Download File - Department Of Pulmonary Medicine

PRESENTED BY:
DR. HITESH GOUR
J.R. PULMONARY MEDICINE
DEFINATION
 Paraneoplastic syndromes refer to the disorders that
accompany benign or malignant tumors but are not
directly related to mass effects or invasion by the
primary tumor or its metastases.
 Although, almost every type of malignancy has the
potential to produce hormones or cytokines or to
induce immunologic responses , tumors of
neuroendocrine origin, such as small cell lung
carcinoma and carcinoids are common causes of
paraneoplastic syndromes.
 So, atypical clinical manifestations in a patient with
cancer should prompt consideration of a
paraneoplastic syndrome.
PARANEOPLASTIC SYNDROMES
ETIOLOGY:
 Ectopic hormones refers to hormone production from
an atypical tissue source.
 Several molecular mechanisms has been suggested to
cause ectopic hormone production, but this process
remains incompletely understood.
 Genetic rearrangements can explain aberrant hormone
expression e.g., translocation of the parathyroid
hormone (PTH) gene resulted in high levels of PTH
expression in an ovarian carcinoma, because the
genetic rearrangement brings the PTH gene under the
control of ovary-specific regulatory elements
 ectopic expression is typically characterized by
abnormal regulation of hormone production (e.g.,
defective feedback control)that can lead to substantial
morbidity and can complicate the cancer treatment
plan
Paraneoplastic sundromes associated
with bronchogenic carcinoma
Endocrine:
Cushing's syndrome
SIADH
 Hypercalcemia
Carcinoid syndrome
Hyperglycemia/hypoglycemia
Gynecomastia
Galactorrhea
Growth hormone excess
Calcitonin secretion
Thyroid-stimulating hormone
Neurological
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Lambert-Eaton myasthenic syndrome
Peripheral neuropathy
Encephalopathy
Myelopathy
Cerebellar degeneration
Psychosis
Dementia
Cancer related retinopathy
Opsoclonus and myoclonus
MUSCULOSKELETAL
 Clubbing
 Hypertrophic osteoarthropathy
 Polymyositis
 Osteomalacia
 Myopathy
Cutaneous
 Dermatomyositis
 Acanthosis nigricans
 Pruritus
 Erythema multiforme
 Hyperpigmentation
 Urticaria
 Scleroderma
Vascular/hematologic
 Thrombophlebitis
 Arterial thrombosis
 Granulocytosis
 Nonbacterial thrombotic endocarditis
 Thrombocytosis
 Polycythemia
 Hemolytic anemia
 Red cell aplasia
 Dysproteinemia
 Leukemoid reaction
 Eosinophilia
 Thrombocytopenic purpura
Miscellaneous
 Cachexia
 Fatigue
 Hyperuricemia
 Nephrotic syndrome
Ectopic Corticotropin Syndrome
 Ectopic production of corticotropin or
corticotropin-releasing hormone with associated
Cushing's syndrome has been identified in
patients who have SCLC, carcinoid tumor (lung,
thymus, or pancreas), and neurocrest tumors such
as pheochromocytoma, neuroblastoma, and
medullary carcinoma of the thyroid.
 SCLC accounts for 75% of cases, although only 1%
to 2% of patients with SCLC develop Cushing's
syndrome. Cushing's syndrome is seldom caused
by NSCLC
 Classic features of Cushing's syndrome include
truncal obesity, striae, rounded (moon) facies,
dorsocervical fat pad (buffalo hump), myopathy and
weakness, osteoporosis, diabetes mellitus,
hypertension, and personality changes.
 Because of rapid growth of SCLC ,patients are more
likely to present with edema, hypertension, and
muscular weakness than with the classic features of
Cushing's syndrome.
 Hypokalemic alkalosis and hyperglycemia are usually
present.
 Patients with SCLC and Cushing's syndrome have shortened
survival compared to those without the syndrome, perhaps
because of frequent opportunistic infections.
 The best screen for Cushing's syndrome is the 24-hour urine
free cortisol measurement.
 Elevation of cortisol production, lack of suppression with
high-dose dexamethasone, and plasma corticotropin levels
greater than 200 pg/mL (40 pmol/L) are highly suggestive of
ectopic corticotropin as the cause of Cushing's syndrome in
the absence of a pituitary adenoma. The plasma level of
corticotropinis elevated in many, but not in all patients.
