Paraneoplastic Syndromes: Endocrinologic/Hematologic¶

Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Part 4 – Oncology: Solid Tumors · Chapter 98

Key Clinical Points¶

Ectopic hormone production is defined as secretion from atypical tissue sources with abnormal regulation and peptide processing.
Humoral hypercalcemia of malignancy (HHM) occurs in up to 20% of cancer patients, typically driven by PTHrP with suppressed PTH.
Ectopic ACTH syndrome presents with hypokalemia, metabolic alkalosis, and ACTH >22 pmol/L, commonly associated with SCLC.
Tumor-induced hypoglycemia is linked to IGF-II overproduction (IGF-II/IGF-I ratio >10:1).
Cancer immunotherapy (anti-CTLA-4, PD-1, PD-L1) causes autoimmune endocrinopathies in ~10% of patients.
Paraneoplastic hematologic syndromes include erythrocytosis (erythropoietin), granulocytosis (IL-6/G-CSF), and Trousseau's syndrome.
Treatment of the underlying malignancy is central for all paraneoplastic endocrine syndromes, with adjunctive therapies for symptom control.
Bisphosphonates (zoledronate, pamidronate) and denosumab are first-line for hypercalcemia; vaptans (tolvaptan, conivaptan) treat SIADH.
SIADH correction must be gradual to avoid central pontine myelinolysis.
Trousseau's syndrome is a critical red flag for underlying malignancy.

1. DEFINITION & OVERVIEW¶

Paraneoplastic syndromes are disorders associated with malignancies but not caused by direct tumor effects. Neoplastic cells secrete substances that alter hormonal, hematologic, and other systems.

Definition (Harrison's 22e): Ectopic refers to hormone production from an atypical tissue source. For example, ACTH is expressed eutopically by the anterior pituitary but ectopically in SCLC.

Key features include: • Ectopic expression often involves abnormal regulation (e.g., defective feedback) and unprocessed precursor peptides (e.g., POMC). • Cellular dedifferentiation underlies most cases, with tumors expressing developmental-stage proteins like hCG or α-fetoprotein. • Paraneoplastic syndromes may precede cancer diagnosis (e.g., ectopic ACTH in lung cancer) and resolve with tumor reduction.

1.1 Ectopic vs Eutopic Hormone Production¶

• Eutopic: Produced in the tissue of origin (e.g., ACTH from pituitary cells). • Ectopic: Produced from atypical sources (e.g., ACTH from SCLC). • Mechanisms: Driven by dedifferentiation and epigenetic changes rather than rare genetic rearrangements. • Developmental Proteins: Tumors often express proteins like hCG or α-fetoprotein due to altered transcriptional repression and microRNA pathways.

2. EPIDEMIOLOGY¶

• Humoral hypercalcemia of malignancy (HHM): Occurs in 20% of cancer patients; most common in lung, head/neck, skin, breast, and genitourinary cancers. • SIADH: Present in >50% of SCLC cases. • Ectopic ACTH syndrome: Accounts for 10–20% of Cushing's syndrome cases. • Eosinophilia: Occurs in ~1% of cancer patients (10% in lymphoma, 3% in lung cancer). • Erythrocytosis: Seen in 3% of renal cell carcinoma, 10% of hepatoma, and 15% of cerebellar hemangioblastomas.

3. ETIOLOGY & PATHOPHYISIOLOGY¶

• PTHrP Induction: Driven by hedgehog pathways, TGF-β, Ras mutations, and p53 loss. • Vasopressin Overproduction: May involve derepression of the oxytocin/vasopressin gene locus. • Ectopic ACTH: Arises from unregulated POMC expression in tumors lacking processing enzymes. • CRH Production: Produced by pancreatic islet tumors or SCLC; can cause Cushing's via paracrine mechanisms. • FGF23 Overproduction: Leads to phosphate wasting and hypophosphatemia via klotho/FGFR complexes. • Type 3 Deiodinase: Overexpression in hepatic hemangiomas causes consumptive hypothyroidism.

