Para-neoplastic Syndrome HOSSAM HOSNI MASOUD PROF. OF CHEST DISEASES CAIRO UNIVERSITY

Cancer is NOT one disease The most basic classification of human cancer is the organ or body location in which the cancer arises

Deaths  Incidence 

Terminology Neoplasia Neoplasia – “new growth” Tumor – swelling caused by inflammation, now tumor = neoplasm Cancer Cancer – Latin cancer = crab, malignant tumors Oncology – Greek oncos = tumor

Terminology not invade surrounding tissue or spread to other parts of the body Benign – mass of proliferating cells not subject to normal physiological controls which can increase in size but not invade surrounding tissue or spread to other parts of the body Malignant – mass of proliferating cells not subject to normal physiological control with capacity to extend (invade) adjacent normal tissues and to spread (metastasize) to distant organ sites Neoplasias are classified into two basic types: CANCER refers to virtually all malignant neoplasias

Tumor Invasion

Lung Cancer - Malignant neoplasms are also characterized by their tendency to invade surrounding tissues. Here, the tan tissue of a lung cancer is seen to be spreading along the bronchi into the surrounding lung. The dark round areas are lymph nodes also involved by the neoplasm.

Lung Cancer - This is a squamous cell carcinoma of the lung. It is a bulky mass that extends into surrounding lung parenchyma.

A primary neoplasm is more likely to appear within an organ as a solitary mass. The presence of metastases are the best indication that a neoplasm is malignant. The original clone of cells that developed into a neoplasm may not have had the ability to metastasize, but continued proliferation of the neoplastic cells and acquisition of more genetic mutations within the neoplastic cells can give them the ability to metastasize.

Paraneoplastic syndrome (PNS) Paraneoplastic syndrome (PNS) is a constellation of signs and symptoms that are unrelated to the local effects of the primary tumor or its metastases and can present as the first sign of malignancy. 7 to 10% PNS occurs in 7 to 10% of all patients with cancer.

Cancer Cachexia Paraneoplastic Syndromes –Endocrinopathies –Neuromyopathies –Osteochondral Disorders –Vascular Phenomena –Fever –Nephrotic Syndrome

Progressive weakness, loss of appetite, anemia and profound weight loss (>20 lbs.) Often correlates with tumor size and extent of metastases Etiology includes a generalized increase in metabolism and central effects of tumor on hypothalamus Probably related to macrophage production of TNF- 

PARANEOPLASTIC SYNDROMES Symptom complexes other than cachexia that appear in patients with cancer and cannot be readily explained either by the local or distal spread of the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor. Occur in 10-15% of tumors

Extra-thoracic non metastatic manifestations (Para-neoplastic syndromes) DR. HOSSAM HOSNI

Endocrinal Nephrotic Skin Skeletal Neuro- muscular Vascular

Endocrinal Nephrotic Skin Skeletal Neuro- muscular Vascular

I- Endocrinal: 1. Hyper-calcemia: 2. Syndrome of inappropriate ADH secretion (SIDH) syndrome]: 3. Ectopic ACTH syndrome:4. Carcinoid syndrome:5. Gynecomastia:6. Somatostatinoma:7. Hypoglycaemia:8. Acromegaly:

I- Endocrinal: 1. Hyper-calcemia: – Pathogenesis: 1. Hypercalcemia is common in SqCC which produce a parathyroid like substance resulting in calcium mobilization from bone faster than the ability of the kidney to excrete. 2. Destruction of bone by osteolytic metastatic disease. DR. HOSSAM HOSNI

1. Hyper-calcemia: -Onset:  Usually developed slowly.  When it developed rapidly, it represents a medical emergency. -Clinical picture: 1. Polyuria, nocturia and thirst. If these symptoms persist, this leads to hypovolemia, dehydration and ultimately renal failure. 2. Malaise, weakness. 3. Anorexia, nausea, vomiting and constipation. 4. Mental slowing, confusion, drowsiness and psychotic behaviour and ultimately coma.

(D.D. intracranial metastasis)Management:  If the patient is terminal: o No treatment.  If the patient is not terminal: o Surgical de-bulking or removal of the tumour.

o Measures to lower calcium level: 1. Forced diuresis: 2. Sodium phosphate: Mechanism of action:  Inhibit Ca resportion from bone.  Increase tissue deposition of calcium. 3. Mithramycin: Mechanism of action:  It is a cytotoxic antibiotic and reduces serum calcium when given in a small dose.  25 mg/kg I.V. in 1 litre of dextrose over 6 hours. 4. Corticosteroids:Oral or I.V. steroids are helpful in hypercalcemia due to lymphoma or sarcoidosis. 5. Calcitonin:Alone or with steroids. 6. I.V. infusion of gallium nitrate: Most effective measure. Dose: 200 mg/m2 surface area diluted in 1 litre glucose 5%.

I- Endocrinal: 2. Syndrome of inappropriate ADH secretion (SIDH) syndrome]: – Pathogenesis : 1-Tumour elaborates ADH or arginine vasopressin. 2-Another authors suggested that the mechanism for excessive circulating ADH is that peptide responsible for this syndrome is normally metabolized in the pulmonary vascular bed and this pathway is made unwell able by the presence of the disease in lung. DR. HOSSAM HOSNI

2. Syndrome of inappropriate ADH secretion (SIDH) syndrome]: Clinical features : Common in SCLC. There is increase in plasma ADH detected by RIA. This leads to dilution hyponatremia so that the plasma Na is low in the presence of abnormal water retention resulting in a low plasma osmolarity (<260 mmol/kg water). There is continued loss of Na in urine, but at a level inappropriate for plasma Na concentration (usually mmol/L). So urine osmolarity is disproportional high being at least twice that of plasma. Osmolarity = 2 (Na+K) + glucose + urea

2. Syndrome of inappropriate ADH secretion (SIDH) syndrome]: Clinical picture :  Asymptomatic. Patient may complain of:  Anorexia, nausea, vomiting and headache.  As hyponatremia worsens: Impaired concentration, confusion, and forget fullness.  Seizures and coma may occur.

