PARA NEOPLASTIC SYNDROMES
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PARA NEOPLASTIC SYNDROMES PARA NEOPLASTIC SYNDROMES Presentation Transcript

  • GOOD AFTERNOON.... DISORDERS PARANEOPLASTIC -Dr. ANINDYA MUKHERJEE ( 1 st year PGT, Dept of RADIATION ONCOLOGY,MCH)
  • PARANEOPLASTIC SYNDROMES DEFN: It refers to a group of clinical disorders associated with malignant diseases that are not directly related to the physical effects of the primary or metastatic diseases RELEVANCE: Almost every tumour has the potential to produce PNS Prevalence of PNS indicate they are more common than they are generally appreciated Their clinical features are often overlooked in context of malignancy and its treatment.
  • POSSIBLE EXPLANATIONS......  Tumor production of substances that directly or indirectly cause distant symptoms  Depletion of normal substances that leads to PNS  Host response to the tumour that results in the syndrome
  • ENDOCRINE PNS Refers to ectopic expression from an atypical tissue source,mostly neoplastic cells characterized by EXCESS PRODUCTION And ABNORMAL REGULATION & PEPTIDE PROCESSING
  • OVERVIEW...
  • ECTOPIC ACTH SYNDROME INCIDENCE: 5 to 10% cases of spontaneous Cushing's Syndrome a/w prolonged and inappropriate high exposure to glucocorticoids produced by ACTH secreting non pituitary tumours. ETIOLOGY: 2) 3) 4) 5) 6) 1) Small cell lung cancer(>50%) Thymic carcinoid (15%) Islet tumors (10%) Bronchial carcinoids (10%) Other carcinoids (5%) Pheochromocytoma(2%)
  • GENETICS: 1)The 3rd exon of PROPIOMELANOCORTIN(POMC) gene(on 2p23)encodes the mature ACTH peptide sequence. Incomplete processing of POMC fragments in nonpituitary tumours releases POMC fragments of reduced biological activity Thus,inspite of high frequency of POMC in ectopic sources,only a small proportion of cases develop overt excess ACTH features.
  • GENETICS contd... 2)CRH is produced by pancreatic islet cell tumors,SCLC, MTC,carcinoids and prostrate cancer.High CRH levels can induce pituitary corticotrope hyperplasia and Cushing's Syndrome.Also paracrine increment of ACTH production. 3)ACTH-indepedent Cushing's syndrome: Ectopic expression of G-protein-coupled receptors in adrenal glands,eg-GIP which stimulates adrenal growth and glucocorticoids production.
  • CLINICAL FEATURES: 1)Less marked wt. gain and centripetal fat redistribu -tion(d/t relatively short exposure to high glucocorticoids and Cachexia) 2)Metabolic: 3)Skin: Fluid retention & hypertension Hypokalemia Metabolic Alkalosis Glucose intolerance Steroid psychosis(occaisional) Pigmentation d/t MSH stimulation. Fragility and increased bruising.
  • DIAGNOSIS: 1)Urinary free cortisol levels 2-4 tms normal + plasma ACTH >100pg/ml. 2) Non responsive to High dose(8mg PO) glucorticoid suppresion(as measured by 8 AM serum cortisol)[ excp Bronchial & other carcinoids show suppresion) 3)After CRH stimulation, a 3:1 petrosal sinus: peripheral ACTH Source strongly negates the possibilty of ectopic. 4)Imaging(with guided biopsies)/Octreotide receptor scintigraphy.
  • TREATMENT:  Surgical Excision- mainstay of treatment Adrenal enzyme inhibitors for non resectable cases with features of hypercortisolism- ketoconazole,metyrapone,etomidate.  Cytotoxic chemotherapy for primary malignancy + Octreotide suppression of ACTH release    Desperate measures- B/L adrenalectomy f/b life long glucocorticoids and mineralocorticoid replacement Palliative- Laparoscopic adrenalectomy/medical adrenalectomy with mitotane
  • ONCOGENOUS OSTEOMALACIA C/F- bone pain, phosphaturia, renal glycosuria, hypophosphatemia,normocalcemia, normal PTH levels,low 1,25(OH)D3, increased Alphos   Main culprit- FGF-23(phosphaturic) Associated malignancies- CA lung,Multiple Myeloma, CA prostrate  Treatment- tumour removal /Large doses of Vit D and phosphate 
  • TUMOR INDUCED HYPOGLYCEMIA Mesenchymal tumors,hamangiopericytoma,hepatocellular tumors,etc [NOT INSULINOMAS]     Agent implicted- IGF-II precursor(on 11p15-loss of imprinting) Diagnosis- Features of fasting hypoglycemia in presence of suppressed insulin levels.Increased IGF-II levels in tumor,but decreased serum levels. Rx-tumor removal,frequent meals & IV glucose,Glucagon/Glucocorticoids,avoid hypoglycemic drugs
  • ECTOPIC VASOPRESSIN:TUMOR ASSOCIATED SIADH     Most commonly-SCLC And Carcinoids May be d/t activation of vasopressin gene within tumour C/F- mostly asymptomatic,hyponatremia often detected on biochem-profile. Otherwiseweakness,confusion,lethargy,seizu res.