Table 98-1 Summary of Ectopic Hormones: • PTHrP, 1,25-Dihydroxyvitamin D, Vasopressin • ACTH, CRH, GIP, LH/hCG, Calcitonin, VIP • IGF-II, Insulin • FGF23, GHRH, TSH, Renin

Table 98-4 Summary of Additional Conditions: • Acromegaly (GHRH, GH) • Hyperthyroidism (TSH) • Hypertension (Renin) • Consumptive Hypothyroidism (Type 3 deiodinase)

3.1 Mechanisms of Ectopic Hormone Production¶

• Dedifferentiation and epigenetic changes drive expression. • PTHrP: Stimulated by hedgehog, TGF-β, Ras mutations, and p53 loss. • CRH: Paracrine activation of ACTH in tumors. • FGF23: Disrupts renal phosphate reabsorption via klotho/FGFR complexes.

3.2 Mechanisms of Hematologic Syndromes¶

• Erythrocytosis: Caused by ectopic erythropoietin, G-CSF, or IL-6. • Thrombocytosis: Results from IL-6 or IL-5 overproduction. • Trousseau's syndrome: Linked to procoagulants released by tumors. • Eosinophilia: Driven by IL-5 in lymphomas and leukemias.

4. CLINICAL FEATURES¶

• HHM: Hypercalcemia (Ca >3.5 mmol/L) → fatigue, polyuria, dehydration, and ECG changes. ◦ ECG findings: Shortened ST segments, QT intervals, bundle branch blocks, and bradyarrhythmias. • SIADH: Hyponatremia (<135 mEq/L) → weakness, confusion, seizures; requires gradual correction. • Ectopic ACTH: Hypokalemia, metabolic alkalosis, hyperpigmentation (from MSH); minimal weight gain due to cachexia. • Tumor-induced Hypoglycemia: Occurs during fasting in patients with large tumors (>10 cm) → sweating, tremors, coma; linked to IGF-II/IGF-I ratio >10:1. • Erythrocytosis: Asymptomatic; detected by hematocrit >52% (men), >48% (women). • Eosinophilia: Potential pulmonary infiltrates and dyspnea at counts >5000/μL. • Trousseau's syndrome: Migratory thrombophlebitis; marker for underlying malignancy.

4.1 Hypercalcemia of Malignancy¶

• Presentation: Detected on routine labs in patients with known malignancy. ◦ Severe cases (>3.5 mmol/L): Fatigue, mental status changes, polyuria, nephrolithiasis.

4.2 Ectopic Vasopressin (SIADH)¶

• Hyponatremia: Develops over weeks/months; often asymptomatic. ◦ Risk: Rapid correction → central pontine myelinolysis.

4.3 Ectopic ACTH Syndrome¶

• Features: Hypokalemia, metabolic alkalosis, hyperpigmentation. ◦ Pathophysiology: High cortisol causes skin fragility and severe hypokalemia via mineralocorticoid receptor activation.

4.4 Tumor-Induced Hypoglycemia¶

• Context: Fasting state in patients with large tumors (>10 cm). ◦ Mechanism: IGF-II overproduction (IGF-II/IGF-I ratio >10:1).

4.5 Hematologic Syndromes¶

• Erythrocytosis: Asymptomatic; detected by elevated hematocrit. ◦ Thrombocytosis: May indicate poor prognosis in some cancers. ◦ Trousseau's syndrome: Migratory thrombophlebitis; marker for malignancy.

5. DIFFERENTIAL DIAGNOSIS¶

• HHM vs Hyperparathyroidism: HHM → PTHrP elevated, PTH suppressed. Primary hyperparathyroidism → PTH elevated, PTHrP normal. • SIADH vs Other Hyponatremia: SIADH → Euvolemic state, urine osmolality >100 mOsm/kg. Heart failure → Hypervolemic hyponatremia, low urine osmolality. • Ectopic ACTH vs Pituitary Cushing's: Ectopic ACTH → Lower weight gain, hypokalemia, hyperpigmentation. Pituitary → Centripetal fat redistribution, hypertension, glucose intolerance.

5.1 Hypercalcemia vs Hyperparathyroidism¶

• HHM: PTHrP elevated, PTH suppressed. ◦ Primary hyperparathyroidism: PTH elevated, PTHrP normal.

5.2 SIADH vs Other Hyponatremia¶

• SIADH: Euvolemic hyponatremia, urine osmolality >100 mOsm/kg. ◦ Heart failure: Hypervolemic hyponatremia, low urine osmolality.

5.3 Ectopic ACTH vs Pituitary Cushing's¶

• Ectopic ACTH: Lower weight gain, hypokalemia, hyperpigmentation. ◦ Pituitary Cushing's: Centripetal fat redistribution, hypertension, glucose intolerance.