Treatment : Treatment of SCLC with chemotherapy. Water deprivation: 500 ml of saline + previous 24 hours loss. Infusion of hypertonic saline 3%. Furosemide:  mg of furosemide is given/day to promote diuresis Demeclocycline: When water deprivation is very unpleasant, an antibiotic demeclocycline is given orally. Demeclocycline is an antibiotic which compete with ADH for ADH renal tubular binding site. Dose: o 1gm/day. Contra-indication: Liver and renal insufficiency. 2. Syndrome of inappropriate ADH secretion (SIDH) syndrome]:

I- Endocrinal: 3. Ectopic ACTH syndrome: – Common in SCLC. – Investigations : Elevated serum ACTH and cortisol level. Failure of suppression by exogenous cortisol. – Treatment : Chemotherapy for SCLC. Bilateral adrenalectomy. Amino glutathamide: – Inhibit steroid biosynthesis in adrenal cortex. DR. HOSSAM HOSNI

4. Carcinoid syndrome: 5. Gynecomastia: – Usually found with large cell carcinoma and adenocarcinoma. – Pathogenesis : Due to production of HCG by tumours cells resulting in testiculate oestrogen production or Production of human placental androgen (chorionic somato- mammotrophism. – Differential Diagnosis: Drug induced gynecomastia e.g. spironolactone, cimetidine and dioxin. – Treatment : Surgical removal of the tumour. Tamoxifen (anti-oestrogen). I- Endocrinal:

6. Somatostatinoma: – Due to increased production of somatostatin (GH inhibiting factor). – Usually found with SCLC, also produced by pancreatic endocrine tumours. DR. HOSSAM HOSNI

I- Endocrinal: 7. Hypoglycaemia: – The tumour cells produce insulin like substance. – Usually found with squamous cell carcinoma. – Relieved by tumour resection. 8. Acromegaly: – Due to over production of GH DR. HOSSAM HOSNI

Endocrinal Nephrotic Skin Skeletal Neuro- muscular Vascular

1. Venous thrombosis 2. Fibrinogen deficiency 3. Anaemia 4. Esinophilia II- Vascular and hematogenous manifestations:

1. Venous thrombosis: – Migrating thrombophlebitis leading to : Pulmonary embolism. Massive gangrene of limb. Priapisms. 2.Fibrinogen deficiency: Due to: – Diffuse wide spread clotting or. – Production of fibrinolycin. DR. HOSSAM HOSNI

II- Vascular and hematogenous manifestations: 3. Anaemia: Due to: – Iron deficiency anaemia. – Haemolytic anaemia due to production of hemolycin. – Anaplastic anaemia due to bone marrow replacement. – Megaloblastic anaemia: due to over use of folic acid or B12 DR. HOSSAM HOSNI

II- Vascular and hematogenous manifestations: 4. Esinophilia: – Causes : Increase bone marrow production. Prolonged eosinophil survival time. Production of an eosinophil chemotactic factor is characterized by increase in TLC, neutrophils and eosinophils. DR. HOSSAM HOSNI

Endocrinal Nephrotic Skin Skeletal Neuro- muscular Vascular

Autonomic neuropathy. Peripheral neuropathy. Cerebellar ataxia Polymyositis /Dermatomyositis syndrome The myasthenia (Eaten-Lambert) syndrome: Transverse myelitis (acute transverse myelopathy): Progressive multifocal leukoencephalopathy (PML).

III- Neuromuscular syndrome: Autonomic neuropathy: Postural hypotension and colics. Peripheral neuropathy. Cerebellar ataxia Polymyositis /Dermatomyositis syndrome: – Proximal muscle weakness. – Pain – Tenderness. DR. HOSSAM HOSNI

III- Neuromuscular syndrome: The myasthenia (Eaten-Lambert) syndrome: – It differs from myasthenia gravis in the following: 1. Weakness in the proximal muscles particularly those of pelvic girdle. 2. Bulbar and ocular muscles are not involved. 3. Increase muscle strength temporarily with exercise. Transverse myelitis (acute transverse myelopathy): – Characterized by: Flaccid paralysis with sensory level. Loss of sphincter control. – D.D.: Spinal cord metastasis. Radiation myelopathy. DR. HOSSAM HOSNI

Progressive multifocal leukoencephalopathy (PML): – It is caused by papova virus infection in the brain of an immuno- compromised host. – Characterized by: Progressive intellectual deterioration with impaired consciousness. Motor and sensory deficits. Cortical blindness. III- Neuromuscular syndrome:

Endocrinal Nephrotic Skin Skeletal Neuro- muscular Vascular

IV- Skeletal manifestation: – 1. Clubbing of fingers. – 2. Hypertrophic osteoarthropathy (HOA). V- Skin manifestations: – 1. Erythema gyratum. – 2. Scleroderma. – 3. Dermatomyositis. – 4. Acanthus nigricans. VI- Nephrotic syndrome: Due to immune complex glomerulonephritis. DR. HOSSAM HOSNI

Paraneoplastic Syndromes Nephrotic Syndrome Excessive loss of protein in the urine –probably caused by damage to renal glomeruli by tumor antigen-antibody complexes.