27 - Paraneoplastic Syndromes

Question 1

Paraneoplasia: Definition

Answer 1

■ Symptoms that cannot be attributed to direct tumor invasion or compression .
■ May be the first sign of malignancy
■ Occurs in up to 15% of cancer patients

Question 2

systems affected by Paraneoplastic Syndromes

Answer 2

■ Endocrine
■ Hematologic
■ Neurologic
■ Gastrointestinal
■ Rheumatologic
■ Dermatologic
■ Nephrologic

Question 3

Pathophysiology of paraneoplastic syndromes

Answer 3

■ Immune mediated
– The body may produce antibodies aimed at destroying tumor cells, these antibodies may cross-react with normal causing damage.

■ Non Immune mediated
– Tumors may produce hormones, hormone precursors, a variety of enzymes, or cytokines.

Question 4

Clinical Importance of paraneoplastic syndromes

Answer 4

■ Paraneoplastic syndromes may be the first or most prominent manifestation of a cancer
■ Course of paraneoplastic syndrome usually parallels disease
■ Metabolic or toxic effects of syndrome may constitute a more urgent hazard than underlying cancer
■ Complicates therapy of primary malignancy

Question 5

Answer 5

Given the patient’s presentation with recurrent episodes of painful swelling and erythema of his arms and legs, along with the recent discovery of a pulmonary embolus and a mass in the pancreas, the most likely etiology for his recurrent episodes of swelling is:

■ B: Paraneoplastic hypercoagulable state

The presence of a pulmonary embolus and a pancreatic mass suggests an association with a hypercoagulable state related to the malignancy.

Question 6

Hypercoagulable Syndrome in paraneoplastic syndromes

Answer 6

■ Migratory Superficial thrombophlebitis Trousseau syndrome
■ GI malignancies
– pancreas, stomach, colon
■ Procoagulant molecules released directly into bloodstream is one of many other factors involved
■ Platelets,neutrophil,monocyte, endothelial cells, tissue factor…
■ Patients develop DVT and arterial thrombosis
– manage as other DVT but usually prolonged anticoagulation

Question 7

Microangiopathy in paraneoplastic syndromes

Answer 7

■ Microangiopathic hemolytic anemias (DIC, TTP)
■ TTP most commonly seen in mucin producing malignancies such as gastric cancer
– microangiopathic hemolytic anemia, thrombocytopenia, fever, renal dysfunction, neurologic changes
■ Chemotherapy : mitomycin C, Gemcitabine
■ Distinguish TTP from DIC
– TTP has normal PTT, INR
– DIC usually no or minimal renal impairment,
CNS findings

Question 8

Hematologic paraneoplastic syndromes

Answer 8

■ Erythrocytosis : overproduction of Erytropoeitin
– RCC
– HCC
– Hemangioblatoma
– Uterine fibroids( absence of anemia with menorrhagia
– Pheochromocytoma

■ Granulocytosis
– Lung cancer, gastrointestinal , breast, renal ,
gynecological malignancies

■ Eosinophilia: Hodgkin disease

■ Pure red cell aplasia : thymoma

■ Thrombocytosis: majority of malignancies

Question 9

Answer 9

B, sometimes A and C, but mostly B

Question 10

Hyperkeratotic and proliferative dermatoses - Acanthosis Nigricans in paraneoplastic syndromes

Answer 10

Velvety, hyperpigmented skin lesion neck and axilla most commonly

Rarely associated with malignancies: most commonly gastric adenocarcinoma

Question 11

Dermatologic paraneoplastic syndromes

Answer 11

1. Hyperkeratotic and proliferative dermatoses
   Acanthosis Nigricans
   Palmoplantar keratoderma
   Leser-Trelat sign
2. Inflammatory dermatosis
   Sweet syndrome or
   Acute febrile neutrophilic dermatosis
   Erythroderma
3. Bullous dermatosis
   Paraneoplastic pemphigus
4. Hyperpigmentation
   Cushing syndrome
   Generalized dermal melanosis

Question 12

Hyperkeratotic and proliferative dermatoses - Lesar Trelat sign

Answer 12

*Rapid onset of multiple pruritic seborrheic keratoses
* can be associated with Gastrointestinal malignancies, and lymphoma.

