Endocrine PNS Hematological PNS from Harrison's Principles of Medicine 19th Edition & Devita Oncology

1. PARANEOPLASTIC
SYNDROMES:
ENDOCRINOLOGICAL/HEMATOLOGICAL
Dr. V. B. Kasyapa. J
I year PG
Date: 07-03-2017

2. Definition
• Disorders that accompany benign or
malignant tumors, but are not directly related
to mass effects or invasion
• Almost every tumor has the potential

3. Endocrinal PNS
• It may be Eutopic (natural production site)/ Ectopic (atypical production
site)
• Ectopic expression is often a quantitative change rather than an absolute
change in tissue expression
– Abnormal regulation (defective feedback control)
– Abnormal processing (large, unprocessed precursors)
– Abnormal hormone expression (d/t genetic rearrangements)
• If no clinical presentation; it is an epiphenomenon associated with tumor.

4. Examples
Translocation of PTH gene High levels of PTH expression in other
gland
Genetic rearrangements in
Lymphoma/Leukemia
Growth advantage & altered cellular
differentiation & function
Cellular de-differentitation
(partial/selective depression) in SCLC
poor development PTHrP (PTH related
protein) of early development stage
proteins (hCG, alpha PP) are liberated
Epigenetic modifications that alter
transcriptional repression
microRNA expression

5. • In SCLC,
– Neuro endocrine phenotype by
• Basix-helix-loop-helix(bHLH) transcription factor
Human achaetescute homologue 1(hASH-1)
High levels -> Ectopic ACTH
• Hairy enhancer of split 1(HFS-1)
Notch proteins
– Abnormal expression -> Eutopic ↑ ACTH (cell proliferation&
differentiation)

6. Humoral Hypercalcemia of
Malignancy (HHM)
• (MC) in
– Lung, head & neck, skin, esophagus, breast, GUT,
multiple myeloma, lymphomas
• MOA:
– Over production of PTHrP (MC)
– PTHrP from bone mets
– Over production of 1,25-dihydroxy vit D
– Tumor induced production of osteolytic cytokines &
inflammatory mediators & Osteoclastic activation
factors

7. PTHrP
• ParaTHarmone related Protein
• Normally produced during development & cell
renewal
• MOA:
– Binds to PTH receptors -> hyperparathyroidsm like
features
• Actions:
– Skeletal development, regulates cellular proliferation
& differentiation (skin, BM, breast, hair follicles)

8. • PTHrP increased production d/t
– Mutation in oncogenes
– Altered expression of viral/cellular transcription
factors
– Local growth factors
• PTHrP -> pro-survival AKT pathway & Chemokine
receptor CXR4

9. Bone mets TGF-β
Gli transcription
factor & hedgehog
pathways
PTHrPBreast carcinoma
direct local lysis of
bone
PTHrP
Adult T cell
lymphoma (HTLV-
1)
trans activating
Tax protein
PTHrP promotor
activation
PTHrP

10. In lymphomas,
Increased 1,25-dihydroxy cholecalciferol
production
Increases Ca absorption(from GIT) &
reabsorption (from Kidney)

11. Hematologi
cal
malgnancie
s
Marrow
infiltration
Production
of
osteolytic
cytokines &
inflammato
ry
mediators
IL-1,
Lymphotaxi
n, TNF
Ca
resorption
from bone
Hypercalce
mia

12. Diagnosis
• Unlike hyperparathyroidsm
– ↓/Ⓝ 1,25 – dihydroxy vitD
– Decreased PTH
– Loss of normal coupling of bone formation & resorption
• Like Hyperparathyroidsm
– Hypercalemia >3.5 mmol/L (Bone, Groan, Moan, Stone)
– ↑ nephrogenous cAMP excretion
– Metabolic alkalosis
– Hypophoshatemia
– Hyperchloremic metabolic acidosis (less)

