluate for the presence of bone metastasis.

Lambert-Eaton Myasthenic Syndrome (LEMS)

The most sensitive diagnostic test is positive repetitive nerve stimulation (RNS), which should be done on at least two distal muscles. The typical pattern for LEMS is low amplitude of the compound muscle action potential (CMAP) at rest, and > 10% reduction of the CMAP amplitude on low frequency stimulation (2–5 Hz), and additive response (> 100%) during high frequency stimulation or after exercise. During low-rate RNS, the decrease in CMAP amplitude can be seen in LEMS and MG (myasthenia gravis). A 100% increase in the CAMP in RNS after painful stimuli (high frequency, 20–50 Hz) or rapidly after a short-term maximum voluntary contraction (15–20 s) is specific for LEMS.

If LEMS is suspected, chestimaging should be performed to exclude lung cancer since it is so often the root cause. If lung cancer risk is high and imaging is normal, consider bronchoscopy. If imaging and bronchoscopic studies are negative and the patient is high risk, consider periodic surveillance.

Paraneoplastic Limbic Encephalitis

MRI of brain and spinal cord are useful for excluding other neurologic disorders. Generally, 20% of patients have a normal brain MRI. It will detect early changes, including hyperintense signals in the medial aspect of temporal lobes that are better seen in T2 and FLAIR sequences and do not enhance with contrast. Hyperintense abnormalities may present early and can progress to more overt stereotypical atrophy with time. This is best visualized on T1 weighted imaging.

Paraneoplastic cerebellar degeneration

Initially brain imaging may not show significant findings. However, non-specific MRI findings including changes in periventricular white matter and abnormal T2 signal may be present. Later in the course of the disease, probably due to neuronal loss, CT and MRI will show cerebellar atrophy. Chest-computed tomography is useful to evaluate for small-cell lung cancer, especially in the presence of anti-Hu antibodies. Abdomen-computed tomography and mammography are useful to evaluate for breast or ovarian cancer, particularly if anti-Yo antibodies are present in CSF. Finally, a whole-body PET scan will assist in demonstrating occult malignancy and metastasis.

Paraneoplastic opsoclonus-myoclonus

An MRI can be normal in most patients, or it may show areas of increased T2 signal. CSF is consistent with inflammation, as above. EEGs are not usually useful for the diagnosis, as they may show non-specific findings, such as slowing or normal.

Dermatomyositis

Chest radiographs or computed tomography may reveal a lung nodule, mass, or mediastinal adenopathy.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a paraneoplastic syndrome associated with lung cancer?

Pulmonary diagnostic studies are not typically indicated for ectopic Cushing’s syndrome, SIADH, hypercalcemia of malignancy, paraneoplastic limbic encephalitis, paraneoplastic cerebellar degeneration, or paraneoplastic opsoclonus-myoclonus, or when dermatomyositis is associated with malignancy.

In cases of Lambert-Eaton Myasthenic syndrome, clinicians should consider monitoring for signs of respiratory involvement, although such signs are rare. LEMS is associated with negative inspiratory force less than 25 H₂O and FVC less than 15-20 ml/kg.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a paraneoplastic syndrome associated with lung cancer?

Ectopic Cushing’s Syndrome

Inferior petrosal vein sampling of ACTH is often required to definitively exclude a pituitary source of ACTH and confirm ectopic ACTH secretion when the diagnosis cannot be made on clinical grounds alone. Lung biopsy to confirm diagnosis of small cell lung cancer, carcinoid, pulmonary tumorlet or non-small-cell lung cancer can be helpful in making or excluding the diagnosis, as can biopsy procedure, to be determined by location of the lesion. Bronchoscopy, EBUS-guided transbronchial needle aspiration, CT-guided transthoracic needle biopsy, thoracoscopic lung biopsy, or mediastinoscopy can be used to obtain tissue for diagnosis of primary malignancy. However, false positive immunohistochemical staining of small lung cell cancers due to biologically inert but immunoreactive ACTH producing cells has been reported.

Lambert-Eaton Myasthenic Syndrome (LEMS)

Signs and symptoms of LEMS almost always precede SCLC diagnosis and 96% of SCLC patients can be diagnosed within 12 months of LEMS onset.

