Paraneoplastic Syndromes

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 Tumor Inflammation, such as metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis, mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast effect, or invasion of the tumor Tumor Inflammation.

Epidemiology

• Occurs in around 10% of cancer patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Men and women are equally affected.
• May occur with any malignancy Malignancy Hemothorax

Etiology

There are 2 primary mechanisms:

• Immunologic response to the presence of a neoplasm in the body leading to:
  • Cytotoxic Cytotoxic Parvovirus B19 T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions attacking tumor Tumor Inflammation antigens and similar antigens in nonneoplastic tissue
  • Production of onconeural or paraneoplastic 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: Types and Functions targeting an antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination (e.g., acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (AChRs))
• 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 and Types, peptides, or cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response produced by the tumor Tumor Inflammation (e.g., Cushing syndrome due to ectopic adrenocorticotropic hormone Adrenocorticotropic hormone An anterior pituitary hormone that stimulates the adrenal cortex and its production of corticosteroids. Acth is a 39-amino acid polypeptide of which the n-terminal 24-amino acid segment is identical in all species and contains the adrenocorticotropic activity. Upon further tissue-specific processing, acth can yield alpha-msh and corticotropin-like intermediate lobe peptide (clip). Adrenal Hormones (ACTH) secretion Secretion Coagulation Studies)

Classification

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 Thymoma A neoplasm originating from thymic tissue, usually benign, and frequently encapsulated. Although it is occasionally invasive, metastases are extremely rare. It consists of any type of thymic epithelial cell as well as lymphocytes that are usually abundant. Malignant lymphomas that involve the thymus, e.g., lymphosarcoma, Hodgkin’s disease (previously termed granulomatous thymoma), should not be regarded as thymoma. Primary Lymphatic Organs
  • Medullary thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy 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 Cortisol Glucocorticoids ( hypercortisolism Hypercortisolism Cushing’s syndrome or hypercortisolism is a disorder characterized by features resulting from chronic exposure to excess glucocorticoids. Cushing’s syndrome may be exogenous, due to chronic glucocorticoid intake, or endogenous, due to increased adrenal secretion of cortisol or adrenocorticotropic hormone (ACTH) production from the pituitary gland or ectopic sources. Cushing Syndrome)
• Clinical presentation may include:
  • Fluid retention
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance intolerance 
  • Hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi
• 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 Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics:
    • Suppresses morning cortisol Cortisol Glucocorticoids
    • Fails to suppress ACTH from an ectopic source
• Management:
  • Medical therapy:
    • Ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles
    • Metyrapone Metyrapone An inhibitor of the enzyme steroid 11-beta-monooxygenase. It is used as a test of the feedback hypothalamic-pituitary mechanism in the diagnosis of Cushing syndrome. Adrenal Insufficiency and Addison Disease
    • Mitotane
  • Treatment of underlying malignancy Malignancy Hemothorax (usually not enough to reduce cortisol Cortisol Glucocorticoids 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 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
  • 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 Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess cancers
  • Multiple myeloma 
  • Lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum 
• Increased calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes is from tumors producing PTHrP PTHrP Hypercalcemia → humoral 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 of malignancy Malignancy Hemothorax (HHM)
• Other sources of ↑ calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes in malignancy Malignancy Hemothorax:
  • From tumors with ectopic parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy hormone (PTH) secretion Secretion Coagulation Studies (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 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes found on laboratory tests
  • Marked elevation may present with:
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • 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 Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis, hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome
  • HHM:
    • Suppressed PTH
    • Elevated PTHrP PTHrP Hypercalcemia