  • TUMOR ASSOCIATED SIADH Contd..  DIAGNOSIS- Hypo-osmotic hyponatremia - Urine osmolarity > 100mOsm/L - Euvolemia - Absence of conditions that stimulate ADH Secretion like vol.contractn,vomitting, Adrenal dysfunction & hypothyroidism. - Other causes of SIADH including drugs are excluded.
  • TUMOR ASSOCIATED SIADH Contd..  TREATMENT-Gradual correction is the basic tenet. (unless of course,there is seizures/altered Mentation) -Treatment of underlying malignancy is Primary but not done first hand(slow response) -Fluid restriction to less than urine output + insensible losses.
  • TUMOR ASSOCIATED SIADH Contd.. - DEMECLOCYCLINE-150-300 mg P/O tid. CONIVAPTAN(V2 receptor antagonist) - Severe hyponatremia(<115meq/L) or mental Status changes requires hypertonic(3%) Saline + frusemide - Rate of Na+ correction should be 0.5-1 Meq/L/hr to prevent CPM & rapid fuid shifts
  • NEUROLOGICAL PNS....    Chiefly mediated by immune responses triggered by onconeuronal antigens. Pathogenesis-Extensive CD4+ and CD8+T cells infiltration(both humoral and cellular immune mechanisms implicated),microglial activation,gliosis & variable neuronal loss. Others- Inflammatory neuropathies/myopathies.
  • OVERVIEW....
  • RELEVANT ANTIBODIES AND TUMORS
  • ANTIBODIES Contd....
  • APPROACH TO SUCH A PATIENT... KEYPONTS TO REMEMBER..    Symptoms often appear before the presence of tumor is detected. Rapid downhill course Prompt tumour control improves the neurological outcome
  • PND OF THE CNS AND DORSAL GANGLIA PROBLEMS FACED:    Biopsy difficult to obtain.. No specific radiological features(MRI can only rule out direct spread of cancer,esp metastatic or leptomeningeal) Anti neuronal antiobodies detection: - 60%-70% of CNS PNDs - <20% of PNS PNDs  CSF profile – non specific(mild pleocytosis,incresed protein conc,variable ologoclonal bands)
  • PND OF THE NERVE AND MUSCLE  Diagnosis made on clinical,electrophysiologic and pathologic grounds Viz :  CECT chest mandatory for LEMS If negative PET indicated Or  Serum & urine immunofixation studies required for Peripheral neuropathy of unknown origin, Or  Detection of monoclonal gammopathy should require a search for B/plasma cell malignancy
  • SUBACUTE SENSORY NEUROPATHY AND ENCEPHALOMYELONEURITIS     Multiple sites in CNS and PNS are affected. Anti-Hu antibodies detected when a/w SCLC.High titres correlate with symptoms.Anti-Hu Abs are a marker for systemic immune suppression of tumor progression. Clinical spectrum- Pure sensory neuropathy,a/w other autoimmune disorders(mostly) Rx- Tumor removal,immune suppression.
  • LIMBIC ENCEPHALITIS    Extreme heterogenity d/t autoAbs against novel Ag targets. C/F- Rapid onset psychosis, focal epilepsies, status epilepticus. Diagnosis- Mesial temporal T2-MRI contrast enhancement.Hypermetabolic temporal lobe on FDGPET,CSF lymphocytosis.
  • FLAIR-MRI of a pt with limbic encephalitis and LGI1 Ab
  • Limbic encephalitis contd... CANCER ASSOCIATED ANTIBODY SCLC ANTI-Hu,ANNA-3, PCA2 TESTICULAR CANCER Ma-2 BREAST CANCER Anti-Ri THYMOMA Anti-synaptic vesicle LYMPHOMA Not specified WITHOUT ASSOCIATED CANCER Antibodies aginst voltage gated K+ channels
  • Limbic encephalitis contd....treatment  One of the most treatable PNS.  Anti-Ma2 a/w good prognosis.Orchiectomy effective.  IMMUNOSUPPRESSION RESPONSIVE LE: -Corticosteroids and IgG,Rituximab -Immunotherapy against LE a/w anti-NMDA rec Ab or Anti-AMPA/GABAb rec Ab.  LE in young female often leads to an ovarian teratoma.
