Paraneoplastic Syndrome

Question 1

PARANEOPLASTIC SYNDROME

Answer 1

Disorders that accompany benign or malignant
diseases but are not directly related to mass
effects or invasion

Question 2

common causes of paraneoplastic syndromes

Answer 2

Tumors of neuroendocrine origin, such as small
cell lung carcinoma (SCLC) and carcinoids,
produce a wide array of peptide hormones

Question 3

almost every type of malignancy has the

potential to

Answer 3

produce hormones or cytokines, or to

induce immunologic responses

Question 4

Eutropic

Answer 4

expression of a hormone from its normal

tissue of origin

Question 5

Ectopic

Answer 5

hormone production from an atypical

tissue source

Question 6

Ectopic expression is often

characterized by

Answer 6

abnormal regulation of
hormone production (e.g., defective
feedback control) and peptide
processing

Question 7

Hypercalcemia

of malignancy

Answer 7

Parathyroid
hormone-related
protein (PTHrP)

Squamous cell
(head, neck,
lung, skin)
breast, GIT

Question 8

SIADH

Answer 8

Vasopressin

Lung (squamous,
small cell), GIT,
GUT, ovary

Question 9

Cushing’s

syndrome

Answer 9

ACTH Lung (small cell,
bronchial
carcinoid,
adenocarcinoma)

Question 10

HUMORAL HYPERCALCEMIA OF MALIGNANCY (HMM) occurs in upto

Answer 10

20% of patients wtith cancer

Most common in cancers of lung, head and neck,
skin, esophagus, breast, genitourinary, multiple
myeloma, lymphomas

Question 11

PTHrP

Answer 11

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.

Question 12

Another cause of HHM

Answer 12

excess production of

1,25- dihydroxyvitamin D

Question 13

PTHrP is stimulated by

Answer 13

§ Hedgehog pathways
§ Gli transcription factors
§ TGF-ß
§ Ras oncogene
§ Loss of p53

Question 14

CLINICAL MANIFESTATION of HMM

Answer 14

• 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

Question 15

Diagnosis of HMM

Answer 15

• 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

Question 16

TREATMENT of HMM diet

Answer 16

Hypocalcemic diet (also removal of excess
calcium in medications, IVF)

Question 17

Oral phosphorus

Answer 17

(250 mg po 3-4x daily) until
serum phosphorus > 1mmol/L (>3 mg/dL)
• Saline rehydration to dilute serum calcium and
promote calciuresis

Question 18

Furosemide (loop diuretic)

Answer 18

life threatening
hypercalcemia
o Used for acute management

Question 19

Bisphosphonates

Answer 19

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

Question 20

Dialysis

Answer 20

severe hypercalcemia (if
medication is not sufficient)

Question 21

Calcitonin

Answer 21

o Calcitonin 2-8 U/kg sc every 12 hrs)

o Severe hypercalcemia

Question 22

Glucocorticoids

Answer 22

(prednisone 40-100 mg per orem in 4
divided doses) on a full stomach, for patients with;
o Lymphoma
o Multiple myeloma
o Leukemia

Question 23

ECTOPIC VASOPRESSIN: Tumor-Association SIADH Etiology

Answer 23

ectopic vasopressin production by

tumors (common cause)

Question 24

ECTOPIC VASOPRESSIN: Tumor-Association SIADH Compensatory

Answer 24

decreased thirst,
suppression of aldosterone, production of atrial
natriuretic peptide

Question 25

Examples of tumors causing SIADH are

Answer 25

Small Cell | Lung CA and carcinoids (most common)

Question 26

CLINICAL MANIFESTATIONS of SIADH

Answer 26

• Asymptomatic • Hyponatremia o Actually hyponatremia is not a clinical manifestation • Weakness, lethargy, nausea, confusion, depressed mental status, seizures Suppressed thirst mechanism o Compensatory mechanism

Question 27

DIAGNOSIS of SIADH

Answer 27

* Hyponatremia * Decreased serum osmolality * Normal or increased urine osmolality

Question 28

Fluid restriction in SIADH

Answer 28

o less than urine output plus insensible losses • Treatment of primary cancer

Question 29

Demeclocycline

Answer 29

(150-300 mg 3-4x daily) o Inhibit vasopressin action along the renal distal tubule o Slow onset of action (1-2 weeks)

Question 30

Hypertonic saline (3%) or NSS plus furosemide

Answer 30

severe hyponatremia (< 115 meq)

Question 31

• Slow Na correction (0.5-1 meq/L per hr)

Answer 31

``` 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 ```

Question 32

ECTOPIC ACTH PRODUCTION: Cushing’s Syndrome

Answer 32

10-20% of cases o If 10 patients have cancer, 1 or 2 of them will have Cushing Syndrome • Neuroendocrine tumors

Question 33

Common CS cancers

Answer 33

``` • 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. ```

Question 34

CLINICAL MANIFESTATIONS of CS

Answer 34

• 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)

Question 35

DIAGNOSIS of CS

Answer 35

``` • 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. ```

Question 36

TREATMENT of CS

Answer 36

``` 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) ```

Question 37

Tumor- Induced Hypoglycemia Excess Production of IG F -II

Answer 37

• 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.

Question 38

Central Pontine myelinosis

Answer 38

Loss of myelin in base pontine and pontine tegmentum- electrolyte disturbances- Osmotic demyelination disorder

Question 39

HEMATOLOGIC SYNDROME

Answer 39

• The elevation of granulocyte, platelet, and eosinophil counts

Question 40

In most patients with myeloproliferative disorders is caused by the proliferation of the myeloid elements due to

Answer 40

underlying disease rather | than a paraneoplastic syndrome

Question 41

The paraneoplastic hematologic syndromes in | patients with solid tumors are

Answer 41

less well characterized than the endocrine syndromes because the ectopic hormone(s) or cytokines responsible have not been identified in most of these tumors

Question 42

Erythrocytosis

Answer 42

Erythropoietin Renal Cancer, Hepatocarcinoma, Cerebellar Hemiangioblastoma

Question 43

Granulocytosis

Answer 43

G -CSF, GM -CSF, IL-6 ``` Lung Cancer, Gastrointestinal Cancer, Ovarian Cancer, Genitourinary Cancer, Hodgkin’s disease ```

Question 44

Thrombocytosis

Answer 44

IL-6 ``` Lung Cancer, Gastrointestinal Cancer, Breast Cancer, Ovarian Cancer, Lymphoma ```

Question 45

Eosinophilia

Answer 45

IL-5 Lymphoma, Leukemia, Lung Cancer

Question 46

Thrombocytophebitis

Answer 46

Unknown ``` Lung Cancer, Pancreatic Cancer, Gastrointestinal Cancer, Breast Cancer, Genitourinary Cancer, Ovarian Cancer, Prostate Cancer, Lymphoma ```