    • Normal to low 1,25-dihydroxyvitamin D ( PTHrP PTHrP Hypercalcemia 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 Calcitonin A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. Other Antiresorptive Drugs
  • 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). Peritoneal Dialysis and Hemodialysis (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 Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia 
    • 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 Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation
• Management:
  • Fluid restriction
  • Demeclocycline Demeclocycline A tetracycline analog having a 7-chloro and a 6-methyl. Because it is excreted more slowly than tetracycline, it maintains effective blood levels for longer periods of time. Tetracyclines
  • Vasopressin antagonists ( conivaptan Conivaptan Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), tolvaptan Tolvaptan A benzazepine derivative and selective vasopressin v2 receptor antagonist that is used to treat euvolemic and hypervolemic hyponatremia. It is also used in the treatment of rapidly progressing autosomal dominant polycystic kidney disease to slow the rate of cyst development and renal insufficiency. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH))
  • Severe 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: hypertonic Hypertonic Solutions that have a greater osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation 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 Islet cell Pancreatic Neuroendocrine Tumors (PanNETs) tumor Tumor Inflammation 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:
  • ↑ Utilization of glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • ↓ Hepatic release of glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance due to insulin-like growth factor (IGF)-2 (or in rare cases, IGF-1)
• Presentation:
  • Lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • 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 Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance, 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, proinsulin, C peptide, beta-hydroxybutyrate Beta-hydroxybutyrate Butyric acid substituted in the beta or 3 position. It is one of the ketone bodies produced in the liver. Ketone Body Metabolism
  • Sulfonylurea/meglitinide screening Screening Preoperative Care
  • Confirmed 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, 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 level, C peptide and beta-hydroxybutyrate Beta-hydroxybutyrate Butyric acid substituted in the beta or 3 position. It is one of the ketone bodies produced in the liver. Ketone Body Metabolism → imaging studies to look for tumor Tumor Inflammation
• Management:
  • Emergency 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: SC or IM glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions
  • 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 Malignancy Hemothorax
• Associated with:
  • Reduced acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS ( ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS) release 
  • Development of 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: Types and Functions:
    • Target the P/Q-type voltage-gated calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel (VGCC)
    • VGCC facilitates normal calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes flux, allowing ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS 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 Proximal Muscle Weakness Lambert-Eaton Myasthenic Syndrome (without muscle atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation)
  • Reduced or absent deep tendon reflexes Deep Tendon Reflexes Neurological Examination
  • Ptosis Ptosis Cranial Nerve Palsies (most common cranial nerve finding)
  • Symptoms improve with time after repetitive movement (which differs from 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).
• 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 Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology and sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology nerve conduction studies
  • Repetitive nerve stimulation Repetitive Nerve Stimulation Lambert-Eaton Myasthenic Syndrome (RNS)
  • Needle electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (EMG)
  • Anti-P/Q-type VGCC antibody testing 
• Management:
  • Treat underlying malignancy Malignancy Hemothorax
  • Amifampridine Amifampridine 4-aminopyridine derivative that acts as a potassium channel blocker to increase release of acetylcholine from nerve terminals. It is used in the treatment of congenital myasthenic syndromes. Lambert-Eaton Myasthenic Syndrome
  • Low-dose guanidine 
  • Pyridostigmine Pyridostigmine A cholinesterase inhibitor with a slightly longer duration of action than neostigmine. It is used in the treatment of myasthenia gravis and to reverse the actions of muscle relaxants. Cholinomimetic Drugs (last option, owing to serious adverse effects)
  • Refractory weakness:
    • IV immune globulin
    • Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants

