Paraneoplastic Syndromes

Paraneoplastic syndromes are a heterogeneous group of disorders caused by an abnormal immune response to a neoplasm. The substances produced are not due to the direct effect of the tumor, such as metastasis, mass effect, or invasion. Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview, cytokines, and other substances are generated and affect multiple organ systems. About 10% of cases of cancer are affected by paraneoplastic syndromes. The common cancers that present with paraneoplastic syndromes include cancer of the lung, breast, ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries, kidney, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, and stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and lymphomas.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Paraneoplastic syndromes are clinical syndromes that arise from an immune response to a neoplasm, producing substances that are not a direct effect of the tumor, such as metastasis, mass effect, or invasion of the tumor.

Epidemiology

  • Occurs in around 10% of cancer patients
  • Men and women are equally affected.
  • May occur with any malignancy

Etiology

There are 2 primary mechanisms:

  • Immunologic response to the presence of a neoplasm in the body leading to:
    • Cytotoxic T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells attacking tumor antigens and similar antigens in nonneoplastic tissue
    • Production of onconeural or paraneoplastic antibodies targeting an antigen (e.g., acetylcholine receptors (AChRs))
  • Hormones, peptides, or cytokines produced by the tumor (e.g., Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion)

Classification

Table: Paraneoplastic endocrinopathies
Clinical syndrome Associated neoplasia Pathogenesis
Cushing syndrome
  • Small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
  • Pancreatic carcinoma
  • Thymoma
  • Medullary thyroid carcinoma
  • Carcinoid tumor
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
ACTH or ACTH-like substance production
SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
  • Small cell carcinoma
  • Intracranial neoplasms
Antidiuretic hormone (ADH) or vasopressin production
Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
  • Squamous cell lung carcinoma
  • Renal carcinoma
  • Breast carcinoma
  • Head and neck cancers
  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Ovarian carcinoma
Parathyroid hormone–related hormone (PTHrP)
Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
  • Ovarian carcinoma
  • Fibrosarcoma
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Other mesenchymal sarcomas
Insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin or insulin-like substance
Table: Neurologic paraneoplastic syndromes
Clinical syndrome Associated neoplasia Pathogenesis
Lambert-Eaton myasthenic syndrome Lambert-Eaton Myasthenic Syndrome Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma. Lambert-Eaton myasthenic syndrome affects the voltage-gated calcium channels at the presynaptic membrane. Lambert-Eaton Myasthenic Syndrome SCLC Autoantibodies to presynaptic Ca2+ channels (anti–voltage-gated calcium channel)
Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis
  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis
  • Non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
Anti-AChR antibody
Paraneoplastic cerebellar degeneration
  • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
  • Lung cancer
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Lymphoma
Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins against antigens in cerebellar Purkinje cells (anti-Purkinje cell antibody)
Paraneoplastic encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis/encephalomyelitis (e.g., limbic encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis)
  • Small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
  • Seminoma
  • Thymoma
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Anti-Hu or antineuronal nuclear antibody (ANNA)-1
Table: Hematologic paraneoplastic syndromes
Clinical syndrome Associated neoplasia Pathogenesis
Hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state or venous thrombosis (Trousseau syndrome)
  • Pancreatic cancer
  • Bronchogenic carcinoma
  • Gastric carcinoma
Mucin release that activates clotting factors
Nonbacterial thrombotic endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis (sterile thrombi) Mucin-secreting adenocarcinoma Thromboplastin-like substance (hypercoagulable state)
Polycythemia
  • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Cerebellar hemangioma
  • Hemangioblastoma Hemangioblastoma Hemangioblastomas are vascular neoplasms of the CNS. Hemangioblastomas are rare and are often associated with von Hippel-Lindau disease (VHL). The most common presentation is a headache and, depending on the size and location of the tumor, patients may present with sensory deficits and motor weakness. Hemangioblastoma
  • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
Erythropoietin production
DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation
  • Acute promyelocytic leukemia
  • Prostatic carcinoma
  • Other adenocarcinoma
Tumor products that activate clotting
Table: Mucocutaneous paraneoplastic syndromes
Clinical syndrome Associated neoplasia Pathogenesis
Acanthosis nigricans
  • Gastric carcinoma
  • Adenocarcinomas in other sites
  • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
Secretion of epidermal growth factor
Leser-Trélat sign GI adenocarcinomas Hypersensitivity to growth factor
Dermatomyositis
  • Ovarian, cervical, uterine cancers
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Lung cancer
  • Gastric, colorectal, and pancreatic cancers
Immunologic response to proteins expressed by the tumor; antibodies deposit where skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and muscle antigens are found
Necrolytic migratory erythema Glucagonoma Glucagonoma A glucagonoma is a glucagon-secreting neuroendocrine tumor that originates from the β-cells in the pancreatic islets. Most glucagonomas are malignant, and many of them are part of the autosomal dominant condition known as multiple endocrine neoplasia syndrome type 1 (MEN 1). Elevated levels of glucagon lead to increased gluconeogenesis and glycogenolysis. Glucagonoma Unknown
Sweet syndrome
  • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
  • Myelodysplastic syndrome
Immune reaction to tumor(s) and other antigens
Table: Other paraneoplastic syndromes
Clinical syndrome Associated neoplasia Pathogenesis
Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome (membranous nephropathy)
  • Lung cancer
  • Colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix cancer
  • Prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
  • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Tumor antigen, immune complex deposition
Hypertrophic osteoarthropathy and fingers clubbing Lung cancer Fibrovascular proliferation

