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Paraneoplastic syndromes
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- 2. Introduction Group ofclinical disorders associated with malignant diseases that are not directly related to the physical effects of the primary or metastatic tumor. The syndromes may be due to - Tumor production of substances causing distant symptoms - Depletion of normal substances - Host response to the tumor Successful treatment leads to disappearance of syndrome but many do not predictably resolve with treatment
- 3. Paraneoplastic Endocrine SyndromesSYNDROME CLINICAL PRESENTATION LABSASSOC CANCERS TREATMENT SIADH Gait disturbance, falls, hedache, nausea, fatigue, cramps, anorexia, confusion, lethargy, seizures, coma Hyponatremia: mild, sodium 130- 134 mEq/L; moderate, sodium, 125-129 mEq/L; severe, sodium <125 mEq/L; Increased urine osmolality SCLC, Mesotheliom a, Bladder, Endometrial, Prostate, Oropharynx, Thymoma, Lymphoma, Breast, GI, Adrenal Restrict fluids and encourage adequate salt and protein intake; Demeclocycline 300-600mg BD Conivaptan, 20- 40mg/d iv; Tolvaptan 10- 60mg/d oral Hyperclcemia Altered mental status, weakness, ataxia, lethargy, hypertonia, renal failure, HTN, bradycardia Mild – 10.5- 11.9mg/dl Mod- 12- 13.9mg/dl Severe->14mg/dl Low to normal PTH Breast, MM, RCC, NSCLC, Lymphoma, Ovarian, Endometrial Saline, Diuretics, Pamidronate, Zoledronate, Steroids, Calcitonin
- 4. SYNDROME CLINICAL PRESENTATIO N LABS ASSOC CANCERS TREATMENT Cushing’s Syndrome Muscle Weakness, peripheral edema,HTN, Weight gain, Centripetal fat distribution Hypkalemia, Elevated Cortisol, normal to elevated midnight serum ACTH SCLC, Bronchial Carcinoid, Thymoma, MCT, GI, Pancreas, Ovarian Ketoconazole 600- 1200mg/d, Octrotide, Aminoglutethe mide, Metyrapone, Mitotane, Etomidate, Mifepristone Hypoglycemi a Sweating, anxiety, tremors, palpitations, hunger, weakness, seizures, confusion, coma Non islet cell tumor Low glucose, low insulin, low C-peptide Insulinomas Low glucose, elevated insulin, elevated c- Mesotheliom a, sarcomas, GI, Lung Glucose, Dexamethaso ne, Prednisone, Diazoxide, Octreotide, Human GH
- 5. Paraneoplastic Hematologic Syndromes SYNDROME CLINICAL FEATURES LABSASSOC CANCERS TREATMENT Eosinophilia Dyspnea, Wheezing Hypereosino philia; Elevated IL- 2,3,5 HL, NHL, CML, ALL, Lung, GI, Thyroid, Renal, Breast Inhaled steroids, Prednisone, 1mg/kg/d orally Granulocytosis Asymptomatic Elevated Neutrophils, Elevated LAP GI, Lung, Breast, GU, Brain, HL, sarcoma Specific treatment not indicated PRCA Dyspnea, Pallor, Fatigue, Syncope Anemia, Platelets and WBC WNL Thymoma, Leukemia/Lym phoma, MDS Blood transfusions, Prednisone, Cyclosporine, Cyclophosphami de, Plasma Exchange,
- 6. DISORDERS OF CUTANEOUS DISCOLOURATIONAND DEPOSITION DISEASE DESCRIPTION MALIGNANCY Acanthosis Nigricans Gray brown symmetric velvety plaque on neck, axilla, flexor areas and anogenital region Gastric Adenocarcinoma Tripe Palms Hyperpigmented velvety thickened palms with hyper keratotic ridges Gastric, Lung Generalized Melanosis Diffuse gray brown skin pigmentation Melanoma, ACTH producing tumors Pachydermoperiostosi sa Thickening of skin, lips, ears, lids, scalp, excessive clubbing Lung Amyloidosis Macroglossia, Superficial waxy Multiple Myeloma or Waldenstrom’s
- 8. Cutaneous Manifestations of Cancer They may precede, be concurrent with, or follow the discovery of the underlying malignancy. Appropriate Systematic Evaluation A TRUE paraneoplastic process satisfies two criteria : Strong association of dermatoses with malignancy and its parallel course
- 9. Papulosquamous Eruptions DISEASE DESCRIPTIONMALIGNANCY COMMENT Bazex Disease Symmetric, psoriasiform acral hyperkeratosis SCC of Esophagus, HNC, Lung Male predominance Paget Disease Erythematous keratotic patch over genital areas Breast, Uterine, Ovarian, Prostate, Anal <3% of breast cases Erythema Gyratum Repens Advancing concentric rings of erythema Lung, Breast, Uterus, GI 80% assoc with malignancy Necrolytic Migratory Erythema Macules and Papules progressing to epidermal necrolysis Glucaganoma Clinically similar to Zn deficiency Exfoliative dermatitis Progressive erythema f/b scaling Mycosis Fungoides, HD 10-20% of all exfoliative dermatitis Acquired Ichthyosis Generalized dry, crackling skin, HD, Multiple Myeloma, Differentiate from