Treatment:
 Adrenal enzyme inhibitors such as metyrapone,
aminoglutethimide, and ketoconazole, given alone or in
combination. Ketoconazole given orally at a dosage of 400 to
1200 mg/day or metyrapone 250 to 750 mg three times per day
control hypercortisolism within a few days to weeks,
 Dose adjustments are based on achieving normal urinary free
cortisol levels or morning plasma cortisols of 7 to 11 ýg/mL.
 Symptomatic hypoadrenalism may result from treatment.
 When Cushing's syndrome arises from SCLC, it is advisable to
proceed with appropriate chemotherapy and carefully watch
for superimposed infections.
 Cushing's syndrome related to a bronchial carcinoid or thymic
carcinoid is best treated by surgical resection of the tumor.
Syndrome of Inappropriate
Antidiuretic Hormone Secretion
 SIADH production defined as low serum and a dilute
plasma osmolality along with a higher or
“inappropriate” urine osmolality in the presence of
continous urinary sodium excreation.
 10% of patients with SCLC exhibit SIADH,.SCLC
accounts for approximately 75% of cases of SIADH.
 Antidiuretic hormone (vasopressin) is secreted in the
anterior hypothalamus and exerts its action on the
renal collecting ducts by enhancing the flow of water
from the lumen into the medullary interstitium,
thereby concentrating the urine.
 The criteria for the diagnosis of SIADH include (1)
hyponatremia associated with serum hypoosmolality
(<275 mOsm/kg), (2) inappropriately elevated urine
osmolality (>200 mOsm/kg) relative to serum
osmolality; (3) elevated urine sodium (>20 mEq/L); (4)
clinical euvolemia without edema; and (5) normal renal,
adrenal, and thyroid function.
 The serum uric acid is usually low, and the urine
osmolality–to–serum osmolality ratio is frequently
greater than 2.
 The severity of symptoms is related to the degree of
hyponatremia and the rapidity of the fall in serum
sodium.
 Symptoms of hyponatremia include
anorexia, nausea, and vomiting. With a
rapid onset of hyponatremia, symptoms
caused by cerebral edema may include
irritability, restlessness, personality changes,
confusion, coma, seizures, and respiratory
arrest.
Treatment:
 In minimally symptomatic or asymptomatic
patients, fluid restriction of 500 to 1000 mL/24 hr
is the initial treatment of choice.
 Conivaptan is an intravenous vasopressin receptor
antagonist that has been shown to be useful in
correcting hyponatremia but its use is limited to
the hospital.
 If further treatment is needed, oral demeclocycline (900–1200
mg/day) is given. It induces a nephrogenic diabetes insipidus and
blocks the action of antidiuretic hormone on the renal tubule,
thereby increasing water excretion.
 The onset of action varies from a few hours to a few weeks, so this
drug is not recommended for acute emergency treatment.
 Demeclocycline has potential kidney toxicity.
 In patients who have more severe or life-threatening
symptoms (serum sodium <115 mEq/L), treatment consists of
intravenous saline, supplemental potassium, and diuresis
with loop diuretics such as furosemide or ethacrynic acid.
 With severe confusion, convulsions, or coma, treatment
is with 300 mL of 3% saline given over 3 to 4 hours in
combination with a loop diuretic (saline without a
diuretic will not increase the sodium concentration).
 Rapid correction of the sodium may have life-
threatening consequences, and caution is advised.
 The rate of correction of the sodium is best limited to a
maximum of 20 mEq/L/day, until a level of 120 to 130
mEq/L is reached.
 Faster correction has been associated with the
development of central pontine myelinolysis, which may
result in quadriplegia, cranial nerve abnormalities that
manifest as pseudobulbar palsy, alteration in mental
status, and subsequent death.
 For patients with SIADH due to SCLC, treatment
with chemotherapy should be initiated as soon as
possible and is likely to result in improvement in
the hyponatremia within a few weeks.
 After an initial response to chemotherapy, SIADH
may recur when the tumor relapses
Hypercalcemia
 Hypercalcemia in association with malignancy may
arise from a bony metastasis or, less commonly, from
secretion by the tumor of a parathyroid hormone–
related protein (PTHrP) or other bone-resorbing
cytokine.
