PRESENTED BY: DR. HITESH GOUR J.R. PULMONARY MEDICINE
Slide 2
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.
Slide 3
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
Slide 4
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
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
Slide 12
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.
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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.
Slide 15
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 g/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.
Slide 16
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.
Slide 17
The criteria for the diagnosis of SIADH include (1)
hyponatremia associated with serum hypoosmolality ( 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 osmolalitytoserum 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.
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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.
Slide 20
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.
Slide 21
If further treatment is needed, oral demeclocycline (9001200
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
Slide 22
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.
Slide 23
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
Slide 24
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.
Slide 25
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.
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Slide 27
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.
Slide 28
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.
Slide 29
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.
Slide 30
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 short- lived.Given when the calcium is
greater than 14 mg/dL or needs to be lowered urgently (onset of
action is 46 hr)
Slide 31
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
Slide 32
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.
Slide 33
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.
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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.
Slide 36
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.
Slide 37
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
Slide 38
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 myocyte- specific 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.
Slide 39
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.
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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.
Slide 42
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
Slide 43
. 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.
Slide 44
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.
Slide 45
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.
Slide 46
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.
Slide 47
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.
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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.
Slide 50
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.
Slide 51
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.
Slide 52
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 antiCV-2, has been
associated with SCLC and thymomas.
Slide 53
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).
Slide 54
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 limited- stage disease, complete response to therapy, and
longer survival compared with patients who had SCLC and no ANNA-1
antibody.
Slide 55
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.
Slide 56
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.
Slide 57
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 antiacetylcholine receptor antibodies, which are
present in approximately 90% of myasthenic patients.
Slide 58
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.
Slide 59
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.
Slide 60
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.
Slide 61
LEMS MYASTHENIA GRAVIS Antibodies against the nerve where
acetylcholine is released. Starts at extremeties and moves up.
Weakness improves upon activity. Associated with SCLC. Therapy -
aminopyridines Antibodies against the muscle receptors for
acetylcholine. Starts at eye and moves down. Weakness worsens upon
activity. Associated with thymoma. Therapy- acetylcholine esterase
inhibitors.
Slide 62
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.
Slide 63
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.
Slide 64
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.
Slide 65
Cancer associated retinopathy It is a rare paraneoplastic that
occurs as the first sign 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.
Slide 66
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.
Slide 67
Miscellaneous Cachexia and fatigue Cancer cachexia is the most
common manifestation of 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.
Slide 68
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.
Slide 69
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.