Question 13

Hyperkeratotic and proliferative dermatoses - Palmoplantar Keratoderma

Answer 13

thickening of the skin of palms and soles associated wth squamous cell carcinoma

also known as tylosis and howel-evans syndrome

Question 14

45-year-old female presenting with dysphagia, she
reports thickening of the skin of her palms and soles.
Her father was diagnosed with metastatic
esophageal cancer last year.
■ Her skin lesion is most likely associated with, except:
■ A : squamous cell carcinoma
■ B :Autosomal recessive disease
■ C :Also known as Tylosis
■ D :Howel-Evans syndrome

Answer 14

B

Question 15

Inflammatory dermatosis in dermatologic paraneoplastic syndromes - Erythroderma

Answer 15

*Diffuse erythema of the skin usually associated with induration and scaling
* cutaneous T-cell lymphoma
* Other less commonly associated malignancies: leukemia, lung ,prostate , liver, ovaries, rectum

Question 16

Bullous dermatosis - dermatologic paraneoplastic syndromes - Paraneoplastic pemphigus

Answer 16

*Erosive painful mucositis with skin lesion resembling pemphigus or pemphigoid bullae or plaques resembling lichen planus
*NHL, CLL, Castleman disease, carcinoma

Question 17

dermatologic paraneoplastic syndromes - Heliotrope erythema

Answer 17

Question 18

dermatologic paraneoplastic syndromes - Gottron’s papules

Answer 18

Question 19

dermatologic paraneoplastic syndromes: Polymyositis/Dermatomyositis

Answer 19

■ Increased risk of malignancy in DM>PM
■ If skin changes then dermatomyositis diagnosed
– heliotrope rash, Gottron’s papules
■ Proximal muscle weakness, muscle pain,
■ Swallowing difficulties, elevated creatinine
kinase
■ Adenocarcinomas of the cervix, lung, ovaries,
pancreas, bladder, and stomach

left - heliotrope rash, right - gottron's papules

Question 20

Answer 20

The symptoms described, including cough, hemoptysis (coughing up blood), deformity of the tip of the fingers, and diffuse bone and joint pain, along with the CT scan revealing a left upper lobe mass with squamous cell carcinoma, and a bone scan showing diffuse uptake, are suggestive of hypertrophic pulmonary osteoarthropathy (HPOA).

Therefore, the most likely explanation for the symptoms described is:
c. Hypertrophic Pulmonary Osteoarthropathy (HPOA)

This condition is often associated with lung cancer, and the symptoms described align with the characteristic features of HPOA.

Question 21

Hypertrophic Osteoarthropathy

Answer 21

■ Hypertrophic Pulmonary Osteoarthropathy
– Most commonly seen in NSCLC
– Digital clubbing
– Pain over the distal third of arms, legs and adjacent joints , synovial effusions
– Periosteal new bone formation seen on X-ray but the bone scan is more sensitive in detecting the phenomenon early
– NSAIDS for pain relief
– Treat the underlying cancer

Question 22

54-year-old female brought by the EMT to the ED with
episode of diaphoresis at home followed by loss of
consciousness. She has been complaining of a 30 pound
weight loss over the past 2 months according to her family and was recently found to have a large liver lesion on recent CT scan. She was previously healthy, on no medications, she was planning to have a biopsy tomorrow. Her BP was 100/60 HR 70 temperature 97.5 F, she was unresponsive.

Your next step is to
A Order an MRI of her brain
B Check her Blood sugar
C Give naloxone
D Order EEG

Answer 22

Given the presented scenario, the patient’s history of diaphoresis, loss of consciousness, recent weight loss, and the presence of a large liver lesion on a recent CT scan suggest a potential concern for hypoglycemia, especially with the reported low blood pressure (100/60) and unresponsiveness.

Therefore, the next step would be to:
B. Check her blood sugar (BS)

This is crucial to assess for hypoglycemia, which could be a contributing factor to the symptoms described.

Question 23

paraneoplastic hypoglycemia - mechanism

Answer 23

Proposed mechanisms of paraneoplastic
hypoglycemia:
-Secretion of insulin or insulin-like factor
-Increased glucose utilization by tumor
-Inhibition of glucose release from liver

Question 24

paraneoplastic hypoglycemia - related cancers and clinical presentation

Answer 24

-Non islet cell tumor hypoglycemia NICTH
Hepatocellular carcinoma
Fibroma,carcinoid,mesenchymal tumors.
-clinical signs depend on degree and
duration of hypoglycemia
Diaphoresis, confusion, lethargy, coma

Question 25

Answer 25

Given the presented scenario, the patient's change in mental status, significant increase in urine volume, and a large lung lesion on a recent CT scan suggest a potential concern for paraneoplastic syndrome associated with a lung lesion. Therefore, the next step would be to: B. Check her calcium Paraneoplastic syndromes can sometimes lead to electrolyte imbalances, and checking calcium levels is relevant in this context.

