Presentazione sul tema: "Sindromi paraneoplastiche"— Transcript della presentazione:
1Sindromi paraneoplastiche Andrea M.IsidoriDipartimento di Fisiopatologia MedicaDir. Prof. Andrea Lenzi
2Alterazioni funzionali degli organi interessati dal tumore primitivo Effetti sistemici delle neoplasieAlterazioni funzionali degli organi interessati dal tumore primitivoAlterazioni funzionali degli organi interessati dalla crescita metastaticaEffetti metaboliciEffetti tossiciEffetti 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 tumoraliSindromi paraneoplastiche
3Tumor Host Interactions Local and Systemic Effects (primary site)Metastases (secondary site)( dedifferentation)Cancer CachexiaParaneoplastic SyndromesEndocrinopathiesNeuromyopathiesGastrointestinal motility syndromesOsteochondral DisordersVascular PhenomenaFeverDermatological Syndromes
4Paraneoplastic syndromes 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 “presenting symptom” di una neoplasia misconosciuta (early diagnosis) e un riconoscimento precoce spesso ottimizza le possibilità di interventoRientrano nella diagnosi differenziale di sindromi comuni (ipercalcemia, iponatriemia, ipopotassiemia)
5Paraneoplastic syndromes Le neoplasie più frequentemente associate a sindromi paraneoplastiche sono:Lung carcinoma (most common)Renal carcinomaHepatocellular carcinomaLeukemiasLymphomasBreast tumorsOvarian tumorsNeural cancersGastric cancersPancreatic cancers
6Cancer CachexiaProgressive weakness, loss of appetite, anemia and profound weight loss (>20 lbs.)Often correlates with tumor size and extent of metastasesEtiology includes a generalized increase in metabolism and central effects of tumor on hypothalamusProbably related to macrophage production of TNF-a and IL-1
7Endocrine syndromesHematologic syndromesCutaneous or dermatologic syndromesNeurologic syndromesOsteoarticular or rheumatologic syndromesOcular syndromes
9I primi reports su sindromi endocrine in pazienti affetti da neoplasie maligne non endocrine risalgono agli anni ’20...Lancet 1928A case of pluriglandular syndrome: diabetes of bearded women.Brown WHSurg Gynecol Obster 1923Parathyroid hyperplasia and bone destruction in generelized carcinomatosis.Klemperer P
12Demonstration of elevated hormone concentrations in the blood Endocrine Pathology 2003Paraneoplastic Endocrine Syndromes: A ReviewDeLellis RA, Xia L.“…A number of criteria have been proposed for the diagnosis of paraneoplastic endocrine syndromes…Demonstration of elevated hormone concentrations in the bloodFinding of normal or suppressed endogenous hormone productionDemonstration of hormone concentration gradients across the tumorBiochemical or clinical resolution of the syndrome following surgery, radiotherapy or chemotherapyDemonstration of hormone messenger RNA and corresponding hormonal product in tumoral cells
13Meccanismi patogenetici Endocrine Pathology 2003Paraneoplastic Endocrine Syndromes: A ReviewDeLellis RA, Xia L.Meccanismi patogeneticiTheory of randon genetic derepressionAttivazione di geni normalmente inattivi per effetto di mutazioni o modificazioni epigeneticheDedifferentiation TheoryRegressione delle cellule tumorali ad uno stato maturativo precoce con produzione di proteine e ormoni fetali ed embrionali (ex. PTHrP)
14Paraneoplastic Syndromes Endocrinopathies 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 metastasisParathyroid carcinoma (PTH)
15Paraneoplastic 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
16Ipercalcemia 0,1% della popolazione generale fino a 3-5% >50aaFino al 58% dei pz adulti oncologici ospedalizzati0,5-1,3% in età pediatrica<5% tumori maligni tratto genitale femminileMieloma, K squamoso del polmone (quasi nel 100% dei casi),K mammario, k renale, k del tratto genitale femminile, Linfoma HTLV,Am J Med 1997Hypercalcemia of MalignancyMundy G, Guise TA
17Hypercalcemia Primary hyperparathyroidism 23% Paraneoplastic syndrome Metastasis %(lung, breast cancer, multiple myeloma)Granulomatous desease (tuberculosis, sarcoidosis)Genetic disorders (Familial hypocalciuric hypercalcemia)Long immobilizationMedications (lithium, thiazide diuretics, supplements)DehydrationHyperparathyroidism and cancer are responsible for more than 90% of sustained hypercalcemia.