Early stage of SCLC is difficult to detect by conventional radiography or bronchoscopy. Computed tomography (CT), 18F-fluorodeoxyglucose-positron emission tomography (PET) or PET/CT are more sensitive to identify occult SCLC. Negative initial screening deserves investigation for occult malignancy every 6 months for at least 2 years after onset of LEMS.

Paraneoplastic cerebellar degeneration

Serum and CSF measurements of anti-neuronal antibodies, including PCA-1 (anti-Yo for ovary or breast), ANNA-1 (anti-Hu for SCLC), PCA-Tr (anti-Tr for Hodgkin), CRMP-5 (anti-CV2 for SCLC or thymoma) can be helpful in making or excluding this diagnosis. Chest imaging is indicated if no diagnosis of malignancy has been made in the setting of this condition, as the condition may precede development of cancer by two years. Brain MRI with contrast can also be helpful.

Paraneoplastic opsoclonus-myoclonus (POMS)

Once this condition is suspected, a CSF analysis to exclude other inflammatory and infectious etiologies is indicated. POMS may be associated with several onconeural autoantibodies which may be compatible with involvement of humoral immune mechanism. However, given seronegativity of the most patients, indicates the cell-mediated immune mechanism as the major responsible mechanism for the pathogenesis of opsoclonus. Chest imaging is indicated if no diagnosis of lung cancer has been made.

Dermatomyositis

Electromyography will reveal increased spontaneous activity with fibrillations, complex repetitive discharges, low-amplitude, short duration polyphasic motor unit action potential, and positive sharp waves in the presence of dermatomyositis. Muscle biopsy will reveal perivascular or interfascicular septal inflammation and perifascicular atrophy.

Other:

No diagnostic procedures in specific are typically indicated for SIADH, hypercalcemia of malignancy, or paraneoplastic limbic encephalitis.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a paraneoplastic syndrome associated with lung cancer?

Pathology/cytology/genetic studies are not typically indicated for paraneoplastic syndromes associated with lung cancer.

If you decide the patient has a paraneoplastic syndrome associated with lung cancer, how should the patient be managed?

Ectopic Cushing Syndrome

In cases where the primary tumor cannot be definitively treated, inhibiting steroidogenesis and direct antagonism of steroid hormone receptors is necessary. Direct inhibitors of steroidogenesis include ketoconazole, metyrapone, and mitotane. These agents are typically considered first line therapies for treating refractory Cushing syndrome regardless of etiology. Etomidate is another direct steroidogenesis inhibitor that may be highly effective for acute management of fulminant symptomatic Cushing syndrome refractory to other definitive therapies. Etomidate can only be administered intravenously and is sedating. It therefore requires constant hemodynamic monitoring and ICU admission.

Mifepristone is a glucocorticoid type II receptor antagonist which may be an effective adjunctive agent in addition to direct steroidogenesis inhibitors, and can be used as monotherapy. Mifepristone reduces body weight, increases insulin sensitivity, and therefore improved hyperglycemia associated with Cushing’s disease. Somatostatin analogues (SSAs) and dopamine agonists have been used, alone or in combination with adrenolytic agents, for patients with recurrence, incomplete resection or occult tumours. Somatostatin analogues (SSAs) octreotide, lanreotide, and pasireotide can also effectively control hormonal production from neuroendocrine tumors associated with Cushing syndrome. Cabergoline is a dopamine agonist may also be effective in a subset of tumors that secrete ectopic ACTH.

Ketoconazole and metyrapone are typically used as first line therapies, and may be combined to improve the control of cortisol production. Ketoconazole is effective at doses of 400-1600 mg/day, in divided doses every 6-8 hours and may cause elevated liver enzymes and hepatic injury, gastrointestinal side effects, hypogonadism and gynecomastia. Metyrapone is given at doses of 500-6000 mg/day, in divided doses every 6-8 hours. The side effects of mitotane include hypokalemia, hypertension, hirsutism, edema and gastrointestinal side effects. Mifepristone (300-1200 mg daily) is associated with adrenal insufficiency, hypokalemia and menorrhagia. Somatostatin analogs at standard agent-specific doses. All SSAs may cause cholestasis and biliary symptoms, GI side effects, and hyperglycemia.

