Paraneoplastic Syndromes

Madison Li (M4)Email: huihui.li@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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