Paraneoplastic Endocrinopathies

Cushing syndrome

  • Cancer association: 
    • Small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer (most common)
    • Pancreatic carcinoma 
    • Thymoma
    • Medullary thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer
    • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
    • Carcinoid tumors Carcinoid tumors Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome
  • Ectopic ACTH: approximately 20% of cases of Cushing syndrome
  • ↑ Ectopic ACTH → ↑ cortisol (hypercortisolism)
  • Clinical presentation may include:
    • Fluid retention
    • Hypertension
    • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
    • Glucose intolerance 
    • Hyperpigmentation
  • Physical examination findings include moon facies, truncal obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, and gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia, among others. 
  • Tests:
    • ↑ ACTH
    • High-dose dexamethasone:
      • Suppresses morning cortisol
      • Fails to suppress ACTH from an ectopic source
  • Management:
    • Medical therapy:
      • Ketoconazole
      • Metyrapone
      • Mitotane
    • Treatment of underlying malignancy (usually not enough to reduce cortisol levels)

Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia

  • Cancer association: 
    • Lung cancer
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer 
    • Renal carcinoma
    • Head and neck cancers
    • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma 
    • Lymphoma 
  • Increased calcium is from tumors producing PTHrP → humoral hypercalcemia of malignancy (HHM)
  • Other sources of ↑ calcium in malignancy:
    • From tumors with ectopic parathyroid hormone (PTH) secretion (e.g., small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer)
    • Osteolytic activity of skeletal metastases
  • Presentation:
    • Asymptomatic and elevated calcium found on laboratory tests
    • Marked elevation may present with:
      • Fatigue
      • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
      • Nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis
      • Psychosis or mental status changes
  • Tests:
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia, hypercalciuria, hypophosphatemia
    • HHM:
      • Suppressed PTH
      • Elevated PTHrP
      • Normal to low 1,25-dihydroxyvitamin D (PTHrP has less tendency to stimulate 1,25-dihydroxyvitamin D production)
  • Management (depends on severity) includes:
    • Hydration
    • Bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates
    • Calcitonin
    • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of Dialysis (last resort)

SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

  • Cancer association: 
    • Lung cancers 
    • Intracranial malignancies
  • Presentation:
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia noted on laboratory tests
    • Signs and symptoms can include:
      • Lethargy 
      • Confusion
      • Seizure
      • Depressed mental status
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests showing:
    • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
    • Reduced serum osmolality
  • Management:
    • Fluid restriction
    • Demeclocycline
    • Vasopressin antagonists (conivaptan, tolvaptan)
    • Severe hyponatremia: hypertonic solution infusion

Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia

  • Cancer association:
    • Ovarian carcinoma
    • Fibrosarcoma
    • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
    • Other mesenchymal sarcomas
  • Multiple mechanisms of non–islet cell tumor hypoglycemia:
    • ↑ Utilization of glucose
    • ↓ Hepatic release of glucose due to insulin-like growth factor (IGF)-2 (or in rare cases, IGF-1)
  • Presentation:
    • Lethargy
    • Somnolence
    • Diaphoresis
    • Confusion
    • Coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:
    • ↓ Glucose, insulin, proinsulin, C peptide, beta-hydroxybutyrate
    • Sulfonylurea/meglitinide screening
    • Confirmed hypoglycemia, insulin level, C peptide and beta-hydroxybutyrate → imaging studies to look for tumor
  • Management:
    • Emergency hypoglycemia: SC or IM glucagon
    • Treatment of underlying cancer
    • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids

Neurologic Paraneoplastic Syndromes

Lambert Eaton myasthenic syndrome ( LEMS LEMS Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma. Lambert-Eaton myasthenic syndrome affects the voltage-gated calcium channels at the presynaptic membrane. Lambert-Eaton Myasthenic Syndrome)

  • Cancer association: small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
  • About 50% associated with malignancy
  • Associated with:
    • Reduced acetylcholine (ACh) release 
    • Development of antibodies:
      • Target the P/Q-type voltage-gated calcium channel (VGCC)
      • VGCC facilitates normal calcium flux, allowing ACh release.
    • VGCCs are expressed on the surface membrane of small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer cells.
  • Presentation:
    • Progressive proximal muscle weakness (without muscle atrophy)
    • Reduced or absent deep tendon reflexes
    • Ptosis (most common cranial nerve finding)
    • Symptoms improve with time after repetitive movement (which differs from myasthenia gravis).
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:
    • Motor and sensory nerve conduction studies
    • Repetitive nerve stimulation (RNS)
    • Needle electromyography (EMG)
    • Anti-P/Q-type VGCC antibody testing 
  • Management:
    • Treat underlying malignancy
    • Amifampridine
    • Low-dose guanidine 
    • Pyridostigmine (last option, owing to serious adverse effects)
    • Refractory weakness:
      • IV immune globulin
      • Prednisone

Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis

  • Cancer association: 
    • Thymomas
    • Non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
  • Due to antibody-mediated destruction of AChRs at the neuromuscular junction
  • Presentation: 
    • Fatigue, weakness
    • Ptosis, diplopia
    • Dysphagia
    • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
    • Unlike LEMS LEMS Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma. Lambert-Eaton myasthenic syndrome affects the voltage-gated calcium channels at the presynaptic membrane. Lambert-Eaton Myasthenic Syndrome, symptoms do not improve with repeated movement.
  • Diagnosis:
    • Autoantibodies against the acetylcholine receptor (AChR-Abs)
    • RNS studies 
    • Single-fiber electromyography (SFEMG)
  • Management:
    • Treat underlying malignancy.
    • Acetylcholinesterase inhibitors
    • Immunosuppressive agents (e.g., glucocorticoids)
    • Plasmapheresis
    • IV immunoglobulin
    • Monoclonal antibodies

Paraneoplastic cerebellar degeneration

  • Cancer association: 
    • Lung cancer
    • Ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Lymphoma
  • Multiple associated autoantibodies:
    • Anti-Yo or Purkinje cell antibody (PCA): most common
    • Anti-Ri (ANNA-2)
    • Anti-Tr (Delta/Notch-like epidermal growth factor-related receptor)
    • Anti-VGCC (also associated with LEMS LEMS Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder affecting the neuromuscular junction and has a strong association with small cell lung carcinoma. Lambert-Eaton myasthenic syndrome affects the voltage-gated calcium channels at the presynaptic membrane. Lambert-Eaton Myasthenic Syndrome)
  • Presents with features of oscillopsia, diplopia, dysarthria, and ataxia
  • A diagnosis of exclusion:
    • Not all biomarkers have testing (serum and CSF) available.
    • If cancer is not found initially, search for occult malignancy.
  • Management:
    • Cancer treatment
    • Immunotherapy (though overall prognosis is poor)