The ideal choice for medical therapy should be individualized on the base of efficacy, cost and occurrence and tolerability of side effects.

Bilateral adrenalectomy is a very effective treatment for refractory Cushing syndrome and is well tolerated if considered early enough during the disease. Despite its effectiveness, definitive management with adrenalectomy is often deferred until morbidity associated with severe Cushing syndrome eliminates the option of surgical management. Emergency adrenalectomy is usually recommended when the likelihood of effective management with other modalities is low and must be considered while the patient is still well enough to tolerate surgery.

Although in SCLC-related ECS systemic chemotherapy may provide longer survival, bilateral adrenalectomy is useful when the patient is not responsive to chemotherapy due to the extent of tumor burden associated with advanced disease. Reducing cortisol level before starting curative treatments (surgery or chemotherapy) may alleviate ECS associated complications, such as infection. Though bilateral adrenalectomy requires subsequent glucocorticoid and mineralocorticoid replacement, the palliative effects may be significant. Despite the effectiveness of mitigating the symptoms and morbidity associated with ECS, survival of patients with ECS after successful bilateral adrenalectomy remains less than 60% at 2 years, mainly due to cancer-specific mortality associated with the underlying disease.

SIADH

In addition to treatment of the underlying cancer, symptomatic mild hyponatremia can be treated with fluid restriction. Hypertonic saline infusion is typically reserved for severe refractory hyponatremia, and hyponatremia that presents with marked alteration of mental status or seizure.

A correction of 6 mmol/L is typically sufficient to correct symptoms associated with hyponatremia and minimizes treatment risk, including osmotic demyelination syndrome (ODS) which is the most dreaded complication of overly rapid correction. The rule of thumb for correcting hyponatremia is that the rate of correction should approximate the rate of hyponatremia onset and should not exceed more then 0.5-1 mmol/L/hour with an absolute correction of no more than 12 mmol/L in the first 12-24 hours. More conservative correction may be necessary in patients with alcoholism, severe malnutrition or advanced liver disease that may be more susceptible to ODS.

Because SIADH is driven by an excess of arginine vasopressin (AVP), vaptans which are direct vasopressin receptor antagonists have been developed and are effective agents for managing both acute and chronic euvolemic hyponatremia due to SIADH. Conivaptan and tolvaptan are respectively intravenous and oral V2R receptor antagonists available for use in the United States. Studies have demonstrated efficacy for both short and long-term management of acute and chronic hyponatremia. Though studies have not been designed to demonstrate efficacy beyond that of water restriction alone, the magnitude of corrective effect is similar and these agents offer the benefit of correction of hyponatremia without the need for water restriction which suggests that they may be better tolerated especially for long-term use. These agents may still cause ODS if sodium correction occurs too quickly and may be associated with other side effects such as increased thirst, nausea, polyuria, fever, hypokalemia, orthostatic hypotension, hepatotoxicity, and local site inflammation. These agents are still relatively expensive and are therefore typically reserved for second line use.

Demeclocycline at doses of 150 to 300 mg orally, in divided doses 3-4 times per day is a renal toxin that inhibits AVP action in the kidney and enhances free water clearance over 7-14 days of use. Currently is not recommended as a first line due to absence of evidence to support its safety and efficacy. It is contraindicated in renal failure. Potential side effects include nausea, vomiting, phototoxicity, hepatotoxicity, and nephrotoxicity.

Urea, NSAID (non-steroidal anti-inflammatory drugs) and furosemide + oral salt are other adjunctive treatment options for management of hyponatremia/SIADH.

Hypercalcemia of malignancy

The primary treatments for hypercalcemia are hydration, diuretic therapy, and anti-resorptive administration. Hydration enhances calcium excretion and replaces the frequently significant fluid losses induced by hypercalcemia both by osmotic diuresis and via direct impairment of the urinary concentrating mechanism. Once volume is completely replaced, loop diuretics can further enhance urinary calcium excretion by inhibiting calcium resorption in the distal renal tubule. Anti-resorptive agents such as bisphosphonates, which inhibit osteoclast action and bone resorption, are also a first line treatment for hypercalcemia of malignancy. Pamidronate 60 to 90 mg IV and zolendronic acid 4 mg IV are effective but carry potential risks that include nephrotoxicity, hypocalcemia, and hypophosphatemia.

