Transcript
GOOD AFTERNOON....
PARANEOPLASTIC DISORDERS
-Dr. ANINDYA MUKHERJEE
( 1st 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: 1) Small cell lung cancer(>50%) 2) Thymic carcinoid (15%) 3) Islet tumors (10%) 4) Bronchial carcinoids (10%) 5) Other carcinoids (5%) 6) 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 non-
pituitary 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: Fluid retention & hypertension
Hypokalemia Metabolic Alkalosis Glucose intolerance Steroid psychosis(occaisional)
3)Skin: 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.
Otherwise-weakness,confusion,lethargy,seizures.
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 GANGLIAPROBLEMS 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 FDG-PET,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 SSS-
EMN 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
CA-Breast,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/TYLOSIS
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
PACHYDERMOPERIOSTOSIS
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 T-cell 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
Contd..>>>MICROVASCULAR 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,pheochromocytomas.
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 Contd..GRANULOCYTOSIS
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...
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