Paraneoplastic encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis/encephalomyelitis

  • Cancer association:
    • Small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer
    • Seminoma
    • Thymoma
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Some related antibodies:
    • Anti-Hu (ANNA-1): encephalomyelitis, limbic and brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
    • Anti-Ri (ANNA-2): brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
    • Anti-N-methyl-D-aspartate (NMDA) receptor: encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis associated with ovarian teratoma
  • Manifest as:
    • Limbic encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis, including: 
      • Mood/behavioral changes
      • Seizures
      • Cognitive dysfunction
    • Brain stem encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis, including: 
      • Extraocular movement deficits
      • Dysphagia
      • Nystagmus
      • Opsoclonus
      • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo
      • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Encephalomyelitis: Symptoms vary with the several regions of the nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System involved.
    • Anti-NMDA receptor encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
      • Psychiatric manifestations (anxiety, delusions, hallucinations)
      • Memory deficits
      • Seizures
      • Dyskinesias
      • Language dysfunction
      • Autonomic instability
  • Diagnostic approach:
    • Entails review of clinical features, cancer risk factors, and concomitant lab and imaging findings
    • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are not always found in paraneoplastic encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis.
  • Management: treatment of tumor and immunotherapy

Hematologic Paraneoplastic Syndromes

Trousseau syndrome

  • Migratory thrombophlebitis
  • Cancer association: 
    • Pancreatic carcinoma
    • Gastric carcinoma
    • Bronchogenic carcinoma
  • Associated with procoagulant activity:
    • Tissue factor: forms a complex with factor VII → coagulation cascade
    • Cancer procoagulant: protease in malignant tissue that activates factor X
    • Activators in normal cells such as P-selectin (found in platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets and endothelial cells): ↑ expression of tissue factor
  • Presentation: recurrent, migratory superficial thrombophlebitis
  • Evaluation:
    • Rule out coexisting deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis
    • Comprehensive tests searching for malignancy (imaging, laboratory tests)
  • Management:
    • Supportive (control pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, reduce inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation)
    • Anticoagulation
Trousseau syndrome

Trousseau syndrome:
Thrombophlebitis migrans in a man with pancreatic adenocarcinoma
Tender erythematous rash on the medial aspect of the right forearm Forearm The forearm is the region of the upper limb between the elbow and the wrist. The term "forearm" is used in anatomy to distinguish this area from the arm, a term that is commonly used to describe the entire upper limb. The forearm consists of 2 long bones (the radius and the ulna), the interosseous membrane, and multiple arteries, nerves, and muscles. Forearm and left lower limb

Image: “(A) and (B) Tender erythematous rash” by Thayalasekaran S, Liddicoat H, Wood E. License: CC BY 3.0

Nonbacterial thrombotic endocarditis

  • Marantic endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis, verrucous endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
  • Cancer association: mucin-secreting adenocarcinoma (advanced cancer in 80% of cases)
  • Also seen in systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus)
  • ↑ Coagulable state leads to vegetations made up of fibrin and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets:
    • Deposits are easily dislodged → emboli
    • May lead to strokes and valvular stenosis/regurgitation
  • Presentation:
    • Fever may or may not be present.
    • Often diagnosed when embolic event has occurred:
      • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: abdominal/flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Kidney: hematuria
      • Skin: rash
      • Extremities: digital ischemia
      • CNS: stroke
      • Heart: MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:
    • Comprehensive labs, including blood cultures
    • Rule out SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus, DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation
    • Imaging, including echocardiogram
  • Management:
    • Treat underlying malignancy.
    • Anticoagulation
    • Surgery in select cases
Vegetations of the aortic valve at autopsy

Vegetations of the aortic valve at autopsy:
a: The macroscopic appearance of the aortic valve shows 2 vegetations of 4 mm and 5 mm in diameter.
b: Histologic evaluation shows that the vegetations consist of fibrin without bacterial colonies, consistent with noninfective endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis.