  • AUTONOMIC NEUROPATHY     Pure form rare. 25% of pts with anti-Hu syndrome and SSSEMN have autonomic dysfuction.SCLC mostly associated. Rarely may be the first manifestation of an occult malignancy. C/F- Bladder/Bowel dysfunction,Postural hypotension,Cardiac dysrhythmia Abs against – Nm receptor,Nn receptor,synaptophysin,CV2,VLKC
  • PROGRESSIVE CEREBELLAR DEGENERATION    C/F-difficulty in walking,dysarthria,oscillopsia,loss of dexterity,etc. IMAGING- Diffuse cerebellar atrophy(No contrast enhancing lesion or lesions with mass effect.) Commonest Ab - Anti -Yo(a/w ovarian/breast CA) - Anti- Tr(a/w Hodgkin's ds-Treatment Monitoring+ Good Prognostic marker) - Anti-CRMP(a/w Thymoma) - Anti-Hu & Anti-Zic-4( a/w SCLC)
  • PROGRESSIVE CEREBELLAR DEGENERATION Contd...  Antibody negative PCD- Eaton Lambert syndrome( a/w SCLC)
  • PARANEOPLASTIC VISUAL LOSS     Rare entity – mostly d/t retinal disorders. C/F- Night blindness,Photopsia,Loss of colour perception.Relentlessly progressive. Culprit – Anti-Recoverin( a calcium binding retinal antigen) Antibody. A/w- SCLC, Melanoma, AdenoCA, Lymphoma,Nasopharyngeal CA,etc
  • PARANEOPLASTIC VISUAL LOSS Contd..   DIAGNOSIS- Optic disc pallor,Retinal arteriolar attenuation, Abnormal ERGs, Delayed VERs TREATMENT - Steroids ,Plasmapheresis, IV IgG,Treatment of underlying malignancy.
  • NEUROMUSCULAR JUNCTION DISORDERS  MYASTHENIA GRAVIS: A/w- Thymoma Cause- Ab against contractile proteins  LAMBER EATON MYASTHENIC SYNDROME: A/w- SCLC C/F- Proximal weakness+ Bulbar symptoms Cause- Ab against Voltage gated Ca+ channels EP nerve testing-Augmentation of compound Action potentials on repititive stimulation
  • OTHERS..  PARANEOPLASTIC PERIPHERAL NEUROPATHIES  OPSOCLONUS AND MYOCLONUS  PARANEOPLASTIC MOTOR NEURON DISORDERS  PARANEOPLASTIC MUSCLE RIGIDITY
  • CUTANEOUS PNS Two conditions to be satisfied:  Strong association of dermatosis with malignancy And  Parallel course.
  • PAPULOSQUAMOUS DISORDERS     Acrokeratosis Praneoplastica /Bazex Ds Symetric psoriasiform hyperkeratosis SCC oesophagus,head and neck,lung Male predominance
  • PAPULOSQUAMOUS DISORDERS Contd..     PADGET'S DISEASE Erythematous keratotic patch over nipple,perianal area CABreast,uterine,ovarin,prostrate, anal Direct extension of underlyiing malignancy
  • PAPULOSQUAMOUS DISORDERS Contd..  NECROLYTIC MIGRATORY ERYTHEMA Macules & Papules progressing to epidermal necrolysis  Glucagonoma   Clinically similar to Zn deficiency;somatostatin beneficial
  • PAPULOSQUAMOUS DISORDERS Contd..   ERYTHEMA GYRATUM REPENS Advanced concentric rings of erythema with trailing scales  CA-Lung,breast,uterus,GIT  Unlnown cause
  • PAPULOSQUAMOUS DISORDERS Contd..    DERMATOMYOSITIS Erythema or telengiectasia of knuckes,chest,periorbital regions Misc causes- Lymphoma predominantly.
  • PAPULOSQUAMOUS DISORDERS Contd..    PALMAR HYPERKERATOSIS/TYLOSI S CA-oesophagus(Howel-Evan's syndrome)breast,ovary Punctate form-a/w CA breast
  • DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION    ACANTHOSIS NIGRICANS Gray-brown symetric velvety plaques on neck,axillae,flexor areas.(TRIPE PALMS) Predominantly GastricAdenoCA.
  • DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION     PACHYDERMOPERIOSTOSI S Thickening of skin,lips,ears,lids,forehead,etc A/w- Excessive sweating,clubbing Lung abcess & many benign tumors
  • DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION     GENERALISED MELANOSIS Diffuse gray brown skin pigmentation A/w- Melanoma,ACTH producing tumors Cause- melanin deposits in skin
  • NEUTROPHILIC DERMATOSES    SWEET SYNDROME Fever+neutrophilia+erythemat ous painful juicy plaques on upper half A/w-AML, Myelodysplastic syndrome(probably hypersensitivity)
  • NEUTROPHILIC DERMATOSES    PYODERMA GANGRENOSUM Painful papules,ulcers,violaceous borders&purulent exudates A/w-Multiple myeloma,SCCs,Cutaneous Tcell Hodgkin's lymphoma
  • BULLOUS DISORDERS     PARNEOPLASTIC PEMPHIGUS A/W-B-cell lymphoma,CLL,Castleman's ds,Waldenstrom's macroglobulinemia. Painful oral stomatitis,conjunctival ulcers Resp failure- 30% of cases
  • SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES
  • SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES
  • SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES
  • RENAL MANIFESTATIONS >>>GLOMERULAR DISEASES:  Pathologic entities- Mostly, membranous nephropathy. Others-MPGN,MCD,RPGN,FSGS.    A/w: CA Lung,colon,stomach.;Hodgkin'd ds(a/w MCD) Proposed mechanism: Ab deposition & complement activation against tumor Ag deposited in glomeruli. C/F- That of nephrotic syndrome(heavy proteinuria,renal vein thrombosis,minimal haematuria)
  • RENAL MANIFESTATIONS Contd.. >>>TUBULAR ABNORMALITIES:  Protein cast precipitation syndrome  Paraprotein Ds.  Uric acid nephropathy  Hypercalcemia
  • RENAL MANIFESTATIONS >>>MICROVASCULARContd.. LESIONS 1) HAEMOLYTIC UREMIC SYNDROME: Cause: Mitomycin C/malignancy. 2) GIANT HAEMANGIOMA & HAEMANGIOENDOTHELIOMA: Cause- AML,Gastric CA,Pancreatic CA 3) HENOCH-SCHOENLEIN PURPURA Cause- very rarely d/t Lung CA
  • HAEMATOLOGIC MANIFESTATIONS ERYTHROCYTOSIS A/W- RCC(most common),cerebellar haemangioblastoma,sarcoma,fibroids,pheochromocyto mas. CAUSE - Excess erythropoetin secretion by tumor cells,decreased plasma volume,fuctional interaction between aldosterone,rennin and erythropoetin Rx- Control of underlying neoplasm,occaisional phlebotomy;no specific therapy required
  • HAEMATOLOGIC MANIFESTATIONS GRANULOCYTOSIS Contd.. TLC > 15 X10e9/L with predominance of mature neutrophils(closest D/D -CML) CAUSE-Tumor production of growth factors A/w- Hodgkin's Ds,Gastric CA,Lung CA,Malignant melanoma,Pancreatic and Brain Tumors.
  • HAEMATOLOGIC MANIFESTATIONS Contd..  EOSINOPHILIA : A/W- Hodgkin's Ds,Mycosis Fungoides Cause- increased production of GM-CSF,IL-3,IL-5.  BASOPHILIA : A/W- CML and other myeloproliferative disorders Characteristically asymptomatic.
  • HAEMATOLOGIC MANIFESTATIONS Contd.. THROMBOCYTOSIS: A/W- Hodgkin's lymphoma, leukaemias, early course of Polycythemia vera and CML Cause: Tumor overproduction of Thrombopoetin and IL-6 C/F- Thrombosis & haemorrhage Rx- not indicated generally.
  • HAEMATOLOGIC MANIFESTATIONS Contd..     NON BACTERIAL THROMBOTIC ENDOCARDITIS STERILE,verrucous plaques mainly on aortic and mitral valves Cause- underlying coagulopathy(usually DIC) Cardiac murmurs often absent,Echo-elusive
  • NON BACTERIAL THROMBOTIC ENDOCARDITIS Contd.. A/w- Adeno CA lung & Pancreas Rx- Anticoagulation therapy with heparin
  • HAEMATOLOGIC MANIFESTATIONS Contd..     THROMBOPHLEBITIS Cause- cancer related hypercoagulable state(imbalance between coagulation & fibrinolysis) Recurrent DVT attacks should prompt a search for malignancy Thromoembolism should be aggressively managed with anticoagulation therapy(indefinitely,if reqd.)
  • THANK YOU ALL...