Paraneoplastic Syndrome Flashcards
PARANEOPLASTIC SYNDROME
Disorders that accompany benign or malignant
diseases but are not directly related to mass
effects or invasion
common causes of paraneoplastic syndromes
Tumors of neuroendocrine origin, such as small
cell lung carcinoma (SCLC) and carcinoids,
produce a wide array of peptide hormones
almost every type of malignancy has the
potential to
produce hormones or cytokines, or to
induce immunologic responses
Eutropic
expression of a hormone from its normal
tissue of origin
Ectopic
hormone production from an atypical
tissue source
Ectopic expression is often
characterized by
abnormal regulation of
hormone production (e.g., defective
feedback control) and peptide
processing
Hypercalcemia
of malignancy
Parathyroid
hormone-related
protein (PTHrP)
Squamous cell
(head, neck,
lung, skin)
breast, GIT
SIADH
Vasopressin
Lung (squamous,
small cell), GIT,
GUT, ovary
Cushing’s
syndrome
ACTH Lung (small cell,
bronchial
carcinoid,
adenocarcinoma)
HUMORAL HYPERCALCEMIA OF MALIGNANCY (HMM) occurs in upto
20% of patients wtith cancer
Most common in cancers of lung, head and neck,
skin, esophagus, breast, genitourinary, multiple
myeloma, lymphomas
PTHrP
probably cause osteolysis and
hypercalcemia
o Can be stimulated by mutations in
oncogenes
o Structurally related to PTH and binds to the
PTH receptor, explaining the similar
biochemical features of HHM and
hyperparathyroidism
o Plays a key role in skeletal development and
regulates cellular proliferation and
differentiation in other tissues, including skin,
bone marrow, breast, and hair follicles
o Tumor-bearing tissues commonly associated
with HHM normally produce PTHrP during
development or cell renewal.
Another cause of HHM
excess production of
1,25- dihydroxyvitamin D
PTHrP is stimulated by
§ Hedgehog pathways § Gli transcription factors § TGF-ß § Ras oncogene § Loss of p53
CLINICAL MANIFESTATION of HMM
• Hypercalcemic o With a Calcium level of >3.5 mmol/L (>14 mg/dL) o Hypercalcemia is the initial presenting feature of malignancy.
• Fatigue – seen in lung metastasis
o Fatigue is a non-specific clinical
manifestation.
o Any cancer patient can manifest fatigue.
You have to couple this or look for other
symptoms.
• Mental status changes – metastasis to the brain
o Mental status is also non-specific. It does
not necessarily point to HMM alone
because mental status changes can be
secondary to brain metastasis.
- Dehydration
- Symptoms of nephrolithiasis
Diagnosis of HMM
• Sometimes patients present with paraneoplastic syndrome symptoms prior to diagnoses of a malignancy, the physician should consider malignancy as part of the differential diagnoses. • Known malignancy • Recent onset of hypercalcemia • Very high serum calcium levels o Hypercalciuria o Hyperphosphatemia • Elevated PTHrP confirms the diagnosis • PTH level suppressed • 1,25 Dihydroxyvitamin D o maybe increased in lymphoma
TREATMENT of HMM diet
Hypocalcemic diet (also removal of excess calcium in medications, IVF)
Oral phosphorus
(250 mg po 3-4x daily) until
serum phosphorus > 1mmol/L (>3 mg/dL)
• Saline rehydration to dilute serum calcium and
promote calciuresis
Furosemide (loop diuretic)
life threatening
hypercalcemia
o Used for acute management
Bisphosphonates
used for chronic treatment;
o Pamidronate 30-90 mg IV
o Zolendronate 4-8 mg IV
o Etidronate 7.5 mg/kg/day po for 3-7 days
Dialysis
severe hypercalcemia (if medication is not sufficient)
Calcitonin
o Calcitonin 2-8 U/kg sc every 12 hrs)
o Severe hypercalcemia
Glucocorticoids
(prednisone 40-100 mg per orem in 4 divided doses) on a full stomach, for patients with; o Lymphoma o Multiple myeloma o Leukemia
ECTOPIC VASOPRESSIN: Tumor-Association SIADH Etiology
ectopic vasopressin production by
tumors (common cause)
ECTOPIC VASOPRESSIN: Tumor-Association SIADH Compensatory
decreased thirst,
suppression of aldosterone, production of atrial
natriuretic peptide
Examples of tumors causing SIADH are
Small Cell
Lung CA and carcinoids (most common)
CLINICAL MANIFESTATIONS of SIADH
• Asymptomatic
• Hyponatremia
o Actually hyponatremia is not a clinical
manifestation
• Weakness, lethargy, nausea,
confusion, depressed mental status, seizures
