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.
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)
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
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.)