Another antiresorptive agent is denosumab, which is a human monoclonal antibody to RANKL, and reduces osteoclastic bone resorption. It is recommended for hypercalcemia refractory to bisphosphonates. Denosumab, unlike bisphosphonates, is not cleared by the kidney, and as a result is not contraindicated in renal insufficiency. The optimal dose of denosumab during renal insufficiency is not clear. However, the hypocalcemic effect of denosumab is potentially higher in the setting of renal failure and in these cases a 50% dose reduction is recommended.

Calcitonin (4-8 IU/kg four times per day) reduces bone resorption and induces a slight increase in renal calcium excretion. Potential risks include rebound hypercalcemia after twenty-four hours, vomiting, cramps, and flushing. It is generally not used as a first line agent.

Other adjunctive modes of treatment include gallium nitrate, plicamycin and hemodialysis. Plicamycin (25 mcg/kg for 3-8 doses) blocks RNA synthesis in osteoclasts and is effective in lowering serum calcium, but it is toxic to the bone marrow, liver, and kidney. Gallium nitrate inhibits osteoclast action, blocking bone resorption. There is a slow onset of action, and it is highly toxic for the kidney and bone marrow, but it shows effectiveness in lowering serum calcium.

Corticosteroids (hydrocortisone 200 mg or equivalent in divided doses daily) inhibit 1-α-hydroxylase and production of activated 1, 25-dihydroxyvitamin D. It is most useful in patients with hypercalcemia due to granulomatous disease and lymphoma where 1-α-hydroxylation of vitamin D is the root cause of the hypercalcemia. Potential toxicities are superimposed infections, hyperglycemia, and myopathy.

Lambert-Eaton Myasthenic Syndrome (LEMS)

Cancer-specific therapy with chemotherapy or radiation will lead to a marked improvement, possibly by reducing antigenic response, thereby lowering the concentrations of circulating antibody.

Increasing the release of neurotransmitters or duration of acetylcholine action can improve symptoms. The potassium channel blocker 3, 4-diaminopyridine or amifampridine which is thought to stimulate the Voltage-gated calcium channels (VGCC), is well tolerated and can improve muscle strength and CMAP amplitude. Adverse effects, which tend to occur with high doses, include hyper-excitability, anxiety, and seizures.

Corticosteroids, azathioprine and plasmapheresis can be used as rescue treatments. Persistent symptoms may warrant use of immunosuppressant and immunomodulatory agents such as azathioprine. Plasma exchange therapy is alternative option for LEMS and other autoimmune neurological disorders.

Paraneoplastic Limbic Encephalitis

Response to treatment is generally poor, but effective treatment of the underlying lung cancer may stabilize or even improve the neurologic symptoms. Valproic acid may add an adjunctive benefit in addition to standard chemotherapy in small cell lung cancer patients.

Paraneoplastic cerebellar degeneration

There are no highly effective treatments. Glucocorticoids, cyclophosphamide, plasmapheresis, IVIG, tacrolimus and rituximab have been used with limited efficacy. Plasmapheresis has shown a response rate of up to 40%. Definitive management of the underlying tumor remains the best treatment modality.

Paraneoplastic opsoclonus-myoclonus (POMS)

POMS is poorly responsive to immunotherapy and treatment of the underlying malignancy is the best approach to managing paraneoplastic opsoclonus-myoclonus. Immunotherapy, such as corticosteroids or IVIG does demonstrate some efficacy in patients with idiopathic opsoclonus, but only appears to be helpful in POMS when the underlying tumor has been controlled. Without controlling the tumor, the effect of immunotherapy is mild and non-sustained.

Dermatomyositis

Oral Prednisone (0.5-1.5 mg per kg or 80-100 mg/day) is the initial treatment, until serum creatine kinase levels normalize. Side effects include gastrointestinal symptoms with oral dosing, suppression of adrenal function, immunosuppression, osteoporosis, glucose intolerance, and weight gain.

