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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...
PARA NEOPLASTIC SYNDROMES
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.
PARA NEOPLASTIC SYNDROMES
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....
PARA NEOPLASTIC SYNDROMES
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...

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PARA NEOPLASTIC SYNDROMES

  • 1. GOOD AFTERNOON.... DISORDERS PARANEOPLASTIC -Dr. ANINDYA MUKHERJEE ( 1 st year PGT, Dept of RADIATION ONCOLOGY,MCH)
  • 2. 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.
  • 3. 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
  • 4. ENDOCRINE PNS Refers to ectopic expression from an atypical tissue source,mostly neoplastic cells characterized by EXCESS PRODUCTION And ABNORMAL REGULATION & PEPTIDE PROCESSING
  • 7. 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%)
  • 8. 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.
  • 9. 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.
  • 10. 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.
  • 12. 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.
  • 13. 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
  • 14. 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 
  • 15. 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
  • 16. 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.
  • 17. 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.
  • 18. 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.
  • 19. 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
  • 20. 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.
  • 25. 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
  • 26. 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)
  • 27. 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
  • 28. 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.
  • 29. 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.
  • 30. FLAIR-MRI of a pt with limbic encephalitis and LGI1 Ab
  • 31. 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
  • 32. 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.
  • 33. 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
  • 34. 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)
  • 35. PROGRESSIVE CEREBELLAR DEGENERATION Contd...  Antibody negative PCD- Eaton Lambert syndrome( a/w SCLC)
  • 36. 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
  • 37. PARANEOPLASTIC VISUAL LOSS Contd..   DIAGNOSIS- Optic disc pallor,Retinal arteriolar attenuation, Abnormal ERGs, Delayed VERs TREATMENT - Steroids ,Plasmapheresis, IV IgG,Treatment of underlying malignancy.
  • 38. 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
  • 39. OTHERS..  PARANEOPLASTIC PERIPHERAL NEUROPATHIES  OPSOCLONUS AND MYOCLONUS  PARANEOPLASTIC MOTOR NEURON DISORDERS  PARANEOPLASTIC MUSCLE RIGIDITY
  • 40. CUTANEOUS PNS Two conditions to be satisfied:  Strong association of dermatosis with malignancy And  Parallel course.
  • 41. PAPULOSQUAMOUS DISORDERS     Acrokeratosis Praneoplastica /Bazex Ds Symetric psoriasiform hyperkeratosis SCC oesophagus,head and neck,lung Male predominance
  • 42. PAPULOSQUAMOUS DISORDERS Contd..     PADGET'S DISEASE Erythematous keratotic patch over nipple,perianal area CABreast,uterine,ovarin,prostrate, anal Direct extension of underlyiing malignancy
  • 43. PAPULOSQUAMOUS DISORDERS Contd..  NECROLYTIC MIGRATORY ERYTHEMA Macules & Papules progressing to epidermal necrolysis  Glucagonoma   Clinically similar to Zn deficiency;somatostatin beneficial
  • 44. PAPULOSQUAMOUS DISORDERS Contd..   ERYTHEMA GYRATUM REPENS Advanced concentric rings of erythema with trailing scales  CA-Lung,breast,uterus,GIT  Unlnown cause
  • 45. PAPULOSQUAMOUS DISORDERS Contd..    DERMATOMYOSITIS Erythema or telengiectasia of knuckes,chest,periorbital regions Misc causes- Lymphoma predominantly.
  • 47. DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION    ACANTHOSIS NIGRICANS Gray-brown symetric velvety plaques on neck,axillae,flexor areas.(TRIPE PALMS) Predominantly GastricAdenoCA.
  • 48. 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
  • 49. DISORDERS OF CUTANEOUS DISCOLOURATION AND DEPOSITION     GENERALISED MELANOSIS Diffuse gray brown skin pigmentation A/w- Melanoma,ACTH producing tumors Cause- melanin deposits in skin
  • 50. NEUTROPHILIC DERMATOSES    SWEET SYNDROME Fever+neutrophilia+erythemat ous painful juicy plaques on upper half A/w-AML, Myelodysplastic syndrome(probably hypersensitivity)
  • 53. SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES
  • 54. SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES
  • 55. SKIN NEOPLASMS ASSOCIATED WITH INTERNAL MALIGNANCIES
  • 56. 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)
  • 57. RENAL MANIFESTATIONS Contd.. >>>TUBULAR ABNORMALITIES:  Protein cast precipitation syndrome  Paraprotein Ds.  Uric acid nephropathy  Hypercalcemia
  • 58. 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
  • 59. 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
  • 60. 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.
  • 61. 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.
  • 62. 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.
  • 63. 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
  • 64. NON BACTERIAL THROMBOTIC ENDOCARDITIS Contd.. A/w- Adeno CA lung & Pancreas Rx- Anticoagulation therapy with heparin
  • 65. 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.)