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 Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction
• Presentation:
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, weakness
  • Ptosis Ptosis Cranial Nerve Palsies, diplopia Diplopia A visual symptom in which a single object is perceived by the visual cortex as two objects rather than one. Disorders associated with this condition include refractive errors; strabismus; oculomotor nerve diseases; trochlear nerve diseases; abducens nerve diseases; and diseases of the brain stem and occipital lobe. Myasthenia Gravis
  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. 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 Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques against the acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (AChR-Abs)
  • RNS studies 
  • Single-fiber electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (SFEMG)
• Management:
  • Treat underlying malignancy Malignancy Hemothorax.
  • Acetylcholinesterase inhibitors
  • Immunosuppressive agents (e.g., 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)
  • Plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome
  • IV immunoglobulin Iv Immunoglobulin Dermatomyositis
  • Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus

Paraneoplastic cerebellar degeneration

• 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
  • 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 Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum
• Multiple associated autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques:
  • Anti-Yo or Purkinje cell antibody (PCA): most common
  • Anti-Ri (ANNA-2)
  • Anti-Tr (Delta/Notch-like epidermal growth factor-related receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors)
  • 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 Diplopia A visual symptom in which a single object is perceived by the visual cortex as two objects rather than one. Disorders associated with this condition include refractive errors; strabismus; oculomotor nerve diseases; trochlear nerve diseases; abducens nerve diseases; and diseases of the brain stem and occipital lobe. Myasthenia Gravis, dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease, and ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
• A diagnosis of exclusion:
  • Not all biomarkers have testing (serum and CSF) available.
  • If cancer is not found initially, search for occult malignancy Malignancy Hemothorax.
• Management:
  • Cancer treatment
  • Immunotherapy (though overall prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas 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 Seminoma A radiosensitive, malignant neoplasm of the testis, thought to be derived from primordial germ cells of the sexually undifferentiated embryonic gonad. There are three variants: classical (typical), the most common type; anaplastic; and spermatocytic. The classical seminoma is composed of fairly well differentiated sheets or cords of uniform polygonal or round cells (seminoma cells), each cell having abundant clear cytoplasm, distinct cell membranes, a centrally placed round nucleus, and one or more nucleoli. In the female, a grossly and histologically identical neoplasm, known as dysgerminoma, occurs. Testicular Cancer
  • Thymoma Thymoma A neoplasm originating from thymic tissue, usually benign, and frequently encapsulated. Although it is occasionally invasive, metastases are extremely rare. It consists of any type of thymic epithelial cell as well as lymphocytes that are usually abundant. Malignant lymphomas that involve the thymus, e.g., lymphosarcoma, Hodgkin’s disease (previously termed granulomatous thymoma), should not be regarded as thymoma. Primary Lymphatic Organs
  • 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 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: Types and Functions:
  • Anti-Hu (ANNA-1): encephalomyelitis, limbic and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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 Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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 Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors: 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 Teratoma A true neoplasm composed of a number of different types of tissue, none of which is native to the area in which it occurs. It is composed of tissues that are derived from three germinal layers, the endoderm, mesoderm, and ectoderm. They are classified histologically as mature (benign) or immature (malignant). Imaging of the Mediastinum
• 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Cognitive dysfunction
  • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification 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 Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
    • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
    • 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. Nervous System: Anatomy, Structure, and Classification involved.
  • Anti-NMDA receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 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 Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, delusions, hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia)
    • Memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment deficits
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Dyskinesias
    • Language dysfunction
    • Autonomic instability Autonomic instability Rabies Virus
• 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: Types and Functions 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 Tumor Inflammation and immunotherapy

Hematologic Paraneoplastic Syndromes

Trousseau syndrome Trousseau syndrome Exocrine Pancreatic Cancer

• Migratory thrombophlebitis
• Cancer association:
  • Pancreatic carcinoma
  • Gastric carcinoma
  • Bronchogenic carcinoma
• Associated with procoagulant activity:
  • Tissue factor: forms a complex with factor VII Factor VII Heat- and storage-stable plasma protein that is activated by tissue thromboplastin to form factor viia in the extrinsic pathway of blood coagulation. The activated form then catalyzes the activation of factor X to factor Xa. Hemostasis → coagulation cascade Coagulation cascade The coagulation cascade is a series of reactions that ultimately generates a strong, cross-linked fibrin clot. Hemostasis
  • Cancer procoagulant: protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS in malignant tissue that activates factor X Factor X Storage-stable glycoprotein blood coagulation factor that can be activated to factor Xa by both the intrinsic and extrinsic pathways. A deficiency of factor X, sometimes called stuart-prower factor deficiency, may lead to a systemic coagulation disorder. Hemostasis
  • Activators in normal cells such as P-selectin P-selectin Cell adhesion molecule and cd antigen that mediates the adhesion of neutrophils and monocytes to activated platelets and endothelial cells. Tumor Necrosis Factor (TNF) (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: Histology and endothelial cells): ↑ expression of tissue factor
• Presentation: recurrent, migratory superficial thrombophlebitis Superficial Thrombophlebitis Thromboangiitis Obliterans (Buerger’s Disease)
• Evaluation:
  • Rule out coexisting deep vein thrombosis Thrombosis Formation and development of a thrombus or blood clot in the blood vessel. Epidemic Typhus
  • Comprehensive tests searching for malignancy Malignancy Hemothorax (imaging, laboratory tests)
• Management:
  • Supportive (control pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, 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 Anticoagulation Pulmonary Hypertension Drugs