13. • Subtle variations are due to
– Receptor activation by PTH/PTHrP
– Other cytokines by Malignant cells
• PTHrP measurement (single/double ab, different epitope)
– Ⓝ people – low
– Preg/lactation/tumor – high
• Symptoms
– Weight loss, Fatigue, Muscle weakness, Unexplained skin rash, Other features of
malignancy/PNS
• BM biopsy in anemia/ abnormal smear
• Bone scan with technetium-labled bisphosphonate for osteolytic mets
(↑sensitivity, ↓specificity)
• Confirm by X-Ray

14. Therapy
• Removal of excess Ca in diet, medication & IV
solutions
• Saline rehydration depending on
comorbidities 200 – 500 ml/hr
• Forced diuresis 20 – 80 mg IV Furosemide
– Add in comorbidities & life threatening conditions
– Always use after complete rehydration
• Oral phosphorus 250 mg Neutro-Phos 3-4/day
– Until S.Phosphorus >1 mmol/L (>3 mg/dl)

15. • Bisphosphonates
– Palmidronate 60 – 90 mg IV
– Zoledronate 4 – 8 mg IV
– Etidronate 7.5 mg/kg/day PO for 3-7 consecutive days
– Useful within 1-2 days & for several weeks
• Dialysis (if bisphosphonates are not enough/
contraindicated/ severe)
• Previously,
– Calcitonin 2 – 8 U/kg SC 6-12 hrly
– Mithramycin
– Now only for rapid corection of severe disease with
unavailable dialysis

16. • Glucocorticoids
– Prednisolone 40 – 100 mg PO in 4 divided doses
– For Lymphomas, Multiple myeloma, Leukemia
• In extensive cases
– Left untreated as it has sedation effect

17. SIADH
Supraoptic &
Para
ventricular
nuclei of
Hypothalamus
Posterior lobe
of pituitary (for
release &
storage)
Hypothalamic
magno cellular
neurons
Nonapeptide
ADH/ Arginine-
Vasopressin

18. Receptor Location Action
V1a • Vascular smooth muscle
• Uterus
• Platelets
• Hepatocytes
• Vasoconstriction
• Uterine contraction
• Platelet aggregation
• Glucogenolysis
V1b • Corticotroph cells in anterior
pituitary gland
• ACTH & β-endorphin
production
V2 • Baso-lateral membrane of renal
collecting ducts, principle cells
• Vascular smooth muscle
• Vascular endothelium
• Synthesis & insertion of AQP-2
into apical membrane
• Vasodilation
• Release of vWF & factor VIII

19. ADH
receptor
ADH
AQP - 3
AQP - 4
Activation of
adenylyl cyclase
cADP
cAMP
Protein
kinase A
Activated Protein
kinase A
AQP - 2
AQP - 2
Renal Collecting duct – Principal CellsCollecting
Duct
Medullary Interstitium

20. • Stimuli for ADH secretion
– ↑ plasma osmolality (MI)
– ↓ intravascular volume (↓ effective arterial
volume)
– V1a, V2(low dose) activation
• (MC) malignancy
– 40% of SCLC
– Carcinoids
– Head & Neck tumors (tumors of oral cavity)
– CNS lesions(head trauma, ICSOL) , Genitourinary
tumors, GIT tumors, Ovarian tumors

21. • MOA
– Vasopressin gene activation in tumor cell
– Associated Oxytocin gene expression
– De-repression of locus
– ↑ ADH
• ↓ thirst
• ↑ water retention
– Prolonged ADH action resets osmostats in
hypothalamus, vasopressin secretion
– If additional free water intake/IV fluids increase
causes quick worsening

22. Clinical features
• Symptoms depends on,
– Degree & rapidity of Na levels
– (MC) Chronic
• Mild fatigue, confusion, falls, attention deficit
– Severe hyponatremia <115 mEq/L
– Hypoosmolality  odema of brain cells  ↓brain
electrolyte content  loss of organic solutes such as
creatinine & aminoacids
– Acute Na (<48 hrs)
• Nausea, vomiting, headache, seizures, respiratory arrest,
death