Question 26

paraneoplastic hypercalcemia

Answer 26

Renal consequences of hypercalcemia - renal insufficiency: decreased renal blood flow and GFR -Nephrogenic diabetes insipidus Gastrointestinal symptoms: nausea, constipation anorexia Neuropsychiatric symptoms: lethargy, confusion, coma

Question 27

Hypercalcemia lab values in relevant diseases

Answer 27

Question 28

paraneoplastic hypercalcemia - mechanism

Answer 28

Mechanisms of malignancy associated hypercalcemia: ~80%-parathyroid hormone-related peptide (PTHrP) 16 kD protein with homology to PTH Rare- Ectopic PTH 1,25 dihydroxyVitamin D : Hodgkin lymphoma ~20% osteolytic metastasis -stimulation of local bone resorption at site of metastasis osteoclast activating factor: Multiple myeloma

Question 29

Answer 29

Given the presented scenario, the patient's change in mental status, cough, and weight loss, along with the CT scan revealing a large mass in the left hilum and the MRI of the brain showing no evidence of metastasis or meningeal enhancement, it is important to assess for potential metabolic abnormalities associated with the underlying condition. Therefore, the next step would be to: A. Order a comprehensive metabolic panel This can help evaluate the patient's overall metabolic status and identify any abnormalities that may be contributing to the change in mental status.

Question 30

Paraneoplastic Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Answer 30

■ In malignancy most commonly associated with SCLC – Presents in 10-45% patients with SCLC ■ low Na ( euvolemic), low serum Osm, high urine Osm >100 mOsm/kg ■ multiple causes ■ Impaired ADH regulation with 5 different patterns of ADH secretion described

Question 31

Paraneoplastic SIADH clinical presentation and assessment

Answer 31

■ May be asymptomatic – fatigue, lethargy – CNS toxicity: headache, delirium, seizures – Assessment includes history for offending medications, ■ Conditions that could cause electrolyte imbalances – volume assessment at bedside – lytes, osmolality, urine lytes/osmolality, renal function

Question 32

paraneoplastic Ectopic Hormone Production

Answer 32

Question 33

paraneoplastic ectopic ACTH

Answer 33

Question 34

Answer 34

Given the presented scenario, including the patient's history of smoking, the large mediastinal mass consistent with small cell lung cancer, and the symptoms of leg weakness, the most likely explanation for the leg weakness is a paraneoplastic neurological syndrome associated with small cell lung cancer. The findings on the EMG (post-exercise increased compound muscle action potential amplitude after repetitive low-frequency repetitive nerve stimulation) are suggestive of Lambert-Eaton myasthenic syndrome (LEMS), which is a paraneoplastic syndrome often associated with small cell lung cancer. Therefore, the likely explanation for the leg weakness is: B. Ethan Lambert Syndrome (Lambert-Eaton myasthenic syndrome)

Question 35

paraneoplastic Lambert-Eaton Myasthenic Syndrome (LEMS)

Answer 35

■ ~50% associated with cancer most associated with SCLC, occasionally lymphoma ■ Affects 3% of all SCLC ■ Proximal muscle weakness and fatigability ■ Postexercise facilitation ■ Proximal muscles weaker than distal ■ Autonomic dysfunction: dry mouth, impotence, sluggish pupillary light response ■ Ptosis, dysphagia ■ DTR often absent

Question 36

paraneoplastic Lambert-Eaton Myasthenic Syndrome (LEMS) - mechanism, findings, and treatment

Answer 36

■ Post exercise increased compound muscle action potential amplitude after repetitive low frequency repetitive nerve stimulation presence of antibody interferes with calcium flux affecting release of acetylcholine ■ Strength and DTR improve after use of muscle or voluntary contraction ■ EMG characteristic: post exercise increased compound muscle action potential amplitude after repetitive low frequency repetitive nerve stimulation, ■ Treatment: – Acetylcholinesterase Inhibitor ,IVIG, steroids, immunosuppressive therapy, plasma exchange

Question 37

paraneoplastic Myesthenia Gravis

Answer 37

-Acquired autoimmune disorder caused by circulating acetylcholine receptor antibodies -66% of patients with MG have thymic lymphoid hyperplasia, and 15% of MG patients have thymoma -Approximately 33% of patients with thymoma have MG -Thymomas presenting with MG are less aggressive, tend to have a favorable prognosis