6. INVESTIGATIONS & DIAGNOSIS¶

Hypercalcemia of Malignancy (HHM):
Step 1: Serum calcium >2.5 mmol/L (10 mg/dL).
Step 2: Confirm PTHrP elevated and PTH suppressed.
Step 3: Imaging (CT/MRI) to identify tumor.
Ectopic ACTH Syndrome:
Step 1: ACTH >22 pmol/L.
Step 2: Cortisol elevated.
Step 3: Confirm suppression by dexamethasone.
Step 4: Imaging (e.g., Octreotide scan for SCLC).
SIADH:
Step 1: Hyponatremia (<135 mEq/L).
Step 2: Urine osmolality >100 mOsm/kg.
Step 3: Confirm euvolemic state.
Tumor-Induced Hypoglycemia:
Step 1: Plasma glucose <40 mg/dL during fasting.
Step 2: Calculate IGF-II/IGF-I ratio (>10:1).
Erythrocytosis:
Step 1: Elevated hematocrit.
Step 2: Measure erythropoietin or G-CSF levels.

6.1 Diagnostic Criteria for Hypercalcemia¶

• Serum calcium >2.5 mmol/L (10 mg/dL) ◦ PTHrP elevated, PTH suppressed ◦ Imaging: CT/MRI to identify tumor

6.2 Diagnostic Criteria for Ectopic ACTH¶

• ACTH >22 pmol/L ◦ Cortisol elevated ◦ Suppressed by dexamethasone ◦ Imaging: Octreotide scan for SCLC

7. MANAGEMENT & TREATMENT¶

Hypercalcemia of Malignancy (HHM):
Step 1: Intravenous fluids (0.9% saline).
Step 2: Bisphosphonates (Zoledronate 4 mg IV over 15–30 min; Pamidronate).
Step 3: Denosumab (60 mg SC every 4 weeks).
Step 4: Calcitonin (5–12 IU/kg IV q6h for acute cases).
SIADH:
Step 1: Fluid restriction to 800–1000 mL/day.
Step 2: Vaptans (Tolvaptan 15–30 mg PO BID; Conivaptan 20–40 mg IV q12h).
Step 3: Monitor sodium levels closely to ensure gradual correction.
Ectopic ACTH Syndrome:
Step 1: Tumor resection.
Step 2: Ketoconazole for cortisol suppression.
Tumor-Induced Hypoglycemia:
Step 1: Tumor resection.
Step 2: Glucardon infusion.
Hematologic Syndromes:
Step 1: Treat underlying tumor.
Step 2: Octreotide for erythrocytosis.

7.1 Management of Hypercalcemia¶

• Intravenous fluids (0.9% saline) ◦ Bisphosphonates (zoledronate 4 mg IV over 15–30 min) ◦ Denosumab (60 mg SC every 4 weeks) ◦ Calcitonin (5–12 IU/kg IV q6h for acute cases)

7.2 Management of SIADH¶

• Fluid restriction to 800–1000 mL/day ◦ Vaptans: Tolvaptan 15–30 mg PO BID, conivaptan 20–40 mg IV q12h ◦ Monitor sodium levels closely

8. PROGNOSIS & COMPLICATIONS¶

• HHM: Prognosis correlates with underlying cancer; hypercalcemia worsens survival. • SIADH: Complications include seizures, coma, and central pontine myelinolysis from rapid correction. • Ectopic ACTH Syndrome: Poor prognosis due to advanced malignancy. ◦ Complications: Severe hypokalemia, metabolic alkalosis, hyperpigmentation, and increased infection risk due to immunosuppression. • Hypoglycemia: May be fatal if untreated. • Erythrocytosis: Generally benign.

Table 98-3 Khorana Risk Score for VTE: • High risk (stomach, pancreas) → 2 points • High risk (lung, lymphoma, gynecologic, genitourinary excluding prostate) → 1 point • Hemoglobin <10 g/dL or use of red cell growth factors → 1 point • BMI ≥35 kg/m² (included in assessment) • Risk Category: 0 = Low; 1–2 = Intermediate; ≥3 = High.

8.1 Complications of Ectopic ACTH¶

• Severe hypokalemia, metabolic alkalosis, and hyperpigmentation. ◦ Increased risk of infections due to immunosuppression.

9. SPECIAL CONSIDERATIONS¶

• Cancer Immunotherapy (anti-CTLA-4, PD-1, PD-L1): Causes autoimmune endocrinopathies in ~10% of patients. ◦ Characteristics: Often irreversible; requires hormone replacement therapy. ◦ Conditions: Hypothyroidism, type 1 diabetes, adrenal insufficiency.

