1. Paraneoplastic Syndromes Madison Li (M4) Email: huihui.li@osumc.eduhuihui.li@osumc.edu

2. 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

3. 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

4. Objectives 1 and 2  Correlate the underlying pathophysiology of endocrinopathies - SIADH, Cushing's syndrome, hypercalcemia, and hypoglycemia - to their clinical features

5. 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

6. 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

7.  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)

8. 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

9.  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  1 st 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

10. 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

11.  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

12. 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

13.  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

14. Objectives 1 and 3  Correlate the underlying pathophysiology of paraneoplastic neurological syndromes to their clinical features

15. 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

16.  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)

17.  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)

18. Objectives 1 and 4  Correlate the underlying pathophysiology of paraneoplastic hematological syndromes to their clinical features

19. 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

20.  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  2 nd 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

21.  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

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