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Andrea M.Isidori Dipartimento di Fisiopatologia Medica Dir. Prof. Andrea Lenzi.

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Presentazione sul tema: "Andrea M.Isidori Dipartimento di Fisiopatologia Medica Dir. Prof. Andrea Lenzi."— Transcript della presentazione:

1 Andrea M.Isidori Dipartimento di Fisiopatologia Medica Dir. Prof. Andrea Lenzi

2 Alterazioni funzionali degli organi interessati dal tumore primitivo Alterazioni funzionali degli organi interessati dalla crescita metastatica Effetti conseguenti allazione di mediatori noti ed ignoti (fattori di crescita, citokine, ormoni) prodotti dal tumore o derivanti dallazione di autoAb prodotti dallorganismo contro le cellule tumorali Sindromi paraneoplastiche Effetti tossici Effetti metabolici Effetti sistemici delle neoplasie

3 Tumor Host Interactions Tumor Host Interactions Local and Systemic Effects (primary site) Metastases (secondary site)( dedifferentation) Cancer Cachexia Paraneoplastic Syndromes Endocrinopathies Neuromyopathies Gastrointestinal motility syndromes Osteochondral Disorders Vascular Phenomena Fever Dermatological Syndromes

4 Paraneoplastic syndromes Paraneoplastic syndromes fenomeni legati allinterazione neoplasia-ospite Le Sindromi paraneoplastiche, per definizione, sono fenomeni legati allinterazione 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. Cushings) 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) 4

5 Paraneoplastic 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 5

6 Cancer 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

7 Endocrine syndromes Cutaneous or dermatologic syndromes Hematologic syndromes Neurologic syndromes Osteoarticular or rheumatologic syndromes Ocular syndromes

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

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11 Paraneoplastic Endocrine Syndromes PTHrP, TGFs, ILs, Vit D, PTH HYPERCALCEMIA ONCOGENIC OSTEOMALACIA ACROMEGALY GYNECOMASTIA HYPONATRIEMIA CUSHINGs 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,

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

13 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)

14 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 metastasis Parathyroid carcinoma (PTH) Paraneoplastic Syndromes Endocrinopathies

15 Inappropriate ADH syndrome (Hyponatremia) Small cell undifferentiated lung cancer (vassopressin-like hormone. Hypothalamic tumors (vasopressin ) Cushings Syndrome Small cell undifferentiated lung cancer (ACTH) released through cleavage of pro-opiomelano- cortin gene product. MTC, Thymoma, Ovarian Cancer, Mesothelioma

16 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

17 Primary hyperparathyroidism 23% Paraneoplastic syndrome Metastasis72% (lung, breast cancer, multiple myeloma ) Granulomatous desease (tuberculosis, sarcoidosis) Genetic disorders (Familial hypocalciuric hypercalcemia) Long immobilization Medications (lithium, thiazide diuretics, supplements) Dehydration Hyperparathyroidism and cancer are responsible for more than 90% of sustained hypercalcemia. Hypercalcemia

18 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 Ipercalcemia Assenza di metastasi ossee PTH ridotto, PTHrP aumentato

19 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

20 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…

21 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 LIVELLI CORRETTI DI CALCIO SIERICO Calcio misurato + [ 0.8 x (4.0 – albumina sierica) ] Trattamento Idratazione: NaCl ev 0,25-1 L/h (controllare PVC) Diuretici dellansa (furosemide): mg ev ogni 2-4h (controllo elettroliti) Bisfosfonati ev Calcitonina sc/ev 4-8 U/kg ogni 6-12h Corticosteroidi (cortone acetato-prednisone) Emodialisi

22 La Seconda più frequente S. Paraneoplastica Microcitoma polmonare (60%), NET, k tratto urogenitale Iposodiemia ( 20 mEq/L Osmo urin > 100 mOsm/L / Osm plasma 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

23 Hypovolaemic GI losses Diuretics Mucosal losses Pancreatitis Sodium depletion post diuretics Urinary Na<20 mmol/lUrinary Na>40 mmol/l Diuretics Addisons disease Cerebral salt wasting Salt wasting nephropathy Euvolaemic Hypothyroidism SIADH with ongoing fluid restriction Primary polydipsia Inappropriate fluid replacement SIADH ACTH deficiency Hypervolaemic Cirrhosis Cardiac failure Nephrotic syndrome Cardiac failure or cirrhosis on diuretic therapy 30-40% Causes of hyponatraemia

24 Desmopressin Selective serotonin reuptake inhibitors Carbamazepine Prostaglandins Tricyclic antidepressants Phenothiazines Haloperidol 3,4-Methylenedioxymethamphetamine Quinolones Leveteiracetam Cyclophosphamide Vincristine Malignancy Drugs Small cell lung cancer 75% dei casi Nasopharyngeal cancer Mesothelioma GI tract malignancy Pancreatic malignancy GU tract malignancy Lymphoma Sarcoma Pneumonia, especially Legionella Mycoplasma Tuberculosis Abscess Vasculitis Positive pressure ventilation Pulmonary Tumour Meningitis Encephalitis Abscess Vasculitis Subarachnoid haemorrhage Subdural haemorrhage Traumatic brain injury Intracranial pathology

25 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

26 A COMPARISION BETWEEN THE TWO LARGEST SERIES ON ECTOPIC ACTH SYNDROME EUROPE(UK) vs.USA (NIH) (n=40) (n=90) Median follow-up 60m 26m follow-up 60m 26m Are there regional differences in the ectopic ACTH syndrome in different parts of the developed world in tertiary referral centres?

