Paraneoplastic Syndromes Madison Li (M4) Email: [email protected]@osumc.edu.
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Transcript of Paraneoplastic Syndromes Madison Li (M4) Email: [email protected]@osumc.edu.
Learning Objectives
Primary Learning Objective: Assess the clinical features of paraneoplastic syndromes
and correlate them to their associated malignancies and mechanisms
Secondary Learning Objectives: Describe the major clinical features of paraneoplastic
syndromes Correlate the underlying pathophysiology of
endocrinopathies - SIADH, Cushing's syndrome, hypercalcemia, and hypoglycemia - to their clinical features.
Correlate the underlying pathophysiology of paraneoplastic neurologic syndromes to their clinical features.
Correlate the underlying pathophysiology of paraneoplastic hematologic syndromes to their clinical features
Paraneoplastic Syndromes (PS)
Represent disorders associated with specific cancers
Present as signs/symptoms at sites distant from the primary tumor and its metastasis
Affect up to 8% of cancer patients and various systems (e.g. endocrine, neurologic, hematologic)
Increased prevalence due to improved diagnostic methods and longer life expectancy in cancer patients
Objectives 1 and 2
Correlate the underlying pathophysiology of endocrinopathies - SIADH, Cushing's syndrome, hypercalcemia, and hypoglycemia - to their clinical features
Paraneoplastic Endocrine Syndromes
Arise from tumor secretion of hormones, peptides, cytokines which lead to metabolic derangements
Typically detected after a cancer diagnosis and do not correlate w/ cancer stage or prognosis
Oftentimes, treating underlying malignancy (e.g. removing the tumor) leads to symptom resolution
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Hypo-osmotic, euvolemic hyponatremia (serum
[Na]<135 mmol/L) Results from tumor secretion of ectopic ADH and
ANP Causes: Small cell lung cancer (SCLC), carcinoid
tumors, pancreatic, esophageal, prostate, hematologic malignancies
Presentation: Dependent on serum [Na] and rate of drop in [Na] Significant sx with [Na] <125 mmol/L, esp. if they develop
within 48 hours AMS, seizures, coma, respiratory collapse, DEATH
Development of hyponatremia over time (chronic SIADH) Milder sx Asymptomatic to fatigue, anorexia, HA, mild AMS, confusion
DDx: CHF, nephrotic syndrome, malignant ascites, liver disease, diuretic use
Diagnosis/laboratory findings: Plasma hyponatremia and hypo-osmolality in the presence of
concentrated urine (urine [Na] >40 mmol/L or urine osmolality >100 mmol/L) with normal ECF volume
Essential to assess volume status (e.g. absence of edema, orthostatic changes, normal CVP)
Treatment: Acute: IV hypertonic saline
Increase serum [Na] 1-2 mmol/L/hr (w/ max of 8-10 mmol/L during first 24 hours)
Rapid correction Water egress, brain dehydration, central pontine and extra-pontine myelinolysis
Chronic: Fluid restriction (<1 L/day), pharmacologic inhibition of tubular reabsorption of water
Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Cushing Syndrome
PS accounts for 5-10% of cases Results from tumor secretion of ACTH or CRF
Excess cortisol Causes: Approx. 50-60% of cases arise from
neuroendocrine lung tumors SCLC >50% of cases of ectopic ACTH production Bronchial carcinoid, neural crest tumors 15%
Presentation: Sx: HTN, hypokalemia, muscle weakness, generalized
edema Symptoms often present before cancer diagnosis with
relapse in symptoms likely meaning tumor recurrence
DDx: Pituitary adenoma (Cushing’s disease), adrenal gland tumor/hyperplasia, exogenous glucocorticoid administration
Diagnosis/laboratory findings: Serum cortisol >29 μg/dL, urinary free cortisol >47 μg/24 hours Midnight ACTH >100 ng/L Failure to respond to high-dose dexamethasone suppression
test Obtain CT/MRI and octreotide scan to ID tumor source
Treatment: Pharmacologic 1st line
Inhibition of steroid production (e.g. ketoconazole) Anti-hypertensives, diuretics for sx management Inhibition of ACTH release (octreotide) Blocking glucocorticoid receptors (mifepristone)
Surgery (if symptoms are refractory to treatment)
Cushing Syndrome
Hypercalcemia Occurs in up 10% of all cancer patients with
advanced cancer Poor prognostic sign Causes:
Tumor secretion of parathyroid hormone-related protein (PTHrP) 80% of cases Associated with squamous cell tumors, especially of the lung
Osteolytic activity at sites of skeletal metastases Associated with breast cancer, multiple myeloma, lymphomas
Tumor secretion of Vitamin D Tumor secretion of ectopic PTH
Presentation: Symptom severity depends on:
Severity of hypercalcemia (usually serum [Ca] >14 mg/dL) Rapidity of onset Patient’s baseline neurologic and renal function
Sx: Nausea, vomiting, lethargy, renal failure, coma
DDx: Primary hyperparathyroidism (adenoma/hyperplasia of parathyroid
