Andrea M.IsidoriDipartimento di Fisiopatologia Medica

Dir. Prof. Andrea Lenzi

Alterazioni funzionali degli organi interessati dal tumore primitivo

Alterazioni funzionali degli organi interessati dalla crescita metastatica

Effetti conseguenti all’azione di mediatori noti ed ignoti(fattori di crescita, citokine, ormoni)

prodotti dal tumore o derivanti dall’azione di autoAb prodotti dall’organismo contro le cellule tumorali

Sindromi paraneoplastiche

Effetti tossici Effetti metabolici

Effetti sistemici delle neoplasieEffetti sistemici delle neoplasie

Tumor Host InteractionsTumor Host Interactions

Local and Systemic Effects (primary site) Metastases (secondary site)( dedifferentation) Cancer Cachexia Paraneoplastic Syndromes

EndocrinopathiesNeuromyopathies Gastrointestinal motility syndromesOsteochondral DisordersVascular PhenomenaFeverDermatological Syndromes

Paraneoplastic syndromesParaneoplastic syndromes

Le Sindromi paraneoplastiche, per definizione, sono fenomeni legati all’interazione neoplasia-ospitefenomeni legati all’interazione neoplasia-ospite, ma NON direttamente riconducibili ad effetti metastatici, compressivi, tossici, infettivi o metabolici tumorali.

Sono importanti poiché: Si associano a severa morbilità e mortalità (es. Cushing’s) Sono spesso un “presenting symptom” di una neoplasia

misconosciuta (early diagnosis) e un riconoscimento precoce spesso ottimizza le possibilità di intervento

Rientrano nella diagnosi differenziale di sindromi comuni (ipercalcemia, iponatriemia, ipopotassiemia)

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Paraneoplastic syndromesParaneoplastic syndromes

Le neoplasie più frequentemente associate a sindromi paraneoplastiche sono: Lung carcinoma (most common) Renal carcinoma Hepatocellular carcinoma Leukemias Lymphomas Breast tumors Ovarian tumors Neural cancers Gastric cancers Pancreatic cancers

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Cancer CachexiaCancer Cachexia

Progressive weakness, loss of appetite, anemia and profound weight loss (>20 lbs.)

Often correlates with tumor size and extent of metastases

Etiology includes a generalized increase in metabolism and central effects of tumor on hypothalamus

Probably related to macrophage production of TNF-and IL-1

Endocrine syndromes

Cutaneous or dermatologic syndromes

Hematologic syndromes

Neurologic syndromes

Osteoarticular or rheumatologic syndromes

Ocular syndromes

I primi reports su sindromi endocrine in pazienti affetti da neoplasie maligne non endocrine risalgono agli anni ’20...

Lancet 1928

A case of pluriglandular syndrome: diabetes of bearded women.

Brown WH

Surg Gynecol Obster 1923

Parathyroid hyperplasia and bone destruction in generelized carcinomatosis.

Klemperer P

Paraneoplastic Endocrine

Syndromes

PTHrP, TGFs, ILs, Vit D, PTH

HYPERCALCEMIA

ONCOGENIC OSTEOMALACIA

ACROMEGALY

GYNECOMASTIA

HYPONATRIEMIA

CUSHING’s

HYPOGLYCEMIA

DIVERSE SYNTOMS

HCG

FGF23

GH, GHRH

IGF II

ACTH, CRH

Vasopressin, ANP

HPL, PRL, VIP, Renin, LH, GRP

Spectrum of paraneoplastic endocrine

HYPERGLYCEMIA

Glucagone, GH,

Endocrine Pathology 2003

Paraneoplastic Endocrine Syndromes: A Review

DeLellis RA, Xia L.

“…A number of criteria have been proposed for the diagnosis of paraneoplastic endocrine syndromes…

Demonstration of elevated hormone concentrations in the blood

Finding of normal or suppressed endogenous hormone production

Demonstration of hormone concentration gradients across the tumor

Biochemical or clinical resolution of the syndrome following surgery, radiotherapy or chemotherapy

Demonstration of hormone messenger RNA Demonstration of hormone messenger RNA and corresponding hormonal product in and corresponding hormonal product in tumoral cellstumoral cells

Endocrine Pathology 2003

Paraneoplastic Endocrine Syndromes: A Review

DeLellis RA, Xia L.