Suppressed thirst mechanism
o Compensatory mechanism
DIAGNOSIS of SIADH
- Hyponatremia
- Decreased serum osmolality
- Normal or increased urine osmolality
Fluid restriction in SIADH
o less than urine output plus
insensible losses
• Treatment of primary cancer
Demeclocycline
(150-300 mg 3-4x daily)
o Inhibit vasopressin action along the renal distal tubule
o Slow onset of action (1-2 weeks)
Hypertonic saline (3%) or NSS plus furosemide
severe hyponatremia (< 115 meq)
• Slow Na correction (0.5-1 meq/L per hr)
to prevent central pontine myelinolysis § typically presents as quadriplegia and pseudobulbar palsy § May also identify partial forms that present as confusion, dysarthria, and/or disturbances of conjugate gaze without quadriplegia § Pathology consist of demyelination without inflammation in the base of the pons, with relative sparing of axons and nerve cells § Occasional cases present with lesions outside of the brainstem § MRI useful in establishing diagnosis
ECTOPIC ACTH PRODUCTION: Cushing’s Syndrome
10-20% of cases
o If 10 patients have cancer, 1 or 2 of them
will have Cushing Syndrome
• Neuroendocrine tumors
Common CS cancers
• Small Cell Lung CA (>50%) is the most common cause of ectopic ACTH followed by bronchial and thymic carcinoids, islet cell tumors, other carcinoids, and pheochromocytomas. • Increased expression of the proopiomelanocortin (POMC) gene.
CLINICAL MANIFESTATIONS of CS
• Less marked weight gain (centripetal fat
distribution)
• Fluid retention, hypertension, hypokalemia, metabolic alkalosis, glucose intolerance, steroid psychosis
• Increased skin pigmentation
• Marked skin fragility, easy bruising (due to increased glucocorticoids)
• Severe hypokalemia
• Depression or personality changes
• Diabetes mellitus
• Poor wound healing
• Opportunistic infections (P. carinii, mycotic)
DIAGNOSIS of CS
• Urine free cortisol levels > 2-4x normal • Plasma ACTH level > 22 pmol/L (> 100pg/mL) • High dose dexamethasone (8mg per orem) suppresses 8:00 am serum cortisol (50% decrease from baseline) in 80% of pituitary ACTH-producing adenomas BUT FAILURE TO SUPPRESS ECTOPIC ACTH (90%) o If there is suppression by giving Dexamethasone, then the problem lies with the ACTH producing adenomas. But if there is no suppression, we are dealing with ectopic ACTH in 90% of cases.
TREATMENT of CS
Measures to reduce cortisol levels are often indicated. • Ketoconazole (200-400 mg bid po) • Metyrapone (250-500 mg q 6 hrs) • Mitotane 3-6 g po in 4 divided doses • Glucocorticoids (to avoid adrenal insufficiency)
Tumor- Induced Hypoglycemia Excess Production of IG F -II
• Patients with hypoglycemia not on insulin or oral
hypoglycemic agents, might be a paraneoplastic
syndrome expression
• Mesenchymal tumors, hemangiopericytomas, hepatocellular tumors, and adrenal carcinomas produce excessive amounts of insulin
-like growth factors type II (IGF-II) precursor, which binds weakly
to insulin receptors and strongly to IGF-I receptors, leading to insulin-like actions.
Central Pontine myelinosis
Loss of myelin in base pontine and pontine tegmentum-
electrolyte disturbances- Osmotic demyelination disorder
HEMATOLOGIC SYNDROME
• The elevation of
granulocyte, platelet, and
eosinophil counts
In most patients with myeloproliferative disorders
is caused by the proliferation of the myeloid
elements due to
underlying disease rather
than a paraneoplastic syndrome
The paraneoplastic hematologic syndromes in
patients with solid tumors are
less well
characterized than the endocrine syndromes
because the ectopic hormone(s) or cytokines
responsible have not been identified in most of
these tumors
Erythrocytosis
Erythropoietin
Renal Cancer,
Hepatocarcinoma,
Cerebellar
Hemiangioblastoma
Granulocytosis
G -CSF, GM -CSF, IL-6
Lung Cancer, Gastrointestinal Cancer, Ovarian Cancer, Genitourinary Cancer, Hodgkin’s disease
Thrombocytosis
IL-6
Lung Cancer, Gastrointestinal Cancer, Breast Cancer, Ovarian Cancer, Lymphoma
Eosinophilia
IL-5
Lymphoma,
Leukemia, Lung
Cancer
Thrombocytophebitis
Unknown
Lung Cancer, Pancreatic Cancer, Gastrointestinal Cancer, Breast Cancer, Genitourinary Cancer, Ovarian Cancer, Prostate Cancer, Lymphoma