- 11. Renal Manifestations MembranousNephropathy – Lung, Colon, Stomach Sympt – Proteinuria, HTN, Microscopic Hematuria Immune complexesare thought to play a role Minimal Change Disease – Hodgkin’s, Pancreas, Mesothelioa FSGS – CLL, AML, T cell Lymphomas Membranoproliferative Glomerulonephritis – CLL, Burkitt’s, Hairy Cell, Melanoma
- 12. Neutrophilic Dermatoses DISEASE DESCRIPTIONMALIGNANCY COMMENT Sweet Syndrome Erythematous, painful juicy cutaneous plaques on face, neck, upper extremities AML is MC cause Hematological malignancies Responds to steroids Pyoderma Gangrenosum Painful papules, ulcers, violaceous borders and purulent exudates Multiple Myeloma, SCC, Mycosis Fungoides Responds to steroids, may be assoc with IBD, RA
- 14. Vascular Abnormalities Vasculitisobserved in 4.5 – 8% malignancies. NSCLC, SCC of esophagus, Prostate, Hematological malignancies Purpura – Thrombocytopenia, DIC, vascular injury, vasculitis Multifocal migratory thrombophlebitis - <50 yrs, GI, lung, prostate, ovarian cancer Mondor disease – Cordlike thrombophlebitis of anterior chest seen
- 15. Endocrine and Metabolic DisordersDISEASEDESCRIPTION MALIGNANCY COMMENT Systemic Nodular Panniculitis Violaceous Nodules, Polyarthralgia, Fever,Eosinophilia Adenocarcinoma Pancreas Necrolytic Migratory Erythema Eryhtema, Papules, vesicles and Pustules Glucagonoma Clears after resection of tumor Flushing Episodic reddening Carcinoids, MCT Hypertrichosis lanuginosa acquisita Rapid development of fine, long, silky hair on forehead Unknown High association with cancer Localized Amyloidosis Waxy yellow plaques and nodules Multiple Myeloma, Waldenstrom’s macroglobulinemia Assoc with Primary Systemic Amyloidosis Pruritis Lymphomas, Leukemia, Multiple Unknown Systemic Evaluation
- 17. Bullous disorders ParaneoplasticPemphigus is most frequently seen in B-cell lymphopriferative disorders in cluding lymphomas, CLL, Castleman disease, thymoma, Waldenstrom’s macroglobulinemia and Spindle cell neoplasms. Painful oral stomatitis, conjunctival ulcers and erosive skin lesions. Internal organ involvement is common with 30% patients having respiratory failure. Severe mucosal involvement and pathology reminiscent of erythema multiforme – HALLMARK OF PARANEOPLASTIC PEMPHIGUS Rx – Steroids, Cyclosporine, Mycophenolate mofetil
- 19. Collagen Vascular Diseases Dermatomyositis (DM) linked to malignancy in 25% cases. Heliotrope rash of periorbital skin, Shawl Sign, V neck erythema and Gottron Sign, proximal muscle weakness. MC associated with cancers of reproductive organs in women (MC Breast) and Lung, respiratory tract in both genders. Most frequent pattern is onset of cancer within 1 year of diagnosis of DM.
- 21. Skin Neoplasms Assocwith Internal Malignancy DISEASE DESCRIPTION MALIGNANCY HEREDITY Muir-Torre Syndrome Sebaceous Gland Neoplasm Colon, Lymphoma AD Cowden Syndrome COBBLESTONE Tongue, Fibromas Thyroid, Breast, Endometrial, RCC AD Gardner Syndrome Epidermal and sebaceous cysts, desmoid, lipomas Adenocarcinoma Bowel, Thyroid AD Peutz-Jeghers Polyps of GI and pigmentation of lips, face GI Adenocarcinoma, Pancreatic Cancer AD NF 1 Café au lait spots, neurofibromas Pheochromocytom a AD Tuberous sclerosis Angiofibromas, pigmented Neurological malignancy AD
- 22. DISEASE DESCRIPTION MALIGNANCYHEREDITY VHL Syndrome Skin ecchymoses, retinal malformation, papilloedema RCC, Pheochromocytom a AD Sturge Weber Syndrome Port wine stains in C.N V distribution Rare neurological malignancy Somatic mutation in fibronectin gene AT Telangiectasis Lymphomas, Leukemias AR Bloom Syndrome Photosensitivity, telangiectasis, butterfly erythema of face Leukemias, Lymphomas AR Chediak Higashi Syndrome Recurrent pyoderma, partial albinism Lymphomas AR Werner Syndrome Scleroderma like, premature Sarcomas, Meningiomas AR
- 23. Miscellaneous Lesions MulticentricReticulohistocytosis - Violaceous papules over joints with arthritis mutilans in 50% patients. - Ca. Pancreas, SCC Lung, Melanoma - Due to destructive effects of proteinases. Pruritis - HD, Polycythemia vera, Mycosis Fungoides
- 24. Neurological Manifestations of Cancer SYNDROME% PARANEOPLASTIC Lambert-Eaton myasthenic syndrome 60 Subacute Cerebellar Degeneration 50 Subacute Sensory Neuronopathy 20 Opsoclonus-myoclonus (children) 50 Opsoclonus-myoclonus (adults) 20 Sensory motor peripheral neuropathy 10 Encephalomyelitis 10 Dermatomyositis 10