Meccanismi patogenetici

Theory of randon genetic derepression

Attivazione di geni normalmente inattivi per effetto di mutazioni o modificazioni epigenetiche

Dedifferentiation Theory

Regressione delle cellule tumorali ad uno stato maturativo precoce con produzione di proteine e

ormoni fetali ed embrionali (ex. PTHrP)

Hypercalcemia (Cancer is the most common cause of hypercalcemia by either humoral or metastatic mechanisms)Squamous cell lung cancer (PTH-like

peptide)Multiple myeloma and T-cell lymphoma (IL-1

and perhaps TGF-)Renal cell carcinoma (prostaglandins)Breast (& Prostate) carcinoma, usually by

bone metastasisParathyroid carcinoma (PTH)

Paraneoplastic Syndromes Endocrinopathies

Paraneoplastic Syndromes Endocrinopathies

Inappropriate ADH syndrome (Hyponatremia)Small cell undifferentiated lung cancer

(vassopressin-like hormone.Hypothalamic tumors (vasopressin)

Cushing’s SyndromeSmall cell undifferentiated lung cancer

(ACTH) released through cleavage of pro-opiomelano-cortin gene product.

MTC, Thymoma, Ovarian Cancer, Mesothelioma

Ipercalcemia 0,1% della popolazione generale fino a 3-5% >50aa

Fino al 58% dei pz adulti oncologici ospedalizzati 0,5-1,3% in età pediatrica <5% tumori maligni tratto genitale femminile

Mieloma, K squamoso del polmone (quasi nel 100% dei casi), K mammario, k renale, k del tratto genitale femminile, Linfoma HTLV,

Am J Med 1997

Hypercalcemia of Malignancy

Mundy G, Guise TA

Primary hyperparathyroidism Primary hyperparathyroidism

23%23%

Paraneoplastic syndromeParaneoplastic syndrome

MetastasisMetastasis

72%72%(lung, breast cancer, multiple myeloma(lung, breast cancer, multiple myeloma))

Granulomatous desease (tuberculosis, sarcoidosis) Granulomatous desease (tuberculosis, sarcoidosis)

Genetic disorders (Familial hypocalciuric hypercalcemia) Genetic disorders (Familial hypocalciuric hypercalcemia)

Long immobilizationLong immobilization

Medications (lithium, thiazide diuretics, supplements) Medications (lithium, thiazide diuretics, supplements)

DehydrationDehydration

Hyperparathyroidism and cancer are Hyperparathyroidism and cancer are responsible responsible for more than 90%for more than 90% of sustained of sustained hypercalcemia. hypercalcemia.

Hypercalcemia

Ipercalcemia osteolitica localizzata (Localized Osteolytic Hypercalcemia -LOH-): da produzione locale di fattori paracrini, quali citochine (IL-6, TGFa e b, TNFa), prostaglandina E e metaboliti della Vitamina D, con effetto stimolatorio sugli osteoclasti

Ipercalcemia Maligna (Humoral Hypercalcemia of Malingnancy -HHM-):

da produzione di PTH-RP (PTH-related peptide) o più raramente di PTH

IpercalcemiaAssenza di metastasi ossee

PTH ridotto, PTHrP aumentato

Il PTHrP viene individuato nella seconda metà degli anni ’80, espresso in innumerevoli tessuti normali (es. endometrio, placenta, miometrio e decidua durante la gravidanza)

3 ISOFORME

La porzione NH2-terminale è simile a quella del PTH e determina simili effetti biologici, mentre il resto della molecola possiede altre funzioni (es. regolazione proliferazione cellulare/apoptosi)

Dosabile con metodo RIA (kit specifici per la porzione C-terminale), PCR, IRMA

New Engl J Med 1988

Humoral Hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide

Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF

Cancer 1991

Immunohistochemical evaluation of PTHrP in human lung cancer and normal tissue with newly developed monoclonal antibody

Kitazawa S et al

New Engl J Med 2000

The physiology of parathyroid hormone related protein

Strewler GJ

It has become recently appreciated that the hypercalcemia of malignancy is commonly caused by the increased production of parathyroid hormone-related protein (PTHrP) by the cancer. In fact, the demonstration of increased PTHrP production in a patient with hypercalcemia is regarded as pathognomonic of malignancy. The authors describe a patient with a benign ovarian lesion that produced PTHrP and caused hypercalcemia. They identify other reports of hypercalcemia associated with hypercalcemia and benign tumors, and refer to this syndrome as the humoral hypercalcemia of benignancy. Although apparently rare, a benign PTHrP-producing tumor should be considered in the differential diagnosis of hypercalcemia.