Nonbacterial thrombotic endocarditis Thrombotic endocarditis Endocarditis

• Marantic endocarditis Marantic endocarditis 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 Fibrin A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. Rapidly Progressive Glomerulonephritis 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: Histology:
  • Deposits are easily dislodged → emboli
  • May lead to strokes and valvular stenosis Stenosis Hypoplastic Left Heart Syndrome (HLHS)/ regurgitation Regurgitation Gastroesophageal Reflux Disease (GERD)
• Presentation:
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. 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: Anatomy: abdominal/ flank pain Flank pain Pain emanating from below the ribs and above the ilium. Renal Cell Carcinoma
    • Kidney: hematuria Hematuria Presence of blood in the urine. Renal Cell Carcinoma
    • 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. Skin: Structure and Functions: rash Rash Rocky Mountain Spotted Fever
    • Extremities: digital ischemia Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage
    • 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 Echocardiogram Transposition of the Great Vessels
• Management:
  • Treat underlying malignancy Malignancy Hemothorax.
  • Anticoagulation Anticoagulation Pulmonary Hypertension Drugs
  • Surgery in select cases

Polycythemia Polycythemia An increase in the total red cell mass of the blood. Renal Cell Carcinoma

• 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 Hemangioma A vascular anomaly due to proliferation of blood vessels that forms a tumor-like mass. The common types involve capillaries and veins. It can occur anywhere in the body but is most frequently noticed in the skin and subcutaneous tissue. Imaging of the Liver and Biliary Tract
• Secondary to autonomous erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology production
• Presentation:
  • Hyperviscosity Hyperviscosity Hypercoagulable States syndrome
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Plethoric facies
  • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Hematocrit The volume of packed red blood cells in a blood specimen. The volume is measured by centrifugation in a tube with graduated markings, or with automated blood cell counters. It is an indicator of erythrocyte status in disease. For example, anemia shows a low value; polycythemia, a high value. Neonatal Polycythemia
  • ↑ Erythropoietin Erythropoietin Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. Erythrocytes: Histology without secondary causes
• Management:
  • Treat underlying malignancy Malignancy Hemothorax
  • 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 Acute promyelocytic leukemia An acute myeloid leukemia in which abnormal promyelocytes predominate. It is frequently associated with disseminated intravascular coagulation. Acute Myeloid Leukemia
  • Prostatic adenocarcinoma
  • Other adenocarcinomas (e.g., 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: Anatomy, 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: Anatomy)
• Tumor Tumor Inflammation cells produce tissue factor and other procoagulants.
• Presentation can vary:
  • Microangiopathic hemolytic anemia Microangiopathic Hemolytic Anemia Hemolytic Uremic Syndrome
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, 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
  • Convulsions Convulsions Seizures
  • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome
  • Circulatory failure
• Diagnosis is based on:
  • Clinical features and history
  • Laboratory tests, including:
    • ↓ Fibrinogen Fibrinogen Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides a and b, the proteolytic action of other enzymes yields different fibrinogen degradation products. Hemostasis
    • 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 Types 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 Prothrombin time Clotting time of plasma recalcified in the presence of excess tissue thromboplastin. Factors measured are fibrinogen; prothrombin; factor V; factor VII; and factor X. Hemostasis and aPTT
    • ↑ D-dimer D-dimer Deep Vein Thrombosis
    • 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 in the peripheral smear
• Management:
  • Treat underlying cause ( malignancy Malignancy Hemothorax)
  • Hemodynamic support
  • Blood component replacement

Mucocutaneous and Other Paraneoplastic Syndromes

Acanthosis nigricans Acanthosis nigricans A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. Diabetes Mellitus

• 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: Anatomy, 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: Anatomy, 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 Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (EGFR) contributes to acanthosis nigricans Acanthosis nigricans A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. Diabetes Mellitus associated with malignancy Malignancy Hemothorax.
• 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. Skin: Structure and Functions lesions:
  • Hyperpigmented plaques: can be velvety or verrucous
  • Can occur before the diagnosis of malignancy Malignancy Hemothorax
  • Appear even in nonobese (as opposed to acanthosis nigricans Acanthosis nigricans A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. Diabetes Mellitus associated with insulin resistance Insulin resistance Diminished effectiveness of insulin in lowering blood sugar levels: requiring the use of 200 units or more of insulin per day to prevent hyperglycemia or ketosis. Diabetes Mellitus)
• 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: Anatomy
• Diagnosis is clinical, ↑ suspicion in cases of:
  •  Rapid progression 
  • Palm and sole involvement
  • Mucous membrane Mucous membrane An epithelium with mucus-secreting cells, such as goblet cells. It forms the lining of many body cavities, such as the digestive tract, the respiratory tract, and the reproductive tract. Mucosa, rich in blood and lymph vessels, comprises an inner epithelium, a middle layer (lamina propria) of loose connective tissue, and an outer layer (muscularis mucosae) of smooth muscle cells that separates the mucosa from submucosa. Barrett Esophagus involvement
• Management: treatment of malignancy Malignancy Hemothorax may lead to resolution.