Image: “Newly recognized cerebral infarctions on postmortem imaging: a report of three cases with systemic infectious disease” by BMC Medical Imaging. License: CC BY 4.0

Polycythemia

  • Cancer association: 
    • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma 
    • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
    • Hemangioblastoma Hemangioblastoma Hemangioblastomas are vascular neoplasms of the CNS. Hemangioblastomas are rare and are often associated with von Hippel-Lindau disease (VHL). The most common presentation is a headache and, depending on the size and location of the tumor, patients may present with sensory deficits and motor weakness. Hemangioblastoma
    • Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
    • Cerebellar hemangioma
  • Secondary to autonomous erythropoietin production
  • Presentation:
    • Hyperviscosity syndrome
    • Headache
    • Plethoric facies
    • Hypertension
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests
    • ↑ Hemoglobin, hematocrit
    • ↑ Erythropoietin without secondary causes
  • Management: 
    • Treat underlying malignancy
    • Risk-based treatment (partly depends on thrombotic risk)

DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation

  • Cancer association:
    • Acute promyelocytic leukemia
    • Prostatic adenocarcinoma
    • Other adenocarcinomas (e.g., colon, stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach)
  • Tumor cells produce tissue factor and other procoagulants.
  • Presentation can vary:
    • Microangiopathic hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
    • Dyspnea, respiratory failure
    • Convulsions
    • Renal failure
    • Circulatory failure
  • Diagnosis is based on:
    • Clinical features and history
    • Laboratory tests, including:
      • ↓ Fibrinogen
      • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
      • ↑ Prothrombin time and aPTT
      • ↑ D-dimer
      • Hemolytic anemia in the peripheral smear
  • Management:
    • Treat underlying cause (malignancy)
    • Hemodynamic support
    • Blood component replacement

Mucocutaneous and Other Paraneoplastic Syndromes

Acanthosis nigricans

  • Cancer association:
    • Gastric carcinoma (most common)
    • Others:
      • Adenocarcinoma of the lung, ovary, kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys, pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, breast
      • Hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
  • Activation of epidermal growth factor receptor (EGFR) contributes to acanthosis nigricans associated with malignancy.
  • Skin lesions:
    • Hyperpigmented plaques: can be velvety or verrucous
    • Can occur before the diagnosis of malignancy
    • Appear even in nonobese (as opposed to acanthosis nigricans associated with insulin resistance)
  • Can occur with tripe palm: 
    • Also called acanthosis palmaris and acquired pachydermatoglyphia
    • Thickened palm, with accentuated palmar ridges, similar to mucosa of the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
  • Diagnosis is clinical, ↑ suspicion in cases of:
    •  Rapid progression 
    • Palm and sole involvement
    • Mucous membrane involvement
  • Management: treatment of malignancy may lead to resolution.
Acanthosis nigricans

Acanthosis nigricans:
Dark discoloration that usually develops in body folds or creases, here affecting the right axilla Axilla The axilla is a pyramid-shaped space located between the upper thorax and the arm. The axilla has a base, an apex, and 4 walls (anterior, medial, lateral, posterior). The base of the pyramid is made up of the axillary skin. The apex is the axillary inlet, located between the 1st rib, superior border of the scapula, and clavicle. Axilla and Brachial Plexus. Skin becomes thick owing to hyperkeratosis and may appear velvety.

Image: “Acanthosis nigricans before starting chemotherapy” by Kubicka-Wołkowska J, Dębska-Szmich S, Lisik-Habib M, Noweta M, Potemski P. License: CC BY 4.0

Leser-Trélat Sign

  • Cancer association: GI adenocarcinomas (e.g., stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach, colorectal)
  • Growth factors and cytokines from the tumor likely contribute to the rapid appearance of the lesions.
  • Presentation: seborrheic keratoses (multiple)
    • Raised skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions with “stuck on” appearance
    • Well-demarcated with verrucous surface
    • Painless, pruritic
  • Diagnosis is clinical.
  • Management: Treat the underlying malignancy.
Leser-trélat sign

Leser-Trélat sign:
Seborrheic keratoses on the back of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand that appeared and increased in size in a short period