Question 38

Neurologic paraneoplastic syndromes - overview

Answer 38

■ <1% of cancer patients develop a neurologic PNS ■ 80% detected before cancer diagnosis ■ Small cell Lung cancer 5%, lymphoma and myeloma 10% ■ Most are due to autoimmune phenomena ■ Ag expressed by tumor cells cause immune response producing onconeural Ab cross-reacts with normal neuronal antigens ■ Anti-Hu, anti-Yo. ■ 30% with PNS have no antibodies detected ■ Antibodies can be detected in patient with no neurologic illness

Question 39

neurological paraneoplastic syndromes - systems affected, diseases, and symptoms

Answer 39

■ Central Nervous system -Limbic encephalitis -Cerebellar degeneration ■ Neuromuscular Junction -Lambert-Eaton -Myasthenia gravis ■ Peripheral nervous system -Subacute sensory -Autonomic

Question 40

Cancer Cachexia (paraneoplastic)

Answer 40

"Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass” The criteria for cancer cachexia is a weight loss greater than 5 percent. -Affects 50 to 80% of cancer patients -Independent determinant of prognosis : the symptoms of anorexia, weight loss, xerostomia, and dysphagia were all predictive of decreased survival

Question 41

paraneoplastic cancer cachexia - mechanism

Answer 41

Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 are possible mediators of cancer A tumor-produced lipid-mobilizing factor (LMF) may contribute to the wasting of fat tissue ATP-ubiquitin-proteasome pathway JAK/STAT pathway

Question 42

summation of paraneoplastic syndrome considerations

Answer 42

■ Paraneoplastic syndromes may be the first or most prominent manifestation of a cancer. ■ Course of paraneoplastic syndrome usually parallels disease. ■ Metabolic or toxic effects of syndrome may constitute a more urgent hazard than underlying cancer. ■ Complicates therapy of primary malignancy

Question 43

Answer 43

Given the presented scenario, the patient's history of diaphoresis, loss of consciousness, recent weight loss, and the presence of a large liver lesion on a recent CT scan, the next step would be to assess for potential hypoglycemia, especially with the reported low blood pressure and unresponsiveness. Therefore, the next step would be: B. Check her blood sugar (BS) This is important to rule out or confirm hypoglycemia, which could be a contributing factor to the symptoms described.

Question 44

Answer 44

Given the presented scenario, the patient's change in mental status, cough, and weight loss, along with the CT scan revealing a large mass in the left hilum and the MRI of the brain showing no evidence of metastasis or meningeal enhancement, the next step would be to assess for potential metabolic abnormalities associated with the underlying condition. Therefore, the next step would be: A. Order a comprehensive metabolic panel This can help evaluate the patient's overall metabolic status and identify any abnormalities that may be contributing to the change in mental status.

Question 45

Answer 45

The presented scenario suggests that the patient has features consistent with Cushing's syndrome, which is characterized by hypertension, hyperglycemia, hypokalemia, buffalo hump, purplish striae, and diffuse hyperpigmentation. Given the history of a large lung mass and biopsy revealing small cell lung cancer, the likely cause for her symptoms is ectopic ACTH Cushing syndrome. Therefore, the cause for her hypertension, hyperglycemia, and hypokalemia is: C. Ectopic ACTH Cushing syndrome

Question 46

Answer 46

Given the presented scenario, including the patient's history of smoking, the large mediastinal mass consistent with small cell lung cancer, and the findings on EMG (post-exercise increased compound muscle action potential amplitude after repetitive low-frequency repetitive nerve stimulation), the likely explanation for the leg weakness is Lambert-Eaton myasthenic syndrome (LEMS). Therefore, the likely explanation for the leg weakness is: B. Ethan Lambert Syndrome (Lambert-Eaton myasthenic syndrome) LEMS is a paraneoplastic syndrome often associated with small cell lung cancer.

Question 47

Answer 47

Given the presented scenario, including the left upper lobe mass biopsy revealing squamous cell carcinoma, diffuse bone and joint pain, and deformity of the fingers, the most likely explanation for the symptoms is: c. Hypertrophic Pulmonary Osteoarthropathy (HPOA) HPOA is a condition associated with lung cancer, particularly non-small cell lung cancer, and it can present with digital clubbing, joint pain, and periostosis (thickening of the bones).