 The most common cancers to cause hypercalcemia are
those of the kidney, lung, breast, head, and neck and
myeloma and lymphoma.
 Squamous cell histology is the most common cell type
associated with hypercalcemia, and generally patients
have advanced disease (stage III or IV) and are
unresectable.
 Symptoms of hypercalcemia include anorexia, nausea,
vomiting, constipation, lethargy, polyuria,
polydipsiaand dehydration. Confusion and coma are
late manifestations, as are renal failure and
nephrocalcinosis.
 Cardiovascular effects include shortened QT interval,
broad T wave, heart block, ventricular arrhythmia, and
asystole. Individual patients may manifest any
combination of these signs and symptoms in various
degrees.
 Hypercalcemia of malignancy that is not caused by
bony metastases results from accelerated bone
resorption, decreased bone deposition, or increased
renal tubular reabsorption of calcium.
 Accelerated bone resorption is caused by activation of
osteoclasts by cytokines or PTHrP in most cases.
 Serum parathyroid hormone levels are usually normal or
low, but an elevated level of PTHrP can be detected in the
serum in approximately one half of these patients.
Cytokines or PTHrP are secreted autonomously by the
tumor.
 Not only does PTHrP cause renal calcium reabsorption, but
also it interferes with renal mechanisms for reabsorption of
sodium and water, with resultant polyuria.
 Polyuria and vomiting result in dehydration; decreases in
glomerular filtration further aggravate the hypercalcemia.
Treatment:
 Mild elevation of serum calcium may not require
treatment, so the decision is based on the patient's
symptoms.
 For patients who have widely metastatic and incurable
malignancy, it may be most appropriate to give
supportive care only and not treat the hypercalcemia.
The average life expectancy in this situation is 30 to 45
days, even with aggressive treatment.
 Most patients who have a serum calcium of 12 to 13
mg/dL or higher are treated.
 The four basic goals of treatment are to (1) correct
dehydration; (2) increase renal excretion of calcium;
(3) inhibit bone resorption; and (4) treat the
underlying malignancy.
 Because of the polyuria, patients with hypercalcemia
are volume contracted. Initial treatment is with
intravenous normal saline, using 3 to 6 L/24 hr as
tolerated, with careful attention to volume status.
 Zoledronate is given 4 mg intravenously over 15
minutes.
 Adverse effects are generally mild and transient
and include fever, hypophosphatemia,
asymptomatic hypocalcemia and, occasionally,
renal failure.
 Calcitonin inhibits bone resorption, increases
renal calcium excretion, and has a rapid onset of
action, but the duration of action is shortlived.Given when the calcium is greater than 14
mg/dL or needs to be lowered urgently (onset of
action is 4–6 hr)
 The effects of calcitonin and bisphosphonates
are additive. Tachyphylaxis may occur to
calcitonin after 48 hours.
 Thiazide diuretics are not used because they
increase calcium reabsorption in the distal
tubule.
 Normal calcium levels are achieved within 4 to
10 days in 85% of patients and last a median of
30 to 40 days
Musculoskeletal Effects
clubbing of digits
 May be a manifestation of lung cancer or other
diseases.
 Most commonly seen in adenocarcinoma of
the lung and less frequently in other cell types.
 Clubbing may involve the fingers and toes and
consists of selective enlargement of the
connective tissue in the terminal phalanges.
 Physical findings include loss of the angle
between the base of the nail bed and the
cuticle, rounded nails and enlarged fingertips.
 In digital clubbing proliferation of
connective tissue beneath the nail matrix is
observed.
 Clubbing is an isolated finding and is
usually asymptomatic.
 Non-malignant causes of clubbing include
pulmonary fibrosis, congenital heart
disease, and bronchiectasis.
Hypertrophic pulmonary
osteoarthropathy (HPO)
 Is an uncommon process associated with lung cancer.
 HPO is characterized by painful arthropathy that usually
involves the ankles, knees, wrists, and elbows and is most
often symmetrical.
 The pain and arthropathy are caused by proliferative
periostitis that involves the long bones but may also affect
metacarpal, metatarsal, and phalangeal bones. Patients
may have clubbing of fingers and toes in addition to the
painful arthralgias.
 The pathogenesis of HPO is uncertain, but it may arise
from a humoral agent(VEGF/PDGF).