Image: “Seborrheic keratoses on the back of the hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand” by Case Reports in Medicine. License: CC BY 4.0

Dermatomyositis

  • Cancer association:
    • Ovarian, cervical, uterine cancers
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
    • Lung cancer
    • Gastric, colorectal, and pancreatic cancers
  • Oncoproteins expressed by tumors → inflammatory immune response → autoantibodies deposit in sites with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and muscle antigens
  • Clinical findings:
    • Gottron papules: erythematous or violaceous papules on the bony prominences of the hands
    • Heliotrope eruption: violaceous patches on the periorbital skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, occasionally with eyelid edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Facial erythema (involves nasolabial folds)
    • Photodistributed poikiloderma: shawl sign presents on the upper back and the V sign presents on the neck and upper chest.
    • Ragged cuticles
    • Inflammatory myopathy: symmetric, progressive, proximal weakness
  • Management: 
    • Treat underlying malignancy
    • Corticosteroids
Dermatomyositis

Dermatomyositis:
Clinical features of dermatomyositis include:
(a): Heliotrope erythema
(b): Palmar erythema
(c): Periungual erythema
(d): Flagellate erythema

Image: “Cutaneous features of DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus” by Norrenberg S, Gangji V, Del Marmol V, Soyfoo MS. License: CC BY 3.0

Necrolytic migratory erythema

  • Cancer association: glucagonoma
  • Findings:
    • Weeping or erythematous eruption
    • Found in acral sites, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin flexures, or body orifices
  • Diagnosis:
    • Skin findings
    • Evidence of elevated glucagon and glucagon-secreting pancreatic tumor
  • Management:
    • Treat the malignancy.
    • Octreotide
Necrolytic migratory erythema

Necrolytic migratory erythema:
A: Extremely erythematous skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin eruptions on the pretibial area
B: Biopsy showing a zone of necrolysis and vacuolated keratinocytes

Image: “Necrolytic migratory erythema” by Castro, P.G., et al. License: CC BY 2.0

Sweet syndrome

  • Acute febrile neutrophilic dermatoses
  • Cancer association:
    • AML AML Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the uncontrolled proliferation of myeloid precursor cells. Seen predominantly in older adults, AML includes an accumulation of myeloblasts and a replacement of normal marrow by malignant cells, which leads to impaired hematopoiesis. Acute Myeloid Leukemia
    • Myelodysplastic syndrome
  • Arises from hypersensitivity reaction to tumor and antigens → ↑ cytokines → neutrophil activation and infiltration
  • Manifests as:
    • Tender, swollen papules or plaques or nodules
    • Can be erythematous or violaceous
  • Diagnosis: 
    • Typical appearance
    • Histopathology showing neutrophilic infiltration without leukocytoclastic vasculitis
  • Management:
    • Treatment of malignancy
    • Prednisone
Sweet syndrome

Sweet syndrome: painful, erythematous, pseudovascular plaques of acute febrile neutrophilic dermatosis
a: Erythematous plaque on the left shoulder
b: Nodular lesion on the arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm
c: Erythematous plaque on a finger

Image: “Sweet’s syndrome–a comprehensive review of an acute febrile neutrophilic dermatosis” by Cohen PR. License: CC BY 2.0

Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome

  • Membranous nephropathy
  • Cancer association:
    • Lung cancer
    • Colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix cancer
    • Prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer
    • Breast cancer Breast cancer Breast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
  • Antigens, which can be nonrenal, are identified in the immune complex deposition.
  • Clinical and diagnostic findings:
    • Proteinuria
    • Increased creatinine
    • Biopsy shows diffuse thickening of the capillary walls of the glomeruli
  • Management:
    • Treat the underlying malignancy
    • Progressive renal function decline: immunotherapy