- 25. Approach to apatient with Paraneoplastic Neurological Disease Complete history and Neurological examination MRI with and without contrast MRI and FDG-PET – Monitor response to therapy PET-CT – Most sensitive to identify occult tumors CSF Examination Effective tumor ablation either with surgery or systemic therapies is more effective then immunosuppression. Immunosuppression with steroids, plasma exchange, IvIg (frequent choice),
- 26. Limbic Encephalitis Clinicalsymptoms range from rapid onset psychotic symptoms to status epilepticus May be mistaken for Herpes Simplex Encephalitis. MRI – Mesial temporal contrast enhancement or T2 signal hyper intensities. CSF – Elevated protein, lymphocytic pleocytosis. SCLC, Testicular Cancer, Breast Cancer, HL, NHL. Treatable forms of CNS Paraneoplasms Rx – Treatment of Primary + Immunosuppression
- 27. Autonomic Neuropathy 25%patients with anti-Hu syndrome and SSN-EMN have autonomic dysfunstion Usually associated with SCLC Autonomic dysfuction may occur in patients with Myasthenia Gravis GI dysmotility is usually a core complaint with orthostatic hypotension, hypoventilation, sleep apnea and cardiac dysrhythmias. Treatment may stabilize disease but usually unable to reverse
- 28. Progressive Cerebellar Degenaration (PCD) Difficulty with walking, diplopia, vertigo, loss of dexterity, dysarthria, oscillopsia CSF – lymphocytic pleocytosis, mild elevated protein, oligoclonal bands Breast Cancer, Ovarian Cancer, Hodgkin’s Disease Antibody negative PCD may occur in conjunction with Lambert-Eaton syndrome. MC associated tumor is
- 29. Paraneoplastic Visual Loss Photoreceptor degeneration causes night blindness, photopsias, and blurred vision. Colour perception loss if cones are involved. ERG is abnormal. MC antibody – anti carcinoma associated retinal antigen antibody; target antigen is recoverin. SCLC, NSCLC, Breast Cancer Progressive vision loss with retinal pigment changes – Melanoma or Adenocarcinoma of gut Melanoma associated retinopathy
- 30. Opsoclonus-Myoclonus Disorder ofocular motility and multifocal myoclonus. Described in children with Neuroblastoma No one antigen seems to be common Anti-Ri Breast or Gynecological Cancer Paraneoplastic OM without Ri antibodies assoc with Hodgkin’s Lymphoma
- 31. Paraneoplastic MND Separatedinto three groups in a series by MSKCC 1. Anti-Hu antibodies 2. Assoc with Breast cancer 3. Assoc with underlying solid tumors Patients with HL and NHL also reported Patients present with multifocal motor weakness
- 32. Paraneoplastic Peripheral Neuropathies Subacutesensorimotor neuropathy usually presents with progressive distal, symmetric sensory loss and weakness in legs. Lung Cancer is MC associated Nerve Biopsy – Axonal injury and demyelination Can also occur in women with breast cancer. Demyelinating neuropathies may respond to therapy but axonal neuropathies respond poorly to immunosuppresion Acute polyradiculoneuropathy (APN) increased frequency with Hodgkin’s lymphoma which responds to plasmapharesis and IvIg.
- 33. Contd.. Secondary amyloidosismay also cause painful sensorimotor neuropathy in patients Waldenstrom’s – Rx is Fludarabine, Rituximab, Stem Cell Transplant Myeloma – POEMS Syndrome Painful mononeuritis multiplex – SCLC, Prostate, Endometrial, Lymphoma, RCC Inflammatory Brachial Neuritis - HL
- 34. Neuromuscular Junction Disorders Typicalmyasthenia assoc with Thymoma in 15% cases. All patients to undergo CT chest to rule out thymoma. Lambert Eaton syndrome assoc with SCLC – Proximal weakness, paresthesias, erectile dysfunction; Most patients benefit from plasmapharesis and immunosuppressants Augmentation of compound motor action potential with repetitive
- 35. Paraneoplastic Syndrome with MuscleRigidity Stiff-person syndrome - stiffness and rigidity in paraspinal and abdominal muscles - Breast, HL, Colon - Antibodies against amphiphysin or glutamic acid decarboxylase Neuromyotonia - spontaneous and continuous muscle fiber activity of peripheral origin - Myasthenia in thymoma, HL, Plasma cell dyscrasia, SCLC Peripheral nerve hyper excitability disorders
- 36. Movement Disorders Hyperkineticsyndromes predominate Chorea – SCLC, ALL, RCC, HL Parkinson’s – extremely rare; reported in a man with multiple myeloma; mechanism unclear. Hypokinetic parkinsonism like features reported in testicular seminoma Movement disorders also reported in a patient of B-cell lymphoma.