27 ECTOPIC ACTH SYNDROME 4 patients had markedly fluctuant levels of ACTH – cyclical Cushings syndrome 1 pancreatic carcinoid 1 thymic carcinoid 1 bronchial carcinoid 1 occult source

28 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. Bartholomews NIH

29 ECTOPIC ACTH SYNDROME 40 patients 26 revealed on imaging (overt) 14 not apparent 9 became apparent (covert) 5 remained hidden (occult) Barts experience: (Isidori et al., 2005)

30 COVERT COVERT ECTOPIC ACTH SYNDROME Of 9 tumours not initially identified: Revealed by CT 4 Revealed by whole-body catheter *2 Found at surgery/autopsy3 USING MODERN CROSS-SECTIONAL IMAGING VIRTUALLY ALL ECTOPICS WHICH CAN BE FOUND WILL BE FOUND (Isidori et al., 2005) *before high-quality CT

31 Mean ACTH levels: Overt 207 ng/l Covert 125 ng/l Mean Cortisol levels Overt 1422 nmol/l Covert 1065 nmol/l Mean K + levels Overt 2.7 mmol/l Covert 2.8 mmol/l Hypokalaemia in 70% Mean ACTH levels: Overt 205 ng/l Covert 109 ng/l Mean UFC Overt 8810 nmol/24h Covert nmol/24h Mean K + levels Overt 3.4 mmol/l Covert 3.5 mmol/l Hypokalaemia in 74% St. Bartholomews NIH

32 ECTOPIC ACTH SYNDROME Dynamic 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%)

33 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

34 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%)

35 ECTOPIC ACTH SYNDROME TUMOUR MARKERS 28% show raised gastrin 28% show raised calcitonin 10% show raised urinary 5-HIAA At NIH 31% show raised calcitonin 30% show raised 5-HIAA

36 WHOLE 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

37 IMAGING CT LOCALISED TUMOUR IN 82% (NIH=92%) 111 In-octreotide localised tumor in 2/8 (25%) At NIH, 21/43 (49%) were positive BUT IT VERY RARELY IDENTIFIES TUMOURS NOT OTHERWISE SEEN! ECTOPIC ACTH SYNDROME

38 TREATMENT 28/40 treated with steroidogenesis inhibitors for median 9 months Metyrapone Ketoconazole Mitotane One patient needed intravenous etomidate ECTOPIC ACTH SYNDROME

39 TREATMENT 12 patients had primary resection, 10 curative 12 patients had bilateral adrenalectomy 14 patients received radiotherapy 11 patients received chemotherapy 2 patients received 131 I-MIBG therapy CONCLUSION – Control cortisol excess, remove tumour where possible, consider removing adrenals where not ECTOPIC ACTH SYNDROME

40 Kaplan-Meier survival curve for ectopic ACTH patients Survival (months) Small cell NET mets NET (Isidori et al., 2005)

41 Prevalence of Tumours responsible of EAS Percentage (%) Lung/Mediast. Carcinoids Lung SCLC / Adenok Thymic tumours Medullary Thyroid K Islet Cell Tumours Pheochromocytomas GI carcinoids GI adenocarcinomas Disseminated NET Localized NET Miscellaneous Tumours Never-found Thoracic Tumours Abdominal Tumours Total n=383

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43 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 erythropoietins Renal cell carcinoma, Cerebellar hemangioma, Hepatocarcinoma Paraneoplastic Syndromes Endocrinopathies

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45 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 45 Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008

46 Clinical presentation of a para- neoplastic dysmotility syndrome Pseudoachalasia Gastroparesis Paraneoplastic chronic intestinal pseudoobstruction (CIPO) Chronic constipation Pseudoachalasia Gastroparesis Paraneoplastic chronic intestinal pseudoobstruction (CIPO) Chronic constipation 46 Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008

47 47 Autoimmunity Reviews 6 (2007) 162–168 autonomic paraneoplastic neurological Hu-related syndromes

48 Treatment of paraneoplastic dysmotility Treatment of paraneoplastic 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) 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) 48 Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008

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50 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 dellepidermide. Pemfigo Iperpigmentazione vellutata, di colore marrone scuro o nero, a livello di ascelle, aree sottomammarie e pieghe inguinali Soprattutto K gastrico. Acanthosis nigricans Placca eritematosa, simile ad un eczema Quando 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

51 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 Ittiosi Associata ai linfomi di Hodgkin Placche cutanee a scaglie Comparsa improvvisa o aumento in numero e dimensioni di cheratosi seborroica Neoplasie gastrointestinali Snd di Leser-Trèlat Snd di Sweet Dermatosi neutrofila febbrile acuta (febbre, leucocitosi neutrofila, placche o noduli eritematosi a livello di testa, collo e arti superiori In particolare in corso di leucemia acuta mieloblastica, sindromi mielodisplastiche e malattie mieloproliferative.

52 Paraneoplastic Syndromes Think about it…

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