 For patients who smoke and have a new onset of
arthralgias, HPO must be considered
 A radiograph of the long bones (i.e., tibia and
fibula) usually shows characteristic periosteal new
bone formation. An isotope bone scan typically
demonstrates diffuse uptake by the long bones.
 Large cell and adenocarcinoma are the most common
histologic types associated with HPO.
 The symptoms of HPO may resolve after tumour
resection.
 For inoperable patients, treatment is with
nonsteroidal anti-inflammatory agents. Recently, case
reports have observed resolution or marked
improvement of symptoms with bisphosphonate
treatment
Dermatomyositis-polymyositis
 Dermatomyositis and ploymyositis are associated with
neoplasms in 40% of all cases.
 Besides ovarian cancer SCLC is the most frequent type of
cancer.
 Dermatomyositis is characterized by infarcts, perifascicular
atrophy , endothelial cell swelling and necrosis, vessel wall
membrane attack complex deposition and myocytespecific MHC-1 upregulation in the muscle.
 Histopathological findings include hyperkeratosis ,
epidermal basal cell vacuolar degeneration and
apoptosis,increased dermal mucin deposition cell poor
interface dermatitis.
 Myositis is charcterized by muscle weakness and
muscle pain.
 Typically proximal muscles are involved.
 Myositis-specific autoantigens are expressed at high
levels in regenerating cell in myositic muscles and
cancer cells. This may provide a link between cancer
and paraneoplastic myositic syndrome.
Hematologic/vascular Effects
 Anemia frequently occurs in patients who have
lung cancer and may be caused by iron deficiency,
chronic disease, or bone marrow infiltration.
 Eosinophilia is more commonly associated with
Hodgkin's disease but may occur in patients who
have lung cancer.
 Production of various cytokines by neoplastic cells
may result in eosinophilia, leukocytosis, or
thrombocytosis, of which thrombocytosis is by far
the most common.
 The association of deep venous thrombosis and
malignancy was described by Trousseau over a
century ago, and lung cancer is the most common
malignancy associated with Trousseau's syndrome
 Thromboembolism in the patient who has
malignancy is often refractory to warfarin
treatment.
 Treatment with low-molecular-weight heparin
(LMWH) on a chronic basis may be effective
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.
 In a randomized trial, patients with cancer and deep vein thrombosis,
pulmonary embolism, or both were randomized to receive LMWH
(dalteparin) subcutaneously once daily or oral warfarin daily for 6
months.
 At 6 months, the probability of recurrent thromboembolism was 9%
with dalteparin treatment and 17% with warfarin, a difference that was
highly significant.
 The risks of major bleeding or any bleeding were not different in the
two groups.
 The other advantage of LMWH is that it is unnecessary to monitor the
anticoagulant effect, except in some patients with renal insufficiency.
 A recent Cochrane analysis concluded that, for long-term treatment in
patients with cancer, LMWH reduced venous thromboembolism
events, but not death, as compared with vitamin K antagonists. There
was no significant difference in the risk of bleeding.
Granulocytosis
 Granulocytosis with absolute cell count of 10,000 to
25,000 occurs in 20% of patients of non-small cell lung
cancer.
 The specific ectopic harmone responsible for
paraneoplastic granulocytosis has not been
characterized, although some non-small cel tumours
may produce various cytokines like IL-6, G-CSF or
GM-CSF.
 Bone marrow biopsy is usually normal.
 Diagnosis is made on exclusion, granulocytosis per se
does not produce any symptom in these patients.
Thrombocytosis
 It is common phenomena observed in 40% patients of
both small cell and non small cell carcinomas.
 Exact mechanism of thrombocytosis is not known, it is
most likely linked to megakaryocyte cytokine i.e. IL-6.
 It is asymptomatic , diagnosed if bone marrow biopsy
is normal and platelet count exceeds 500,000/mm2.
Acromegaly
 Carcinoid tumour is the most common cause
of acromegaly associated with lung cancer.
 SCLC can also produce acromegaly.
 Its due to the release of GHRH & rarely by GH.
 Pts develop thick leathery skin, prominent skin
folds, hypertrophy of face & extremities,
diabetes & hypertension.
 Increased levels of GHRH & IGF-1 in presence of
lung tumour establishes diagnosis.
 Respond to surgical resection as well as
radiotherapy.
