Sindromi paraneoplastiche

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

2. Effetti sistemici delle neoplasie Alterazioni funzionali degli organi interessati dal tumore primitivo Alterazioni funzionali degli organi interessati dalla crescita metastatica Effetti metabolici Effetti tossici 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

3. TumorHost 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. Paraneoplasticsyndromes • Le Sindromi paraneoplastiche, per definizione, sono fenomeni 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 “presentingsymptom” di una neoplasia misconosciuta (earlydiagnosis) e un riconoscimento precoce spesso ottimizza le possibilità di intervento • Rientrano nella diagnosi differenziale di sindromi comuni (ipercalcemia, iponatriemia, ipopotassiemia)

5. Paraneoplasticsyndromes • 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

6. CancerCachexia • 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-a and IL-1

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

8. Sindromi paraneoplastiche endocrine

9. 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

11. Spectrum of paraneoplastic endocrine HYPERCALCEMIA HYPONATRIEMIA PTHrP, TGFs, ILs, Vit D, PTH GYNECOMASTIA Vasopressin, ANP HCG CUSHING’s ACTH, CRH ACROMEGALY Paraneoplastic Endocrine Syndromes GH, GHRH HYPOGLYCEMIA IGF II ONCOGENIC OSTEOMALACIA HYPERGLYCEMIA FGF23 HPL, PRL, VIP, Renin, LH, GRP Glucagone, GH, DIVERSE SYNTOMS

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

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. Paraneoplastic SyndromesEndocrinopathies • 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-a) • Renal cell carcinoma (prostaglandins) • Breast (& Prostate) carcinoma, usually by bone metastasis • Parathyroid carcinoma (PTH)

15. Paraneoplastic SyndromesEndocrinopathies • Inappropriate ADH syndrome (Hyponatremia) • Small cell undifferentiated lung cancer (vassopressin-like hormone. • Hypothalamic tumors (vasopressin) • Cushing’s 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. Hypercalcemia Primaryhyperparathyroidism23% Paraneoplasticsyndrome Metastasis72% (lung, breastcancer, multiple myeloma) Granulomatousdesease (tuberculosis, sarcoidosis) Geneticdisorders (Familialhypocalciurichypercalcemia) Long immobilization Medications (lithium, thiazidediuretics, supplements) Dehydration Hyperparathyroidism and cancer are responsiblefor more than 90% of sustainedhypercalcemia.

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. 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 New Engl J Med 2000 The physiology of parathyroid hormone related protein Strewler GJ 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) Cancer 1991 Immunohistochemical evaluation of PTHrP in human lung cancer and normal tissue with newly developed monoclonal antibody Kitazawa S et al Dosabile con metodo RIA (kit specifici per la porzione C-terminale), PCR, IRMA

20. Am J Clin Pathol 1996 The Humoral hypercalcemia of benignancy. A newly appreciated syndrome - Knecht TP et al PTHrP nelle lesioni tumorali BENIGNE… • 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.

21. IPERCALCEMIA NEOPLASTICA • 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 LIVELLI CORRETTI DI CALCIO SIERICO Calcio misurato + [ 0.8 x (4.0 – albumina sierica) ] Trattamento Idratazione: NaClev 0,25-1 L/h (controllare PVC) Diuretici dell’ansa (furosemide): 20-40 mg ev ogni 2-4h (controllo elettroliti) Bisfosfonatiev Calcitonina sc/ev 4-8 U/kg ogni 6-12h Corticosteroidi (cortone acetato-prednisone) Emodialisi

22. ParaneoplasticSIADH La Seconda più frequente S. Paraneoplastica Microcitoma polmonare (60%), NET, k tratto urogenitale Iposodiemia (<130 mmol/L) / Sodiuria >20 mEq/L Osmourin > 100 mOsm/L / Osm plasma < 260 mOsm/L Ann NY Acad Sci 1992 Oxytocin and vasopressin: from genes to peptide Gainer H, Wray S J InternMed 1995 Syndrome of Inappropriate secretion of antidiuretichormone (SIADH) in malignantdiseases Sorensen JB, Anderson MD, Hansen HH

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

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

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 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 Cushing’s 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. Bartholomew’s 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: 1969-2001 (Isidori et al., 2005)

30. COVERTECTOPIC ACTH SYNDROME Of 9 tumours not initially identified: • Revealed by CT 4 • Revealed by whole-body catheter * 2 • Found at surgery/autopsy 3 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  12170 nmol/24h Mean K+ levels Overt  3.4 mmol/l Covert  3.5 mmol/l Hypokalaemia in 74% St. Bartholomew’s 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. ECTOPIC ACTH SYNDROME 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. ECTOPIC ACTH SYNDROME IMAGING • CT LOCALISED TUMOUR IN 82% (NIH=92%) • 111In-octreotide localised tumor in 2/8 (25%) • At NIH, 21/43 (49%) were positive • BUT IT VERY RARELY IDENTIFIES TUMOURS NOT OTHERWISE SEEN!

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

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

40. 1.00 0.75 0.50 0.25 0.00 0 100 200 300 Survival (months) NET Small cell NET mets Kaplan-Meier survival curve for ectopic ACTH patients (Isidori et al., 2005)

41. Prevalence of Tumours responsible of EAS 60 Percentage (%) Total n=383 Thoracic Tumours 50 40 30 Abdominal Tumours 20 10 0 Never-found GI carcinoids Localized NET Thymic tumours Islet Cell Tumours Disseminated NET Medullary Thyroid K Pheochromocytomas GI adenocarcinomas Lung SCLC / Adenok Lung/Mediast. Carcinoids Miscellaneous Tumours

43. Paraneoplastic SyndromesEndocrinopathies • 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

44. Sindromi paraneoplastiche Gastro-motorie

45. Paraneoplastic GI dismotilitysyndromes • 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 Kashyap P and Farrugia G, GastroenterolClin North Am. 2008

46. Clinical presentation of a para-neoplastic dysmotility syndrome • Pseudoachalasia • Gastroparesis • Paraneoplasticchronicintestinalpseudoobstruction (CIPO) • Chronicconstipation Kashyap P and Farrugia G, GastroenterolClin North Am. 2008

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

48. Treatment of paraneoplasticdysmotility • 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 bacterialovergrowth • 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) Kashyap P and Farrugia G, GastroenterolClin North Am. 2008

50. Pemfigo 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. Linfomi, timoma, sarcomi ed altre neoplasie, soprattutto ematologiche Acanthosis nigricans Iperpigmentazione vellutata, di colore marrone scuro o nero, a livello di ascelle, aree sottomammarie e pieghe inguinali Soprattutto K gastrico. Malattia di Paget 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.