Azathioprine may be used as a glucocorticoid-sparing agent at an initial dose of 50 mg/day. A complete blood count (CBC) and liver function tests (LFTs) should be checked after 2 weeks to rule out bone marrow suppression and liver injury. If tolerated, the dose may be increased by 50 mg every week to 1.5 mg/kg/day, and to a maximum dose of 2.5 mg/kg/day if patients do not respond to lower doses after 2-3 months. Once on a stable dose, CBC and LFTs should be rechecked every 3 months. Side effects include nausea, vomiting, hepatotoxicity, leukopenia, oral ulcers, and marrow suppression.

Methotrexate 15-25 mg/week may also be used as a first-line agent. Doses higher than 25 mg weekly may sometimes be necessary but require leucovorin rescue as concomitant therapy. Side effects of methotrexate include stomatitis, hepatic fibrosis, abdominal pain, nausea, cirrhosis, marrow suppression, and pneumonitis.

Mycophenolate mofetil 2 grams/day may be an effective agent but is associated with bone marrow suppression, infection and gastrointestinal side effects.

IVIG 400 to 1000 mg/day is effective but is expensive, requires IV administration and has numerous toxicities.

Case reports describe the use of newer therapeutic agents such as tacrolimus, TNFα blockers (infliximab, etanercept, adalimumab) and anti-receptor antibodies (rituximab, eculizumab). Though some results are favorable the experience with these agents is still limited and they are usually not recommended as a first line of treatment or monotherapy.

What is the prognosis for patients managed in the recommended ways?

Ectopic Cushing's Syndrome

Patients with ECS may die due to complications of Cushing or progression of their underlying tumor. The prognosis of ECS in patients with SCLCs is generally poor with a 1-6 months survival.

SIADH

SIADH is a common event that occurs in up to 10% of small cell lung cancers. Though is it frequently reported as a poor prognostic factor and is correlated with disease recurrence and drug resistance, hyponatremia may improve in a majority of SCLC patients within 3 weeks after initiation of chemotherapy. SIADH often recurs after tumor relapse in up to 70% of patients with lung cancer and is a poor prognostic sign.

Hypercalcemia of malignancy (HHM)

The oval prognosis of lung cancer patients with HHM is poor with a median survival of 1-3 months. Male gender, age > 60, squamous cell histology, lower performance status, higher staging, leukocytosis, bone metastasis, renal failure, severity of hypercalcemia, elevated alkaline phosphatase, brain metastasis, multiple distant metastasis (≥2) correlate with poorer prognosis in these patients.

Lambert-Eaton Myasthenic Syndrome (LEMS)

LEMS responds to treatment of lung cancer, and the prognosis is related to that for the underlying malignancy.

Paraneoplastic Limbic Encephalitis

Delayed diagnosis and onset of treatment is associated with worsening prognosis. Anti-Hu antibodies are associated with a decreased likelihood of neurological improvement. Anti-Ma2-associated encephalitis (isolated or combined limbic, diencephalic, or brainstem involvement), may result in severe neurologic deficits or even death. More than 50% of patients with LE due to SCLC may demonstrate complete or partial improvement with treatment when GABA-B antibodies are present. Immunotherapy and/or treatment of underlying tumor can lead to neurological improvement or stabilization of symptoms in 30-40% of patients. Patients with limited CNS dysfunction have better prognosis and may even achieve complete response to treatment.

Paraneoplastic cerebellar degeneration

Prognosis depends on the underlying malignancy and staging at the time of diagnosis.

Paraneoplastic opsoclonus-myoclonus

Without treatment for the cancer, all reported cases associated with small-cell lung cancer die within three months of diagnosis. The main cause of death is the paraneoplastic opsoclonus-myoclonus, not the cancer. However, treatment of the underlying malignancy results in improvement of symptoms. Anti-neuronal antibodies appear to be associated with a more benign prognosis.

Dermatomyositis

The disease improves with treatment of the underlying malignancy, and the cause of death is usually the malignancy, not the dermatomyositis. Myocardial involvement, older age, fever, malignancy, pulmonary fibrosis, dysphagia, and leukocytosis are poor prognostic markers.

What other considerations exist for patients with paraneoplastic syndromes associated with lung cancer?

For paraneoplastic limbic encephalitis, anecdotal reports suggest that the best chance to affect neurologic outcome depends on prompt diagnosis, early treatment of tumor, and possibly the use of immunotherapy.

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