 Pts ineligible for resection/irradiation should
receive octreotide, which inhibits GHRH secretion
form the tumour & decreases GH & IGF-1 levels in
serum.
Neurologic Effects
 The paraneoplastic neurologic syndromes associated
with lung cancer, mostly small cell type, are quite
variable. They include LEMS, subacute sensory
neuropathy, encephalomyelopathy, cerebellar
degeneration, autonomic neuropathy, retinal
degeneration, and opsoclonus.
 The frequency of any of these neurologic syndromes
in SCLC is approximately 5%, and neurologic
symptoms may precede the diagnosis by months to
years.

Careful radiographic evaluation of the lungs
and mediastinum is indicated in a smoker
who has a suspected paraneoplastic
neurologic syndrome.
 In this setting, even subtle abnormalities of
the mediastinum require a biopsy. A PET
scan may help identify an occult lesion and
facilitate biopsy confirmation of the
diagnosis.
 Patients with paraneoplastic neurologic
syndromes have a better prognosis than those
without the paraneoplastic syndromes with similar
stage and histology.
 These paraneoplastic neurologic syndromes are
thought to be immune-mediated, based on the
identification of a number of antibodies in the
serum that react with both the nervous system and
the underlying cancer.However, not all patients
with paraneoplastic syndromes have identifiable
antibodies in their Serum.
 Predominantly antineuronal nuclear antibody type
1(ANNA-1) , have been associated with SCLC. ANNA-1
binds to the nuclei of all neurons in the central and
peripheral nervous system, including the sensory and
autonomic ganglia, the myenteric plexus, and cells of
the adrenal medulla.
 Such antibodies should not be confused with the anti–
Purkinje cell antibody (anti-Yo), which is
characteristically found in patients who have subacute
cerebellar degeneration as a manifestation of
gynecologic malignancy or breast cancer.
 The CRMP-5 antibody, also known as anti–CV-2, has
been associated with SCLC and thymomas.
 In a review of 162 sequential patients who had
elevated ANNA-1 (anti-Hu), 142 (88%) were proved to
have cancer, 132 of whom had SCLC.
 In 97% of these cases, the diagnosis of SCLC followed
the onset of the associated neurologic syndrome,
usually by less than 6 months but, in 20%, the period
was greater than 6 months.
 Of special note is that 90% of cases had disease
limited to the lung or to the lung and mediastinum
(LD-SCLC).
 In a report from Europe, 144 patients out of 200
with anti-Hu antibodies had a tumour in the chest.
Of these, 111 were proved to be SCLC.
 In one large series, ANNA-1 antibodies were
identified in 16% of all patients with SCLC.
 These antibodies were associated with limitedstage disease, complete response to therapy, and
longer survival compared with patients who had
SCLC and no ANNA-1 antibody.
 These neurologic syndromes seldom improve with
treatment, so the goal is to prevent progression by starting
treatment of the underlying tumor as soon as possible.
 Less common manifestations of neurologic paraneoplastic
syndromes are orthostatic hypotension and intestinal
dysmotility.
 The gastrointestinal symptoms may present as nausea,
vomiting, abdominal discomfort, or altered bowel habits
suggestive of intestinal pseudo-obstruction.
 Many of these patients present with gastrointestinal
symptoms and significant weight loss prior to the diagnosis
of SCLC.
Lambort eaten myasthenic
syndrome
 Proximal muscle weakness, hyporeflexia , and
autonomic dysfunction characterize LEMS.
 Cranial nerve involvement may be present and does not
differentiate LEMS from myasthenia gravis.
 LEMS has been strongly associated with antibodies
directed against P/Q-type presynaptic voltage-gated
calcium channels (anti-VGCC antibodies) of peripheral
cholinergic nerve terminals.
 These anti-VGCC antibodies, identified in
over 90% of patients with LEMS, block the
normal release of acetylcholine at the
neuromuscular junction.
 In contrast, myasthenia gravis is associated
with anti–acetylcholine receptor antibodies,
which are present in approximately 90% of
myasthenic patients.
 Malignancy is present in approximately one half
of patients who have LEMS, and SCLC is by far the
most common malignancy.
 In a recent study of 63 patients with SCLC
examined prospectively, only 3% had clinical and
electrophysiological signs of LEMS, 8% had
elevated anti-VGCC antibodies and 26% had other
neurologic symptoms unrelated to LEMS.