Am J Clin Pathol 1996

The Humoral hypercalcemia of benignancy. A newly appreciated syndrome - Knecht TP et al

PTHrP nelle lesioni tumorali BENIGNE…

• Nel 10-20% dei pz oncologici si presenta come emergenza metabolica• Emergenza per Ca >14 mg/dl (3.5 mmol/L)• Gravità dei sintomi correlata alla velocità di aumento del calcio ionizzato e alla sua concentrazione, alle condizioni generali del e malattie concomitanti

IPERCALCEMIA NEOPLASTICA IPERCALCEMIA NEOPLASTICA

LIVELLI CORRETTI DI CALCIO SIERICOCalcio misurato + [ 0.8 x (4.0 – albumina sierica) ]

TrattamentoTrattamentoIdratazione: NaCl ev 0,25-1 L/h (controllare PVC)Diuretici dell’ansa (furosemide): 20-40 mg ev ogni 2-4h (controllo elettroliti)Bisfosfonati evCalcitonina sc/ev 4-8 U/kg ogni 6-12hCorticosteroidi (cortone acetato-prednisone)Emodialisi

La Seconda più frequente S. ParaneoplasticaLa Seconda più frequente S. Paraneoplastica

Microcitoma polmonare (60%), NET, k tratto urogenitaleMicrocitoma polmonare (60%), NET, k tratto urogenitale

Iposodiemia (<130 mmol/L) / Sodiuria >20 mEq/LIposodiemia (<130 mmol/L) / Sodiuria >20 mEq/LOsmo urin > 100 mOsm/L / Osm plasma < 260 mOsm/LOsmo urin > 100 mOsm/L / Osm plasma < 260 mOsm/L

J Intern Med 1995

Syndrome of Inappropriate secretion of antidiuretic hormone (SIADH) in malignant diseases

Sorensen JB, Anderson MD, Hansen HH

Ann NY Acad Sci 1992

Oxytocin and vasopressin: from genes to peptide

Gainer H, Wray S

Paraneoplastic SIADH

Hypovolaemic

GI losses DiureticsMucosal lossesPancreatitis Sodium depletion post diuretics

Urinary Na<20 mmol/l Urinary Na>40 mmol/l

DiureticsAddison’s diseaseCerebral salt wastingSalt wasting nephropathy

Euvolaemic

HypothyroidismSIADH with ongoing fluid restrictionPrimary polydipsiaInappropriate fluid replacement

SIADH

ACTH deficiency

HypervolaemicCirrhosisCardiac failureNephrotic syndrome

Cardiac failure or cirrhosison diuretic therapy

30-40%

Causes of hyponatraemia

DesmopressinSelective serotonin reuptakeinhibitorsCarbamazepineProstaglandinsTricyclic antidepressantsPhenothiazinesHaloperidol3,4-MethylenedioxymethamphetamineQuinolonesLeveteiracetamCyclophosphamideVincristine

Malignancy

Drugs

Small cell lung cancer 75% dei casiNasopharyngeal cancerMesotheliomaGI tract malignancyPancreatic malignancyGU tract malignancyLymphomaSarcoma

Pneumonia, especially LegionellaMycoplasmaTuberculosisAbscessVasculitisPositive pressure ventilation

Pulmonary

TumourMeningitisEncephalitisAbscessVasculitisSubarachnoid haemorrhageSubdural haemorrhageTraumatic brain injury

Intracranial pathology

Between 1964 and 2002:

413 patients with CS were investigated

60 had an adrenal adenoma,

30 had an adrenal carcinoma,

5 had macronodular adrenal hyperplasia,

274 of pituitary origin (CD)

44 from an ectopic source of ACTH

A COMPARISION BETWEEN THE A COMPARISION BETWEEN THE TWO LARGEST SERIES TWO LARGEST SERIES

ON ECTOPIC ACTH SYNDROMEON ECTOPIC ACTH SYNDROME

EUROPEEUROPE (UK)(UK) vs. vs. USA USA (NIH)(NIH)

(n=40)(n=40) (n=90) (n=90)

MedianMedian follow-up follow-up 60m 60m 26m 26m

Are there regional differences in the ectopic ACTH syndrome in different parts of the developed world

in tertiary referral centres?

