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PARANEOPLASTIC SYNDROMES:
ENDOCRINOLOGICAL/HEMATOLOGICAL
Dr. V. B. Kasyapa. JI year PG
Date: 07-03-2017
Definition• Disorders that accompany benign or
malignant tumors, but are not directly related to mass effects or invasion
• Almost every tumor has the potential
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.
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
• 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)
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
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)
• 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
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
In lymphomas,
Increased 1,25-dihydroxy cholecalciferol production
Increases Ca absorption(from GIT) & reabsorption (from Kidney)
Hematological
malgnancies
Marrow infiltration
Production of
osteolytic cytokines
& inflammat
ory mediators
IL-1, Lymphotax
in, TNF
Ca resorption from bone
Hypercalcemia
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)
• 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
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)
• 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
• 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
SIADH
Supraoptic & Para
ventricular nuclei of
Hypothalamus
Posterior lobe of pituitary
(for release & storage)
Hypothalamic magno cellular neurons
Nonapeptide ADH/
Arginine-Vasopressin
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
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
• 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
• 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
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
DiagnosisEssential 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
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
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
– 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 hrsInitial 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
• 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
– 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)
– 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)
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
• 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)
Overwhelmed shift
shrinkage of glial cells &
cell damage due to
burden
disruption of BBB
inflammatory
mediators damage
oligodendrocytes
demyelination
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
• 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
↑CRH (from pancreatic isletcell tumor, SCLC,
MTC, Carcinoids, Prostate Ca.)
Pituitary cortical hyperplasia
↑ ACTH from tumor
Paracrine activation of
ACTH
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
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
• 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
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)
• 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
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
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
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
Treatment• Avoid hypoglycemia causing drugs• Treat underlying malignancy (↓ attack rate)• Frequent meals, IV glucose (during fasting &
sleep)• Glucagon, glucocorticoids,– To ↑glucose production
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
• In men,– ↑steroidogenesis in Leydig cells & ↑aromatase activity
↑ estrogen & testosteron gynaecomastia & precocious puberty
• In women,– It is asymptomatic
• Serum hCG levels
• Treat underlying cause
Oncogenic osteomalacia• Hypophosphatemic oncogenic osteomalacia/
tumor induced osteomalacia
• ↓↓ S.Phosphorus
• ↑ ↑renal phosphate wasting
• ↓1,25-dihydroxy vitD
• Ⓝ S.Ca & S.PTH levels
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)
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
Erythrocytosis
tumor
RCC, HCC, Cerebellar hemangioblastoma
EPO↑
Rise in hematocrit
>52% in male>48% in Female
Hematocrit Ⓝ
Other tumors
Lymphokines ↑ & other hormones
• Usually asymptomatic• Sometimes DVT
• In suspected malignancy, with ↑hmt with ↑EPO is confirmative
• Remove underlying cause• If not operable phlebotomy
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
Management
• Usually asymptomatic• Seen mainly during advance stages of tumor
• No specific treatment needed• Treat underlying tumor
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
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)
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)
• 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
• 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
• 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
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)
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
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
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.
Treatment• Thymoma-associated PRCA: resection helps• Corticosteroids• Cyclophosphomide• Cyclosporin A• Splenectomy & plasmapheresis• Resistant disease,– Rituximab & Alemptuzumab
GRACIAS