glands) Malignancy Osteolytic hypercalcemia
Diagnosis/laboratory findings: Serum [Ca] >10.3 mg/dL or ionized [Ca] >5.2 mg/dL Hypercalciuria Low serum [Cl] High urine phosphate Low/undetectable plasma PTH
Treatment: Acute:
Fluid resuscitation with normal saline Loop diuretics IV bisphosphonates
Chronic: Bisphosphonates Hemodialysis (if patient has significant renal or cardiac disease)
Hypercalcemia
Hypoglycemia
Known as non-insulinoma or non-islet cell associated tumor hypoglycemia
Causes: Due to tumor production of IGF-2 or insulin
Presentation: Recurrent or constant hypoglycemic episodes (glucose levels
as low as <20 mg/dL) Typically seen in elderly patients with advanced cancer Symptoms occasionally predate the cancer diagnosis
DDx: Insulinoma Diagnosis/laboratory findings:
Low levels of insulin and C-peptide Low levels of GH and IGF-1 Normal to high levels of IGF-2 In the case of an insulinoma:
High levels of insulin and C-peptide with normal IGF-2/IGF-1 ratio
Treatment: If possible, treat underlying malignancy (e.g. surgery) Acute:
D50 (25g dextrose in 50mL of fluid) Immediate Oral glucose pastes/tablets 15-30 minutes
Chronic: Corticosteroids Growth hormone Diazoxide Octreotide Glucagon
Hypoglycemia
Objectives 1 and 3
Correlate the underlying pathophysiology of paraneoplastic neurological syndromes to their clinical features
Paraneoplastic Neurological Syndromes (PNS) Result from development of tumor-directed
antibodies (onconeural antibodies) These antibodies and associated onconeural
antigen-specific T-lymphocytes attack healthy nervous system tissue due to antigenic similarity between normal and malignant tissues
Antibodies classified in 3 categories: Well-characterized antibodies w/ a strong cancer
association Partially characterized antibodies Antibodies associated with both cancer and non-cancer
conditions In ~80% of cases, PNS is detected before the
cancer diagnosis
Presentation: Cognitive/personality changes, ataxia, cranial nerve deficits,
weakness, numbness Symptoms dependent on the tissues affected by the
antibodies Central nervous system Limbic encephalitis, paraneoplastic
cerebellar degeneration Neuromuscular junction Lambert-Eaton myasthenia syndrome
(LEMS), myasthenia gravis Peripheral nervous system Autonomic neuropathy, subacute
sensory neuropathy
DDx: Broad (e.g. result of infection, toxins, metabolic derangements) Must consider if symptoms are due to brain mets,
leptomeningeal disease, spinal cord/nerve root compression, adverse effects of treatment
Paraneoplastic Neurological Syndromes (PNS)
Diagnosis: In addition to a full history and physical exam, obtain:
Imaging (e.g. CT chest/abdomen/pelvis) Antibody serologies CSF analysis EEG Nerve conduction studies/EMG
Since most patients with a PNS diagnosis do not have known cancer at the time, periodic screening is indicated If initial imaging is negative, clinical and radiographic
surveillance indicated every 3-6 months for 2-3 years ~15% of cases associated with thymomas
Treatment: Treat underlying malignancy Immune modulation/suppression NOTE: Even with cancer treatment, there may still be
permanent neurologic damage
Paraneoplastic Neurological Syndromes (PNS)
Objectives 1 and 4
Correlate the underlying pathophysiology of paraneoplastic hematological syndromes to their clinical features
Paraneoplastic Hematological Syndromes
Rarely symptomatic Conditions usually detected after a cancer
diagnosis Usually associated with advanced disease but
rarely require specific treatment May see improvement in syndromes with
treatment of the underlying malignancy
Examples of syndromes: Eosinophilia Lymphomas, leukemias, lung, GI, gynecologic Granulocytosis Lung cancer (esp. large cell lung cancer),
GI, brain, breast, renal, gynecologic Pure red cell aplasia Thymoma
Risk of venous thromboembolism Not a paraneoplastic syndrome but important to know! 4-7x higher risk of an event in a cancer px compared to
someone without cancer 2nd leading case of death in this population Highest risk in those with hematologic cancers (e.g.
leukemias) and certain types of solid tumors (e.g. pancreatic, lung, stomach cancers)
Paraneoplastic Hematological Syndromes
Also increased risk of an event in those receiving chemo and radiation, those who have undergone surgery, and those with metastatic disease
Causes: Mucin production by tumors Exposure to tissue factor-rich surfaces and tissue factor-
bearing microvesicles Cysteine proteinase production leading to thrombin
generation Local hypoxia Endothelial activation and reactive oxygen
species production Fibrin deposition Treatment:
Currently, no protocol for anti-coagulation prophylaxis in high-risk ambulatory patients with cancer
Paraneoplastic Hematological Syndromes
Paraneoplastic Syndrome Quiz
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