ECTOPIC ACTH SYNDROME

4 patients had markedly fluctuant levels of ACTH – cyclical Cushing’s syndrome1 pancreatic carcinoid1 thymic carcinoid1 bronchial carcinoid1 occult source

LUNG 47.5% (major organ)

- CARCINOID 30%- SCLC 17.5%

Intrathoracic in general 55%

OCCULT 12.5%

LUNG 42.2% (major organ)

- CARCINOID 38%- SCLC 3%- Tumorlets 0.9%

Intrathoracic in general 52%

OCCULT 19%

St. Bartholomew’s NIH

ECTOPIC ACTH ECTOPIC ACTH SYNDROMESYNDROME 40 patients

26 revealed on imaging (overt)14 not apparent

○ 9 became apparent (covert)○ 5 remained hidden (occult)

Barts experience: 1969-2001 (Isidori et al., 2005)

COVERTCOVERT ECTOPIC ACTH SYNDROME

Of 9 tumours not initially identified:

Revealed by CT 4Revealed by whole-body catheter *

2Found at surgery/autopsy 3

USING MODERN CROSS-SECTIONAL IMAGINGVIRTUALLY ALL ECTOPICS WHICH CAN BE

FOUND WILL BE FOUND

(Isidori et al., 2005)*before high-quality CT

Mean ACTH levels:Overt 207 ng/lCovert 125 ng/l

Mean Cortisol levelsOvert 1422 nmol/lCovert 1065

nmol/l

Mean K+ levelsOvert 2.7 mmol/lCovert 2.8

mmol/l

Hypokalaemia in 70%

Mean ACTH levels:Overt 205 ng/lCovert 109 ng/l

Mean UFCOvert 8810

nmol/24hCovert 12170

nmol/24h

Mean K+ levelsOvert 3.4 mmol/lCovert 3.5 mmol/l

Hypokalaemia in 74%

St. Bartholomew’s NIH

ECTOPIC ACTH SYNDROMEDynamic Stimulation Tests

High-dose dexamethasone suppression○ 91% show absent suppression (>50%)

CRH stimulation test○ 94% show absent rise (>20%)

One patient showed a response to both tests (1/40=2%)

ECTOPIC ACTH SYNDROME:NIH experience

High-dose dexamethasone suppression○ 86% show absent suppression (UFC)

CRH stimulation test○ 92% show absent rise (>20%)

Dynamic Stimulation Tests

ECTOPIC ACTH SYNDROME

BILATERAL INFERIOR PETROSAL SINUS SAMPLING

1/12 patients showed a central gradient >3 (mesothelioma)At NIH, 1/67 patients showed a central gradient (esthesioneuroblastoma)

Therefore, false positive responses in 2/79 (~2%)

ECTOPIC ACTH SYNDROMETUMOUR MARKERS

28% show raised gastrin28% show raised calcitonin10% show raised urinary 5-HIAA

At NIH31% show raised calcitonin30% show raised 5-HIAA

ECTOPIC ACTH SYNDROMEWHOLE BODY VENOUS CATHETER STUDIES

4/22 WERE POSITIVE○ 2 thymic carcinoids○ 1 mediastinal lymph node○ 1 medullary thyroid carcinoma

BUT THESE WERE ALL STUDIED BEFORE HIGH-RESOLUTION CT SCANNING

IMAGING

CT LOCALISED TUMOUR IN 82% (NIH=92%)

111In-octreotide localised tumor in 2/8 (25%)At NIH, 21/43 (49%) were positiveBUT IT VERY RARELY IDENTIFIES TUMOURS

NOT OTHERWISE SEEN!

