para neoplastic syndromes

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GOOD AFTERNOON.... PARANEOPLASTIC DISORDERS -Dr. ANINDYA MUKHERJEE ( 1 st year PGT, Dept of

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Page 1: PARA NEOPLASTIC SYNDROMES

GOOD AFTERNOON....

PARANEOPLASTIC DISORDERS

-Dr. ANINDYA MUKHERJEE

( 1st year PGT, Dept of RADIATION ONCOLOGY,MCH)

Page 2: PARA NEOPLASTIC SYNDROMES

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.

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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

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ENDOCRINE PNS

Refers to ectopic expression from an atypical tissue source,mostly neoplastic cells characterized by

EXCESS PRODUCTION

And

ABNORMAL REGULATION & PEPTIDE PROCESSING

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OVERVIEW...

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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%)

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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.

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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.

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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.

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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.

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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

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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

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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

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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.

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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.

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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.

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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

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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.

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OVERVIEW....

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RELEVANT ANTIBODIES AND TUMORS

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ANTIBODIES Contd....

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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

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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)

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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

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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.

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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.

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FLAIR-MRI of a pt with limbic encephalitis and LGI1 Ab

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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

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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.

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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

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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)

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PROGRESSIVE CEREBELLAR DEGENERATION Contd...

Antibody negative PCD- Eaton Lambert syndrome( a/w SCLC)

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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

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PARANEOPLASTIC VISUAL LOSS Contd..

DIAGNOSIS- Optic disc pallor,Retinal arteriolar attenuation, Abnormal ERGs, Delayed VERs

TREATMENT - Steroids ,Plasmapheresis, IV IgG,Treatment of underlying malignancy.

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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

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OTHERS.. PARANEOPLASTIC PERIPHERAL NEUROPATHIES

OPSOCLONUS AND MYOCLONUS

PARANEOPLASTIC MOTOR NEURON DISORDERS

PARANEOPLASTIC MUSCLE RIGIDITY

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CUTANEOUS PNS

Two conditions to be satisfied:

Strong association of dermatosis with malignancy

And

Parallel course.

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PAPULOSQUAMOUS DISORDERS

Acrokeratosis Praneoplastica /Bazex Ds

Symetric psoriasiform hyperkeratosis

SCC oesophagus,head and neck,lung

Male predominance

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PAPULOSQUAMOUS DISORDERS Contd..

PADGET'S DISEASE Erythematous keratotic patch

over nipple,perianal area

CA-Breast,uterine,ovarin,prostrate,anal

Direct extension of underlyiing malignancy

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PAPULOSQUAMOUS DISORDERS Contd..

NECROLYTIC MIGRATORY ERYTHEMA

Macules & Papules progressing to epidermal necrolysis

Glucagonoma Clinically similar to Zn

deficiency;somatostatin beneficial

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PAPULOSQUAMOUS DISORDERS Contd..

ERYTHEMA GYRATUM REPENS

Advanced concentric rings of erythema with trailing scales

CA-Lung,breast,uterus,GIT Unlnown cause

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PAPULOSQUAMOUS DISORDERS Contd..

DERMATOMYOSITIS Erythema or telengiectasia of

knuckes,chest,periorbital regions

Misc causes- Lymphoma predominantly.

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PAPULOSQUAMOUS DISORDERS Contd..

PALMAR HYPERKERATOSIS/TYLOSIS

CA-oesophagus(Howel-Evan's syndrome)breast,ovary

Punctate form-a/w CA breast

Page 47: PARA NEOPLASTIC SYNDROMES

DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION

ACANTHOSIS NIGRICANS Gray-brown symetric velvety

plaques on neck,axillae,flexor areas.(TRIPE PALMS)

Predominantly GastricAdenoCA.

Page 48: PARA NEOPLASTIC SYNDROMES

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

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DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION

GENERALISED MELANOSIS

Diffuse gray brown skin pigmentation

A/w- Melanoma,ACTH producing tumors

Cause- melanin deposits in skin

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NEUTROPHILIC DERMATOSES

SWEET SYNDROME Fever+neutrophilia+erythemat

ous painful juicy plaques on upper half

A/w-AML, Myelodysplastic syndrome(probably hypersensitivity)

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NEUTROPHILIC DERMATOSES

PYODERMA GANGRENOSUM

Painful papules,ulcers,violaceous borders&purulent exudates

A/w-Multiple myeloma,SCCs,Cutaneous T-cell Hodgkin's lymphoma

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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

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SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES

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SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES

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SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES

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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)

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RENAL MANIFESTATIONS

Contd..>>>TUBULAR ABNORMALITIES:

Protein cast precipitation syndrome

Paraprotein Ds.

Uric acid nephropathy

Hypercalcemia

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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

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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

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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.

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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.

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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.

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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

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NON BACTERIAL THROMBOTIC ENDOCARDITIS Contd..

A/w- Adeno CA lung & Pancreas

Rx- Anticoagulation therapy with heparin

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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.)

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