Diagnosis:
 The diagnosis of LEMS is based on characteristic
electromyographic findings that show a small
amplitude of the resting compound muscle action
potential and facilitation with rapid, repetitive,
supramaximal nerve stimulation or after brief
exercise of the muscle.
 A single-fiber electromyogram is optimal for
making the diagnosis.
Treatment:
 LEMS is the predominant paraneoplastic neurologic
syndrome that may improve with successful treatment
of the associated lung cancer.
 The use of acetylcholinesterase inhibitors is of limited
benefit in LEMS.
 Diaminopyridine enhances the release of acetylcholine
and has been used with sustained improvement over
months in the majority of patients with LEMS either
with or without cancer.
LEMS
MYASTHENIA GRAVIS
 Antibodies against the nerve
 Antibodies against the muscle
where acetylcholine is
released.
receptors for acetylcholine.
 Starts at eye and moves down.
 Starts at extremeties and
moves up.
 Weakness improves upon
activity.
 Weakness worsens upon
activity.
 Associated with SCLC.
 Associated with thymoma.
 Therapy - aminopyridines
 Therapy- acetylcholine esterase
inhibitors.
Encephalomyelitis and sensory
neuropathy
 It is associated with small cell lung cancer and the
neuronal damage is mediated by IgG anti-HU
antibody known as ANNA-1.
 These patients may present with progressive sensory
loss in hands and feets , myelopathy , brainstem,
cerebellum, cerebral cortex, spinal cord and dorsal
root ganglia.
 Patients present with sensory loss in hands and feet
and brainstem involvement.
 Diagnosis of encephalomyelitis is suggested by the
MRI which shows increased T2 signal in the affected
areas of the brain and is confirmed by demonstration
of anti-hu antibody in the serum.
 Removal of culprit IgG by plasmaphresis and
corticosteroids administration is effective in only 15%
of these patients.
Cerebellar degenration
 Some patients of small cell lung cancer develop
cerebellar degeneration leading to nystagmus,
impaired coordination and ataxia.
 These patients have anti-hu antibodies in serum and
frequently tend to develop encephalitis or sensory
neuropathy.
Cancer associated retinopathy
 It is a rare paraneoplastic that occurs as the first sign
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of occult small cell carcinoma.
Ganglion cells of retina are characterstically damaged
by binding of auto-antibodies to recoverin,a
photoreceptor-specific protein.
These patients have photosenstivity ,rapid loss of
vision, night blindness, visual field defects and
arteriolar narrowing.
Anti-recoverin antibody establishes the diagnosis.
It responds to systemic steroids bt not to the
chemothrapy for primary tumour.
Opsoclonus and myoclonus
 These are rare paraneoplastic syndrome associated
with both small cell and non small cell lung cancers.
 These patients show rapid involuntary conjugate eye
movements in both the horizontal and vertical
directions.
 Some SCLC patients with this syndrome have anti-hu
antibody in serum.
Miscellaneous
Cachexia and fatigue
 Cancer cachexia is the most common manifestation of
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advanced malignant disease(50%) and is responsible
for almost 25% of deaths from cancer.
Symptoms of cachexia include anorexia, weight loss,
muscle loss, anaemia, alterations in carbohydrate,
lipid and protein metabolism.
In cancer patients increased levels of free tryptophan
are found which are closely related to reduced food
intake.
Proinflammatory cytokines including TNF-A , IL-1,6
IFN-G have been implicated in cachexia.
Medroxy progesterone acetate may improve appetite
and stabilize weight. Eicosa pentaenoic acid can lower
the production of proinflammtory cytokines.
 Cancer related fatigue is also extremely common. Upto
90% of cancer patients report fatigue symptoms.
 Basic mechanism of fatigue are broadly charcterized into
two main components: peripheral and central.
 Peripheral fatigue occurs in the N-M junctions and muscle
tissues.
 Central fatigue arises from the progrsseive failure to
transmit motor neuron impulses.
 Hemotopoeitics , antidepressants, corticosteroids and new
wake promoting agent modafinil may be used for the
cancer related fatigue.
conclusions
 Paraneoplastic sydromes are common in lung cancer
patients.
 Some paraneoplastic syndromes can severely affect
organ function and quality of life.
 Treating the underlying cancer is the first step.
 However specific therapy may also be necessary.