Hypertrophic osteoarthropathy

  • Cancer association: lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer (commonly non–small cell lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer)
  • Arises from the stimulation and release of vascular endothelial growth factor (VEGF) brought on by abnormal vascularization and chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation:
    • ↑ Angiogenesis
    • ↑ Stimulation of osteoblasts and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones formation
    • ↑ Edema
  • Presentation:
    • New bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones formation, particularly at the distal ends of long bones, metatarsals, metacarpals, and proximal phalanges (tender on palpation)
    • Arthritis
    • Clubbing of digits
  • Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests:
    • No serologic tests
    • Check chest x-ray to rule out lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer.
  • Management: treat the underlying malignancy.
Hypertrophic osteoarthropathy

Hypertrophic osteoarthropathy:
A: Large right hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand with edematous swelling
B: Periungual erythema and clubbing

Image: “Hypertrophic osteoarthropathy” by Kanen BL, Loffeld RJ. License: CC BY 2.0

References

  1. Bauer, K. (2021). Pathogenesis of the hypercoagulable state associated with malignancy. UpToDate. Retrieved September 15, 2021, from https://www.uptodate.com/contents/pathogenesis-of-the-hypercoagulable-state-associated-with-malignancy
  2. Bauer, K. (2021). Nonbacterial thrombotic endocarditis. UpToDate. Retrieved September 16, 2021, from https://www.uptodate.com/contents/nonbacterial-thrombotic-endocarditis
  3. Dalmau, J., Rosenfeld, M.R. (2020). Overview of paraneoplastic syndromes of the nervous system. UpToDate. Retrieved September 15, 2021, from https://www.uptodate.com/contents/overview-of-paraneoplastic-syndromes-of-the-nervous-system
  4. Dalmau, J., Rosenfeld, M.R. (2021). Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle. UpToDate. Retrieved September 15, 2021, from https://www.uptodate.com/contents/paraneoplastic-syndromes-affecting-spinal-cord-peripheral-nerve-and-muscle 
  5. Jinna S, Khoury J. (2021). Migratory thrombophlebitis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK547702/
  6. Krugh, M., Vaidya, P.N. (2021). Osteoarthropathy hypertrophic. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK540968/
  7. Merola, J. (2021). Sweet syndrome (acute febrile neutrophilic dermatoses): pathogenesis, clinical manifestations and diagnosis. UpToDate. Retrieved September 16, 2021, from https://www.uptodate.com/contents/sweet-syndrome-acute-febrile-neutrophilic-dermatosis-pathogenesis-clinical-manifestations-and-diagnosis
  8. Ofori, E., Ramai, D., Ona, M., Reddy, M. (2017). Paraneoplastic dermatomyositis syndrome presenting as dysphagia. Gastroenterology Research 10:251–254. https://doi.org/10.14740/gr841w
  9. Owen, C. (2021). Cutaneous manifestations of internal malignancy. UpToDate. Retrieved September 16, 2021, from https://www.uptodate.com/contents/cutaneous-manifestations-of-internal-malignancy
  10. Pelosof, L. C., Gerber, D. E. (2010). Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clinic Proceedings 85:838–854. https://doi.org/10.4065/mcp.2010.0099
  11. Rees, J.H. (2004). Paraneoplastic syndromes: when to suspect, how to confirm, and how to manage. Journal of Neurology. Neurosurgery & Psychiatry 75:2. https://doi.org/10.1136/jnnp.2004.040378
  12. Tefferi, A. (2021). Diagnostic approach to the patient with polycythemia. UpToDate. Retrieved September 16, 2021, from https://www.uptodate.com/contents/diagnostic-approach-to-the-patient-with-polycythemia
  13. Thapa, B., Ramphul, K. (2021). Paraneoplastic syndromes. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK507890/
  14. Vella, A. (2021). Nonislet cell tumor hypoglycemia. UpToDate. Retrieved September 16, 2021, from https://www.uptodate.com/contents/nonislet-cell-tumor-hypoglycemia

USMLE™ is a joint program of the Federation of State Medical Boards (FSMB®) and National Board of Medical Examiners (NBME®). MCAT is a registered trademark of the Association of American Medical Colleges (AAMC). NCLEX®, NCLEX-RN®, and NCLEX-PN® are registered trademarks of the National Council of State Boards of Nursing, Inc (NCSBN®). None of the trademark holders are endorsed by nor affiliated with Lecturio.

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details