23. Diagnosis
Essential features Remarks
• Plasma osmolality <275
mOsm/kg of water
• Ruleout
• Hyponatremia with Ⓝ/↑ plasma osmolality
• Translocation by ↑ glucose
• Pseudo-hyponatremia by hyperlipidemia/hyperproteinemia
• Urine osmolality
>100mOsm/kg of water with
hypotonicity
• Rule out
• Beer potomania
• Polydipsia
• Clinical euvolemia • Absence of signs of volume depletion by renal/extra-renal
• Dry mucus membranes, tachycardia, orthostasis
• Volume overload by RF, Nephrotic syndrome, cirrhosis, CHF
• Edema, ascites, JVP↑
• Urinary Na >40mmol/L with Ⓝ
dietary intake
• Ⓝ thyroid & adrenal
formation
• No recent use of diuretic

24. Supplementary features
• ↓ serum uric acid < 4 mg/dl
• ↓ BUN < 10 mg/dl
• ↑ fractional excretion of Na > 1%
• ↑ fractional excretion of urea >55%
• Failure to correct hyponatremia with 2L of NS
• Correction of hyponatremia with fluid restriction
• Abnormal result of Water load test
• Inability to excrete 90% of 20mg/kg water load in 4 hrs (or)
• Failure to achieve urine osmolality < 100 mOsm/kg of water
• ↑ serum ADH despite of hypotonicity & clinical euvolemia

25. Management
• Indirect
– Cancer-specific therapy (less useful)
• In non severe
– Fluid restriction < 800 ml/day (< daily insensible
losses + urine ouput)
• Slow improvement, low compliance, insufficient for
symptomatic
– Urea oral administration 30 gm/day
• Osmotic diuresis, ↑ water excretion
• Poor palatability

26. – Demclocycline 300 – 600 mg BD
• Unpredictable onset
• GI intolerance, photosensitivity, azotemia
– Lithium
• Dysregulation of AQP-2
• Interstitial nephritis, ESRD, ↓efficacy of Demeclocycline
– 3% NaCl infusion 8-12 mmol/L correction/24 hrs
Initial infusion rate = Wt(kg) x rate of correction
• Add loop diuretic 20-40 mg in cardiac patients
• Goal: achieve safe serum Na levels
– ≥120 mmol/L (or) correction of 18 mmol/L

27. • Direct – Vasopressin antagonists
– Penetrate deep compared to ADH
– ↓synthesis/ ↓transport of AQP-2 & ↓free water
reabsorption(aquaresis) & ↑urine volume
– Only for Euvolemic/Hypervolemic Hyponatremia
– CI: Hypovolemia

28. – Conivaptan:
• V1a, V2 receptor inhibitor
• IV
• Loading dose: 20 mg over 30 min
• Maintanance dose: 40 mg/day continuous infusion for
4 days
• Erythema, phlebitis, swelling
• Large vein with site change every 24 hrly
• Interactions: with statins, CCBs, BZDs, antifungals,
chemotherapy(vinka alkaloids, etoposide)

29. – Tolvaptan:
• V2 selective, No intrinsic agonistic activity
• 15 mg PO OD  4 days  60 mg PO OD
• Significant ↑in first 4 days & at 30th day
• Increased thirst, dry mouth, increased urination,
polydipsia
• For Mild, Moderate & Severe asymptomatic
hyponatremia
• Not for Symptomatic (only 3% NaCl)

30. Osmotic Demyelination Syndrome
(ODS)
Rapid ↑in S.Na
brain cells reverse it by loss
of solute by ↑ production
of organic osmolytes &
inorganic ions
prevent shift of water to
outside the cell

31. • RF: S.Na ≤105 mmol/L, hypokalemia, alcoholism,
malnutrition, advanced liver disease
• C/F:
– initial symptomatic improvement
– In few days, new/progressive neurologic symptoms
(confusion to spastic quadriplegia, dysarthria, dysphagia)
• MRI: hypodense non-enhancing (T1),hyperdense (T2)
Overwh
elmed
shift
shrinkage
of glial
cells &
cell
damage
due to
burden
disruption
of BBB
inflammato
ry
mediators
damage
oligodendr
ocytes
demyeli
nation