18Assenza di metastasi ossee PTH ridotto, PTHrP aumentato 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 osteoclastiIpercalcemia Maligna (Humoral Hypercalcemia of Malingnancy -HHM-):da produzione di PTH-RP (PTH-related peptide) o più raramente di PTHIpercalcemiaAssenza di metastasi osseePTH ridotto, PTHrP aumentato
19New Engl J Med 1988 New Engl J Med 2000 Cancer 1991 Humoral Hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptideBroadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AFNew Engl J Med 2000The physiology of parathyroid hormone related proteinStrewler GJIl PTHrP viene individuato nella seconda metà degli anni ’80, espresso in innumerevoli tessuti normali (es. endometrio, placenta, miometrio e decidua durante la gravidanza)3 ISOFORMELa 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 1991Immunohistochemical evaluation of PTHrP in human lung cancer and normal tissue with newly developed monoclonal antibodyKitazawa S et alDosabile con metodo RIA (kit specifici per la porzione C-terminale), PCR, IRMA
20PTHrP nelle lesioni tumorali BENIGNE… Am J Clin Pathol 1996The Humoral hypercalcemia of benignancy. A newly appreciated syndrome Knecht TP et alPTHrP 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.
21IPERCALCEMIA NEOPLASTICA Nel 10-20% dei pz oncologici si presenta come emergenza metabolicaEmergenza 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 concomitantiLIVELLI CORRETTI DI CALCIO SIERICOCalcio misurato + [ 0.8 x (4.0 – albumina sierica) ]TrattamentoIdratazione: NaCl ev 0,25-1 L/h (controllare PVC)Diuretici dell’ansa (furosemide): mg ev ogni 2-4h (controllo elettroliti)Bisfosfonati evCalcitonina sc/ev 4-8 U/kg ogni 6-12hCorticosteroidi (cortone acetato-prednisone)Emodialisi
22Paraneoplastic SIADH La Seconda più frequente S. Paraneoplastica Microcitoma polmonare (60%), NET, k tratto urogenitaleIposodiemia (<130 mmol/L) / Sodiuria >20 mEq/LOsmo urin > 100 mOsm/L / Osm plasma < 260 mOsm/LAnn NY Acad Sci 1992Oxytocin and vasopressin: from genes to peptideGainer H, Wray SJ Intern Med 1995Syndrome of Inappropriate secretion of antidiuretic hormone (SIADH) in malignant diseasesSorensen JB, Anderson MD, Hansen HH
23Causes of hyponatraemia Urinary Na<20 mmol/lUrinary Na>40 mmol/lGI losses DiureticsMucosal lossesPancreatitisSodium depletion post diureticsDiureticsAddison’s diseaseCerebral salt wastingSalt wasting nephropathyHypovolaemic30-40%HypothyroidismSIADH with ongoing fluid restrictionPrimary polydipsiaInappropriate fluid replacementSIADHACTH deficiencyEuvolaemicSIADH rappresenta il 30-40% di tutte le iponatriemieCardiac failure or cirrhosison diuretic therapyCirrhosisCardiac failureNephrotic syndromeHypervolaemic
24Intracranial pathology Small cell lung cancer 75% dei casiNasopharyngeal cancerMesotheliomaGI tract malignancyPancreatic malignancyGU tract malignancyLymphomaSarcomaPulmonaryMalignancyPneumonia, especially LegionellaMycoplasmaTuberculosisAbscessVasculitisPositive pressure ventilationDesmopressinSelective serotonin reuptakeinhibitorsCarbamazepineProstaglandinsTricyclic antidepressantsPhenothiazinesHaloperidol3,4-MethylenedioxymethamphetamineQuinolonesLeveteiracetamCyclophosphamideVincristineIntracranial pathologyTumourMeningitisEncephalitisAbscessVasculitisSubarachnoid haemorrhageSubdural haemorrhageTraumatic brain injuryDrugs
25Between 1964 and 2002:413 patients with CS were investigated60 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
26A COMPARISION BETWEEN THE TWO LARGEST SERIES ON ECTOPIC ACTH SYNDROME EUROPE (UK) vs. USA (NIH)(n=40) (n=90)Medianfollow-up m mAre there regional differences in the ectopic ACTH syndrome in different parts of the developed world in tertiary referral centres?