9.1 Cancer Immunotherapy-Associated Autoimmune Diseases¶

• Hypothyroidism, type 1 diabetes, adrenal insufficiency. ◦ Management: Hormone replacement (levothyroxine, hydrocortisone).

10. KEY PEARLS & CLINICAL TRAPS¶

• Ectopic hormone production is a hallmark of paraneoplastic syndromes. • HHM is the most common endocrinologic paraneoplastic syndrome. • SIADH correction must be gradual to avoid central pontine myelinolysis. • Trousseau's syndrome is a red flag for underlying malignancy. • Ectopic ACTH syndrome may present with hyperpigmentation and hypokalemia.

Reference Tables¶

TABLE 98-1 Paraneoplastic Syndromes Caused by Ectopic Hormone Production¶

Harrison's 22e, p.737

PARANEOPLASTIC SYNDROME	ECTOPIC HORMONE	TYPICAL TUMOR TYPESa
Common
Hypercalcemia of malignancy	Parathyroid hormone–related protein (PTHrP)	Squamous cell (head and neck, lung, skin), breast, genitourinary, gastrointestinal; osteolytic metastases
	1,25-Dihydroxyvitamin D	Lymphomas
	Parathyroid hormone (PTH) (rare)	Lung, ovary
	Prostaglandin E (PGE) (rare) 2 2	Renal, lung
	Vasopressin
Cushing’s syndrome	Adrenocorticotropic hormone (ACTH)	Lung (small cell, bronchial carcinoid, adenocarcinoma, squamous), thymus, pancreatic islet, medullary thyroid carcinoma, pheochromocytoma
	Corticotropin-releasing hormone (CRH) (rare)	Pancreatic islet, carcinoid, lung, prostate
	Ectopic expression of gastric inhibitory peptide (GIP), luteinizing hormone (LH)/human chorionic gonadotropin (hCG), other G protein–coupled receptors (rare)	Macronodular adrenal hyperplasia
Less Common
	Insulin-like growth factor type II (IGF-II) Insulin (rare)
Male feminization	hCGb	Testis (embryonal, seminomas), germinomas, choriocarcinoma, lung, hepatic, pancreatic islet
	Calcitoninc Vasoactive intestinal peptide (VIP)
Rare
Oncogenic osteomalacia	Fibroblast growth factor 23 (FGF23) or phosphatonin	Hemangiopericytomas, osteoblastomas, fibromas, sarcomas, giant cell tumors, prostate, lung
	Growth hormone–releasing hormone (GHRH) Growth hormone (GH)
Hyperthyroidism	Thyroid-stimulating hormone (TSH)	Hydatidiform mole, embryonal tumors, struma ovarii
	Renin
Consumptive hypothyroidism	Type 3 deiodinase	Hepatic and other hemangiomas
	Autoimmune hormone deficiencies Thyroiditis, Graves’ disease

TABLE 98-2 Paraneoplastic Hematologic Syndromes SYNDROME Erythrocytosis Granulocytosis¶

Harrison's 22e, p.740

SYNDROME	PROTEINS	CANCERS TYPICALLY ASSOCIATED WITH SYNDROME
Erythrocytosis	Erythropoietin	Renal cancers, hepatocarcinoma, cerebellar hemangioblastomas
	G-CSF, GM-CSF, IL-6
Thrombocytosis	IL-6	Lung cancer, gastrointestinal cancer, breast cancer, ovarian cancer, lymphoma
	IL-5
Thrombophlebitis	Unknown	Lung cancer, pancreatic cancer, gastrointestinal cancer, breast cancer, genitourinary cancer, ovarian cancer, prostate cancer, lymphoma

TABLE 98-3 Khorana Risk Score for Venous Thromboembolism in Cancer Patients¶

Harrison's 22e, p.742

PATIENT CHARACTERISTICS	RISK SCORE POINTS
Site of cancer
Very high risk (stomach, pancreas)	2
High risk (lung, lymphoma, gynecologic, genitourinary excluding prostate)	1
Hemoglobin level <10 g/dL or use of red cell growth factors	1
BMI ≥35 kg/m2		1
RISK SCORE (POINTS)	RISK CATEGORY	RATES OF sVTE ACCORDING TO SCORES (%)
0	Low	0.3–0.8
	Intermediate
≥3	High	6.7–7.1