paraneoplastic syndromes part i

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