32. Cushing’s Syndrome
• (MC) with,
– SCLC, bronchial & thymic carcinoids, islet cell
tumors, other carcinoids, pheochromocytoma
• MOA,
– ↑expression of Proopiomelanocortin (POMC)
gene
– ↑Corticotropin releasing hormone (CRH)
– ACTH independence/ Ectopic expression of
receptor mediated secretion in adrenal medulla

33. • POMC gene codes for ACTH, MSH(Melanocyte
stimulating hormone), β-lipoprotein, etc…
Abundant, aberrant expression
of Internal promotor in tumor
cells (proximal to third exon)
Codes for ↑ACTH production
No signal sequence for protein
processing
Not secreted (or) large,
biologically inactive fragments
secreted
Less abundant,
unregulated expression
of same promotor in
pituitary cells
↑production of Ⓝ
ACTH

34. ↑CRH (from pancreatic
isletcell tumor, SCLC,
MTC, Carcinoids,
Prostate Ca.)
Pituitary cortical
hyperplasia
↑ ACTH from
tumor
Paracrine
activation of
ACTH

35. Ectopic
expression of G-
protein coupled
receptors in
adrenal medulla
GIP related
receptors
Meals induced
GIP production
Activates
receptors in
Adrenal medulla
Adrenal growth
&
↑glucocorticoid
production

36. Clinical features
• Usually less marked compared to other ectopic
ACTH producing causes
– d/t brief exposure periods, cancer cachexia
• Through mineralocorticoid receptors (usually
action is blocked by 11β-Hydroxysteorid
dehydrogenase type II enzyme. But now
overwhelmed)
– Fluid retension, HTN, hypokalemia
• MSH activity
– ↑pigmentation

37. • Glucocorticoid excess
– Met. Acidosis, glucose intolerance, steroid
psychosis, depression, personality changes, DM,
marked skin fragility, easy bruising & secondary
infections
• D/t malignancy & coagulation profile changes
– Venous thromboembolism

38. Diagnosis
• If known malignancy  easy to find
• Urine free cortisol 2 – 4 x Ⓝ
• Plasma ACTH >22 pmol/L (>100 pg/ml)
– Suppressed in ACTH-independent Cushing’s
• High dose Dexamethasone test 8 mg PO
early morning
– Suppress ACTH (~80%) in pituitary adenomas
– Fail (~90%) in ectopic ACTH
– Can suppress in Bronchial & other carcinoids (by
feedback regulation)

39. • Adrenal blockade with Metyrapone
– Can be done in Carcinoids
• Petrosal sinus catheterisation  CRH
stimulation 3:1(petrosal:peripheral) ACTH
 pituitary source
• Imaging studies,
– For carcinoids, biopsy
• PET/Octreotide scan,
– For source identification

40. Management
• Treat Underlying tumor: not sufficient
• Adrenalectomy,
– If operating for a tumor
– Otherwise favourable outcome (carcinoids)
– Main tumor unresectable
• Medical blockade (MC)
– Metyrapone 250 – 500 mg PO 6th hrly
– Mitotane 3 – 6 gm PO in 4 divided doses
– Ketoconazole 300 – 600 mg BD PO
– Always combine with glucocorticoid replacement

41. Tumor induced Hypoglycemia
• (MC) with Mesenchymal tumors, hemangio
pericytomas, HCC, Adrenal Ca.
• MOA,
– ↑IGF II secretion
– Large size
• Diagnosis,
– ↓S.Glucose, ↓S.Insulin, Ⓝ/↑S.IGF II(d/t
precursor), Symp. Of Hypoglycemia, ↑IGF II
mRNA expression

42. IGF II gene
(11p15)
Biallelic expression by loss of methylation &
loss of imprinting
Gene induction
↑IGF II production
Supress
GH/Insulin/IGF I
Supress IGF Binding Protein
3(IGFBP3)/ALS(Acid Labile Subunit)
Sequesters IGF II Small circulating complex formation
Greater access to Insulin to target tissues
Circulating binding protein
alterations
↑IGF II bioavailability
Imprinted