ECTOPIC ACTH SYNDROME

TREATMENT

28/40 treated with steroidogenesis inhibitors for median 9 months

MetyraponeKetoconazoleMitotane

One patient needed intravenous etomidate

ECTOPIC ACTH SYNDROME

TREATMENT

12 patients had primary resection, 10 curative

12 patients had bilateral adrenalectomy14 patients received radiotherapy11 patients received chemotherapy2 patients received 131I-MIBG therapy

CONCLUSION – Control cortisol excess, remove tumour where possible, consider removing adrenals where not

ECTOPIC ACTH SYNDROME

Kaplan-Meier survival curve for ectopic ACTH patients

0.0

00

.25

0.5

00

.75

1.0

0

0 100

200

300Survival

(months)

Small cell NET mets

NET

(Isidori et al., 2005)

Prevalence of Tumours responsible of EAS

Percentage(%)

0

10

20

30

40

50

60

Lung

/Med

iast

. Car

cino

ids

Lung

SC

LC /

Ade

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Thym

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Med

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Pheo

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Thoracic Tumours

Abdominal Tumours

Total n=383

WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria) - caused by tumor production of vasoactive intestinal polypeptide (VIP).Islet cell tumors, Intestinal carcinoid

tumors Polycythemia - caused by tumor

production of erythropoietinsRenal cell carcinoma, Cerebellar

hemangioma, Hepatocarcinoma

Paraneoplastic Syndromes Endocrinopathies

Paraneoplastic GI dismotility syndromes

A small proportion of patients with occult or established neoplasms develop a gastrointestinal motility disorder, referred to as paraneoplastic dysmotility.

The diagnosis of a paraneoplastic dysmotility requires the onset of gastrointestinal dysmotility associated with the presence of a tumor and presence of specific serum antibodies

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Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008

Clinical presentation of a para-neoplastic dysmotility syndrome

Pseudoachalasia Gastroparesis Paraneoplastic chronic

intestinal pseudoobstruction (CIPO)

Chronic constipation

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Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008

47Autoimmunity Reviews 6 (2007) 162–168

autonomic paraneoplastic neurological Hu-related

syndromes

Treatment of paraneoplastic Treatment of paraneoplastic dysmotility dysmotility No treatments have been convincingly shown

to alter outcome (steroids, cyclophosphamide, plasmapheresis, immunoglobulin)

Treatment of the underlying primary malignancy

Nutritional support either enterally or parenterally

Prokinetics, treatment of bacterial overgrowth One additional management strategy is to use

high dose IV steroids for 3 days and if there is a clinical response switch to 6-mercatopurine or azathioprine (difficult in the case of chemotherapy)

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Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008

Da autoanticorpi contro la desmoplakina I, proteina dei desmosomi delle cellule epiteliali. Le lesioni bollose pemfigoidi sono conseguenza della perdita della normali adesioni intercellulari a livello dell’epidermide.

Pemfigo

Iperpigmentazione vellutata, di colore marrone scuro o nero, a livello di ascelle, aree sottomammarie e pieghe inguinaliSoprattutto K gastrico.

Acanthosis nigricans

Placca eritematosa, simile ad un eczemaQuando localizzata a livello delle areole mammarie è quasi sempre associata a K duttale della mammella, mentre la malattia di Paget extramammaria si associa in circa il 50% dei casi a neoplasie genitali.

Malattia di Paget

Linfomi, timoma, sarcomi ed altre neoplasie, soprattutto ematologiche

Miopatia infiammatoria associata ad un rash cutaneo violaceo, più evidente nelle aree esposte al sole, edema ed eritema periorbitale, placche eritematose a livello delle articolazioni metacarpofalangee e interfalangee prossimali (papule di Gottron)K polmone, stomaco, utero, ovaio

Dermatomiosite

IttiosiAssociata ai linfomi di HodgkinPlacche cutanee a scaglie

Comparsa improvvisa o aumento in numero e dimensioni di cheratosi seborroicaNeoplasie gastrointestinali

Snd di Leser-Trèlat

Snd di SweetDermatosi neutrofila febbrile acuta (febbre, leucocitosi neutrofila, placche o noduli eritematosi a livello di testa, collo e arti superioriIn particolare in corso di leucemia acuta mieloblastica, sindromi mielodisplastiche e malattie mieloproliferative.

Paraneoplastic Syndromes

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