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: Anatomy, colorectal)
• Growth factors and cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response from the tumor Tumor Inflammation 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. Skin: Structure and Functions lesions with “stuck on” appearance
  • Well-demarcated with verrucous surface
  • Painless, pruritic
• Diagnosis is clinical.
• Management: Treat the underlying malignancy Malignancy Hemothorax.

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 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
  • Gastric, colorectal, and pancreatic cancers
• Oncoproteins expressed by tumors → inflammatory immune response → autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques 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. Skin: Structure and Functions and muscle antigens
• Clinical findings:
  • Gottron papules: erythematous or violaceous papules on the bony prominences of the hands
  • Heliotrope eruption: violaceous patches Patches Vitiligo on the periorbital Periorbital Orbital and Preseptal Cellulitis 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. Skin: Structure and Functions, 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 Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion (involves nasolabial folds)
  • Photodistributed poikiloderma Photodistributed Poikiloderma Dermatomyositis: shawl sign Shawl Sign Dermatomyositis presents on the upper back and the V sign presents on the neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess and upper chest.
  • Ragged cuticles
  • Inflammatory myopathy Myopathy Dermatomyositis: symmetric, progressive, proximal weakness
• Management:
  • Treat underlying malignancy Malignancy Hemothorax
  • Corticosteroids Corticosteroids Chorioretinitis

Necrolytic migratory erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion

• Cancer association: 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
• 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. Skin: Structure and Functions flexures, or body orifices
• Diagnosis:
  • 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. Skin: Structure and Functions findings
  • Evidence of elevated glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions and glucagon-secreting pancreatic tumor Tumor Inflammation
• Management:
  • Treat the malignancy Malignancy Hemothorax.
  • Octreotide Octreotide A potent, long-acting synthetic somatostatin octapeptide analog that inhibits secretion of growth hormone and is used to treat hormone-secreting tumors; diabetes mellitus; hypotension, orthostatic; hyperinsulinism; hypergastrinemia; and small bowel fistula. Antidiarrheal Drugs

Sweet syndrome Sweet syndrome Condition characterized by large, rapidly extending, erythematous, tender plaques on the upper body usually accompanied by fever and dermal infiltration of neutrophilic leukocytes. It occurs mostly in middle-aged women, is often preceded by an upper respiratory infection, and clinically resembles erythema multiforme. Sweet syndrome is associated with leukemia. Hematopoietic Growth Factors

• 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 Tumor Inflammation and antigens → ↑ cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response → neutrophil activation Neutrophil activation The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cell-surface receptors on the neutrophil. Ehrlichiosis and Anaplasmosis 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 Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus
• Management:
  • Treatment of malignancy Malignancy Hemothorax
  • Prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants

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 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
  • 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: Anatomy cancer
  • Prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. 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 Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children
  • Increased creatinine
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma shows diffuse thickening of the capillary walls of the glomeruli
• Management:
  • Treat the underlying malignancy Malignancy Hemothorax
  • 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 Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing (VEGF) brought on by abnormal vascularization and chronic inflammation Chronic Inflammation Inflammation:
  • ↑ Angiogenesis Angiogenesis Bartonella
  • ↑ Stimulation of osteoblasts Osteoblasts Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. Bones: Development and Ossification 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. Bones: Structure and Types formation
  • ↑ 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
• 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. Bones: Structure and Types formation, particularly at the distal ends of long bones Long bones Length greater than width. Bones: Structure and Types, metatarsals, metacarpals Metacarpals The five cylindrical bones of the metacarpus, articulating with the carpal bones proximally and the phalanges of fingers distally. Wrist Joint: Anatomy, and proximal phalanges Phalanges Bones that make up the skeleton of the fingers, consisting of two for the thumb, and three for each of the other fingers. Hand: Anatomy (tender on palpation Palpation Application of fingers with light pressure to the surface of the body to determine consistency of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. Dermatologic Examination)
  • Arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
  • Clubbing Clubbing Cardiovascular Examination 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 X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests 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 Malignancy Hemothorax.