43. Treatment
• Avoid hypoglycemia causing drugs
• Treat underlying malignancy (↓ attack rate)
• Frequent meals, IV glucose (during fasting &
sleep)
• Glucagon, glucocorticoids,
– To ↑glucose production

44. Excess Human chorionic gonadotropin
• It has α(MC) & β subunits
• Eutopic
– Trophoblastic tumor
• Ectopic
– Testicular embryonal tumor
– Germ cell tumor
– Extragonadal germinoma
– Lung cancer
– Hepatoma
– Pancreatic isletcell tumor

45. • In men,
– ↑steroidogenesis in Leydig cells & ↑aromatase
activity  ↑ estrogen & testosteron 
gynaecomastia & precocious puberty
• In women,
– It is asymptomatic
• Serum hCG levels
• Treat underlying cause

46. Oncogenic osteomalacia
• Hypophosphatemic oncogenic osteomalacia/
tumor induced osteomalacia
• ↓↓ S.Phosphorus
• ↑ ↑renal phosphate wasting
• ↓1,25-dihydroxy vitD
• Ⓝ S.Ca & S.PTH levels

47. Phosphatoin
(Fibroblast Growth
Factor-23)
Ternary complex
with klotho protein
& Renal FGF
receptors
↓↓renal
phosphorus
reabsorption
• ↓ conversion of 25-hydroxy vitD  1,25-dihydroxy vitD
• Caused in
• Benign mesenchymal tumors (skeletal extremeties/head)
• Hemangiopericytoma
• Fibroma
• Gaint cell tumors
• Sarcomas
• Prostate & lung Ca.
• Octreotide scan may be useful
• Removal of tumor, reverses the pathlogy
• Supplement phosphates & vit D
• Octrotide: may decrease renal wasting (in pts with Somatostatin receptor
subtype-2)

48. Hematological PNS
• These do not include abnormal cells in
lymphomas or leukemias
• These are PNS caused by solid tumors causing
blood cell abnormalities by humoral
mechanisms

49. Erythrocytosis
tumor
RCC, HCC, Cerebellar hemangioblastoma
EPO↑
Rise in hematocrit
>52% in male
>48% in
Female
Hematocrit Ⓝ
Other tumors
Lymphokines ↑ &
other hormones

50. • Usually asymptomatic
• Sometimes DVT
• In suspected malignancy, with ↑hmt with
↑EPO is confirmative
• Remove underlying cause
• If not operable  phlebotomy

51. Granulocytosis
• >8000/µL is seen in tumors
• May be d/t,
– Non PNS (infection, tumor necrosis, steroid
administration, etc…)
– PNS (↑plasma/urinary proteins like G-CSF, GM-CSF &
IL6)
– Idiopathic
• Lung & GI tumors (MC), Breast Ca., Brain &
Ovarian tumors, HL, RCC

52. Management
• Usually asymptomatic
• Seen mainly during advance stages of tumor
• No specific treatment needed
• Treat underlying tumor

53. Thrombocytosis
• >400000/µL
• D/t,
– ↑IL6  ↑production in-vitro & in-vivo
– ↑thrombopoeitin  ↑proliferation of megakaryocytes & ↑platelet production
– Idiopathic
• Usually asymptomatic; no direct relation with thrombosis
• Lung & GI tumors (40%), breats, ovarian, endometrial Ca., lumphomas
• Associated with advanced stage & poor prognosis
• No treatment; treat underlying tumor

54. Eosinophilia
• Translocation of 5q  ↑IL5 Eosinophilia
• Asymptomatic
• Severe (>5000/µL) – chest tightness, wheeze
• In lymphoma(10%), lung, cervical, GI, renal & breast tumors
• Hemogram & CXR PA (diffuse pulmonary inflitrates)
• Treat underlying tumor
• Oral/inhaled corticosteroids
• IL5 antagonists(under trails)