28St. Bartholomew’s NIH 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%
29ECTOPIC ACTH SYNDROME 40 patients 26 revealed on imaging (overt) 14 not apparent9 became apparent (covert)5 remained hidden (occult)Barts experience:(Isidori et al., 2005)
30COVERT ECTOPIC ACTH SYNDROME Of 9 tumours not initially identified:Revealed by CT 4Revealed by whole-body catheter * 2Found at surgery/autopsy 3USING MODERN CROSS-SECTIONAL IMAGINGVIRTUALLY ALL ECTOPICS WHICH CAN BEFOUND WILL BE FOUND*before high-quality CT(Isidori et al., 2005)
32ECTOPIC ACTH SYNDROME Dynamic Stimulation Tests High-dose dexamethasone suppression91% show absent suppression (>50%)CRH stimulation test94% show absent rise (>20%)One patient showed a response to both tests (1/40=2%)
33ECTOPIC ACTH SYNDROME: NIH experience Dynamic Stimulation TestsHigh-dose dexamethasone suppression86% show absent suppression (UFC)CRH stimulation test92% show absent rise (>20%)
34ECTOPIC 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%)
35ECTOPIC ACTH SYNDROME TUMOUR MARKERS At NIH 28% show raised gastrin 28% show raised calcitonin10% show raised urinary 5-HIAAAt NIH31% show raised calcitonin30% show raised 5-HIAA
36ECTOPIC ACTH SYNDROMEWHOLE BODY VENOUS CATHETER STUDIES4/22 WERE POSITIVE2 thymic carcinoids1 mediastinal lymph node1 medullary thyroid carcinomaBUT THESE WERE ALL STUDIED BEFORE HIGH-RESOLUTION CT SCANNING
37ECTOPIC ACTH SYNDROME 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!
38ECTOPIC ACTH SYNDROME One patient needed intravenous etomidate TREATMENT28/40 treated with steroidogenesis inhibitors for median 9 monthsMetyraponeKetoconazoleMitotaneOne patient needed intravenous etomidate
39ECTOPIC ACTH SYNDROME 12 patients had primary resection, 10 curative TREATMENT12 patients had primary resection, 10 curative12 patients had bilateral adrenalectomy14 patients received radiotherapy11 patients received chemotherapy2 patients received 131I-MIBG therapyCONCLUSION – Control cortisol excess, remove tumour where possible, consider removing adrenals where not
40Kaplan-Meier survival curve for ectopic ACTH patients 0.000.250.500.751.00100200300Survival (months)Small cellNET metsNET(Isidori et al., 2005)
41Prevalence of Tumours responsible of EAS 60Percentage(%)Total n=383Thoracic Tumours504030Abdominal Tumours2010GI carcinoidsNever-foundThymic tumoursIslet Cell TumoursLocalized NETMedullary Thyroid KLung/Mediast. CarcinoidsLung SCLC / AdenokPheochromocytomasDisseminated NETGI adenocarcinomasMiscellaneous Tumours
45Paraneoplastic 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 antibodiesKashyap P and Farrugia G, Gastroenterol Clin North Am. 2008
46Clinical presentation of a para-neoplastic dysmotility syndrome PseudoachalasiaGastroparesisParaneoplastic chronic intestinal pseudoobstruction (CIPO)Chronic constipationThe most common neuronal autoantibody associated with a paraneoplastic dysmotility is the type 1 antineuronal nuclear antibody (ANNA-1) [1,2]. ANNA-1 recognizes the nuclear protein Hu which belongs to a family of conserved RNA binding proteins that includes HuC, HuD, HuR and Hel-N1. are expressed in the neurons of the central, peripheral and enteric nervous system, with the exception of HuR which is ubiquitously expressed in proliferating cells . The tumor that most commonly expresses ANNA-1 is small cell lung cancer . Other tumors that mayexpress ANNA-1 include breast, prostate, ovarian carcinomas and lymphomas . Antibodies to ANNA-1 are consequently, most commonly found in patients with small cell lung cancer with associated paraneoplastic gastrointestinal dysmotility. Although there is a very strong association between the presence of ANNA-1 in the setting of a gastrointestinal motility disorder and the presence of an occult or manifest tumor, the exact mechanism by which ANNA-1 antibodies cause enteric neuronal dysfunction is still unclear as the proteins to which the antibody is directed are not expressed on the cell membrane. However, there is some evidence that the antibodies may directly influence motility. A preliminary study in guinea pig ileum suggested that anti-Hu antibodies impair the ascending excitatory reflex and therefore peristalsis. Enteric neuronal degeneration has also been reported in patients with paraneoplastic dysmotility as a possible pathogenetic mechanism Anti HuD positive sera from patientswith paraneoplastic gut dysmotility disorder as well as commercial Anti HuD antibodies were shown to induce apoptosis in a human neuroblastoma cell line (SH-Sy5Y) as well as guinea pig cultured myenteric neurons. Pardi et al described a patient with sudden onset of gastroparesis and small bowel dysfunction and the presence of high circulating levels of ANNA-1 . This patient was subsequently found to have decreased and disorganized interstitial cells of Cajal networks and a small cell lung cancer expressing c-Kit, also expressed on interstitial cells of Cajal.Calcium channels were originally classified based on pharmacology as L, N, P/Q, R, and T channels, a classification still used today. Thisnomenclature corresponds to the current accepted nomenclature that classifies voltage-gated Ca2+ channels into Cav1.1-Cav1.4 (L-type Ca2+ channels), Cav2.1 (P/Q), Cav2.2 (N), Cav2.3 (R), and Cav3.1- Cav3.3 (T) based on the amino acid sequence of the alpha 1 subunit (the poreforming subunit) of the channel. P or Q type calcium ion channels regulate acetylcholine release at the neuromuscular junction as well as central neurotransmission. N type calcium channels are particularly involved in cerebrocortical, cerebellar, spinal and autonomic neurotransmission. Both channel types are expressed in small cell lung cancer and are common targets of autoantibodies in such patients. These antibodies are predominantly seen in patients with Lambert Eaton myasthenic syndrome in association with small cell lung cancer . Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder of neuromuscular transmission. It is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine (ACh) is impaired, causing a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes. The initial presentation can be similar to that of myasthenia gravis, but the progressions of the two diseases have some important differences.Another class of autoantibodies associated with gastrointestinal dysmotility is antibodies against neuronal nicotinic acetylcholine receptors. Antibodies directed towards the extracellular segment of acetylcholine receptor protein in the post synaptic membrane of skeletal muscle are found in patients with myasthenia gravis associated with thymic epithelial tumors . Neuronal nicotinic acetylcholine receptors are also present on neurons in the sympathetic and parasympathetic nervous systems as well as the enteric nervous system. Antibodies targeting this protein can disrupt cholinergic synaptic transmission leading to autonomic failure. These antibodies are seen in both idiopathic and paraneoplastic forms of autonomic neuropathy resulting in autoimmune autonomic neuropathy . Mice injected with rabbit IgG containing ganglionic acetylcholine receptor antibodies develop gastrointestinal dysmotility and autonomic dysfunction. Similar results are obtained by injecting mice with sera from patients with ganglionic acetylcholine receptor antibody.Purkinje Cell Cytoplasmic Autoantibody, type 1 (PCA1) This autoantibody (sometimes called “anti-Yo”) targets a neuronal signal transduction protein Cdr. The antibody was originally defined as a marker of paraneoplastic cerebellar degeneration related to ovarian or breast carcinoma with remarkably limited metastasis [17,18]. In vitro, its Cdr antigen, a prominent cytoplasmic component of large neurons in the central and autonomic/ enteric nervous systems , has been shown to promote neuronal apoptosis and degeneration by inhibiting c-myc transcriptional activity . Paraneoplastic gastrointestinal dysmotility has been documented in a minority of PCA-1 seropositive patients (with and without cerebellar ataxia) in association with gynecological or breast carcinoma .Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008
47autonomic paraneoplastic neurological Hu-related syndromes A possible autoimmune model for autonomic paraneoplastic neurological Hu-related syndromes. In the lymph nodes, the apoptotic tumour cell isphagocytosed by antigen-presenting dendritic cells, and the tumour antigens are processed and presented to circulating CD8+ T lymphocytes (CTL) via themajor histocompatibility complex (MHC) class I pathway. Activated CTL cross the blood brain barrier (BBB) and, together with inflammatory cells, induceneuronal apoptosis through cell-mediated interactions. In addition, plasma cells may cross the BBB or differentiate within the nervous system (activatedthrough cooperation between B cells and T helper CD4+ cells) and produce antibodies (Ab) directed against tumour Hu antigens that crossreact withneuronal antigens with similar epitopes (Hu neuronal proteins). These onconeural antibodies are able to infiltrate neurones by active uptake and bind tointranuclear Hu proteins. Essential processes for cell survival are, thus, compromised and apoptotic neurone death is triggered. Dying or dead neuronesthemselves can be taken up by neighbouring APCs and a positive feedback process initiated, which contributes to epitope spreading.autonomic paraneoplastic neurological Hu-related syndromesAutoimmunity Reviews 6 (2007) 162–168
48Treatment of paraneoplastic dysmotility No treatments have been convincingly shown to alter outcome (steroids, cyclophosphamide, plasmapheresis, immunoglobulin)Treatment of the underlying primary malignancyNutritional support either enterally or parenterallyProkinetics, treatment of bacterial overgrowthOne 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, Gastroenterol Clin North Am. 2008
50Pemfigo Acanthosis nigricans Malattia di Paget 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 ematologicheAcanthosis nigricansIperpigmentazione vellutata, di colore marrone scuro o nero, a livello di ascelle, aree sottomammarie e pieghe inguinaliSoprattutto K gastrico.Malattia di PagetPlacca 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.
51Dermatomiosite Ittiosi Snd di Leser-Trèlat Snd di Sweet 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, ovaioIttiosiAssociata ai linfomi di HodgkinPlacche cutanee a scaglieSnd di Leser-TrèlatComparsa improvvisa o aumento in numero edimensioni di cheratosi seborroicaNeoplasie gastrointestinaliSnd 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.