55. Thrombophlebitis
• (MC) thrombotic conditions in cancer pt
– DVT, Pulmonary Embolism
• Migratory thrombophlebitis in cancer pt
– Trousseau sydrome
– (MC) with Visceral Ca. (pancreatic Ca.)
– Initial symptom
• MOA,
– Immobilisation, post op bed rest, tumor obstruction,
procoagulants & cytokines from tumor, inflammation causing
platelet adhesion & aggregation, endothelial damage d/t
chemotherapy (Bleomycin, L-asparginase, thalidomide
analogues, cisplatin, busulfan, carmustin), association of
primary thrombotic (APS)

56. • C/f:
– Swelling, pain in the leg
– Tenderness, warmth, redness
– Symp.& signs Of pulm embolism (dyspnoea, chest
pain, syncope, tachycardia, cyanosis, hypotension)
– With no H/o cancer
• Will be found in 1 year
• Lung, pancreatic, GI, ovarian, GU, lymphomas
& brain tumors

57. • Diagnosis,
– Impedence plethysmography
– b/l compression USG (noncompressable segment)
– Venography (filling defect)
– Elevation of D-dimer (not reliable much compared to
non-cancerous; ↑ after 65yrs d/t ↑thrombin
deposition & turnover)
– CXR, ECG, ABG, VQ scan
– Pulmonary angiogram (final resort)
– No need to look for cancer in a case of
thrombophlebitis; but look in case of migratory
thrombophlebitis

58. • Treatment,
– UFH/LMWH IV till INR 2-3
• hemorrhagic brain mets, pericardial effusion & proximal DVT
 put an IVC filter(greenfield)
– Warfarrin 3 – 6 months
– LMHW 6 months
– Pneumatic boots (can be used for surgery going pt)
– Prophylaxis in,
• Breast Ca. going for chemo, pts with implanted catheters,
hospitalized & receiving thalidomide analogues
• Routine use during chemo is not indicated
• With LMWH/Low dose Aspirin

59. Anemia
• Hb <12gm/dL (women), <14g/dL (men)
• Criteria
– Liberal (<11 g/dL)
– Moerate ( 9 – 11 g/dL)
– Stringent (<9 g/dL)
• Causes,
– Blood loss, tumor-related myelosuppression,
hemolysis, impaired renal function, iron & B12
def, anemia of chronic disease (ACD)

60. ACD
• d/t
– Infections, autoimmune disorders, CKD, malignancy
IL-6, IL-1, TNF-α, INF-γ JAK & STAT3 activation ↑Hepcidin by liver
↓ duodenal absorption
of iron & Ferroportin
degradation by binding
↓release of iron into
plasma
Entrapment of iron
inside macrophages &
hepatocytes (RE cells)
Normochromic Normocytic anemia, ↓ serum iron &
transferrin saturation, Ⓝ/↑ ferritin

61. Treatment
• Underlying cause treatment; not possible/successful
• RBC transfusion, when Hb <8g/dL
• Erythropoiesis-stimulating agents (ESA)
– Erythropoietin, Darbepoietin
– ↓transfusion rate, ↑Hb levels after chemo
– DVT, HTN, thrombocytopenia with hmrg, tumor
progression, ↑mortality
– Only during palliative therapy
• Newer,
– Hepcidin antagonists, MAB against IL6, STAT3 inhibitors

62. Pure Red Cell Aplasia (PRCA)
• Severe normocytic anemia, reticulopenia, Θ
erythroblast in otherwise Ⓝ bone marrow.
• Acute self-limiting (children), Chronic (adults)
• Parvo virus B19, CVD, drugs (erythropoietin),
hematological malignancies, solid tumors
• Isolated anemia, Ⓝ white cell & platelet, Ⓝ
marrow myeloid & megakaryocytic, complete
absence of Erythroblasts.

63. Treatment
• Thymoma-associated PRCA: resection helps
• Corticosteroids
• Cyclophosphomide
• Cyclosporin A
• Splenectomy & plasmapheresis
• Resistant disease,
– Rituximab & Alemptuzumab

64. GRACIAS