1. Sindromi paraneoplastiche da dismotilità gastrointestinale Rosario Cuomo AOU “Federico II” – Napoli rcuomo@unina.it Joint Meeting GISMAD-AIGO-SIED-SIGE DISTURBI DELLA MOTILITA’ GI NELLE PATOLOGIE SISTEMICHE Joint Meeting GISMAD-AIGO-SIED-SIGE DISTURBI DELLA MOTILITA’ GI NELLE PATOLOGIE SISTEMICHE Verona, martedì 9 Marzo 2010 1

2. Paraneoplastic syndromes Paraneoplastic disorders are non metastatic syndromes that are not attributable to toxicity of cancer therapy, infection, or toxic/metabolic causes. They are clinically important for several reasons: – Paraneoplastic disorders often cause severe and permanent morbidity. – The symptoms are the presenting feature of an otherwise undiagnosed tumor, and so the clinician must be able to recognize and diagnose these syndromes promptly. – The paraneoplastic syndromes are an important part of the differential diagnosis of dysfunction. – Early diagnosis of a paraneoplastic disorder maximizes the likelihood of successful tumor treatment 2

3. Paraneoplastic syndromes The most common cancers associated with paraneoplastic syndromes include – Lung carcinoma (most common) – Renal carcinoma – Hepatocellular carcinoma – Leukemias – Lymphomas – Breast tumors – Ovarian tumors – Neural cancers – Gastric cancers – Pancreatic cancers 3

4. Paraneoplastic syndromes General paraneoplastic symptoms Cutaneous paraneoplastic syndromes Endocrine paraneoplastic syndromes GI paraneoplastic syndromes GI paraneoplastic syndromes Hematologic paraneoplastic syndromes Neurologic paraneoplastic syndromes Neurologic paraneoplastic syndromes Renal paraneoplastic syndrome Rheumatologic paraneoplastic syndromes 4

5. 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 Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008 5

6. Clinical presentation of a paraneoplastic dysmotility syndrome Pseudoachalasia Paraneoplastic Gastroparesis Paraneoplastic chronic intestinal pseudoobstruction Chronic constipation Pseudoachalasia Paraneoplastic Gastroparesis Paraneoplastic chronic intestinal pseudoobstruction Chronic constipation Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008 6

7. SCLC=small-cell lung cancer; lambert-eaton myastenic syndrome 7

8. Enteric Autoantibodies and Gut Motility Disorders Antibodies associated with paraneoplastic and idiopathic dysmotility – Type 1 antineuronal nuclear antibody (ANNA-1) – Type 1 antineuronal nuclear antibody (ANNA-1) recognize nuclear protein Hu (in the neurons of the central, peripheral and enteric nervous system) – Calcium channel antibodies – Calcium channel antibodies (Antibodies to P/Q and N type calcium channels; less frequently found compared to ANNA-1 antibodies; may coexist with ANNA-1) – Antibodies against neuronal nicotinic acetylcholine receptors – Antibodies against neuronal nicotinic acetylcholine receptors (ganglionic antibodies often determine symptoms of gastrointestinal dysmotility) – Purkinje Cell Cytoplasmic Autoantibody, type 1 (PCA1) – Purkinje Cell Cytoplasmic Autoantibody, type 1 (PCA1) (Gastrointestinal dysmotility in a minority of PCA-1 seropositive patients +/- cerebellar ataxia in association with gynecological or breast carcinoma Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008 8

9. Journal of Autoimmunity (1999) 9

10. Autoimmunity Reviews 6 (2007) 162–168 10

11. GASTROENTEROLOGY 2004;126:1872–1883 Antineuronal antibodies of the Hu type in a 55-year-old patient with paraneoplastic syndrome characterized by CIPO related to an occult small-cell lung carcinoma 11

12. A 68-yr-old man developed anorexia, early satiety, nausea, and constipation and lost approximately 20 lb in 3 months. He subsequently developed daily nausea and vomiting with dysgeusia and increased anorexia. Am J Gastroenterol 2002 12

13. Am J Gastroenterol 2002 Normal human jejunal tissue Patient’s jejunal biopsy MP-ICC = c-Kit positive interstizial cell of Cajal in mienteric plexus CM = circular muscle; LM = longitudinal muscle MP-ICC = c-Kit positive interstizial cell of Cajal in mienteric plexus CM = circular muscle; LM = longitudinal muscle 13

14. Am J Gastroenterol 2002 Hematoxylin-eosin stain Immunoreactivity of the Kit protein Metastatic small-cell lung carcinoma cells in the biopsied mediastinal lymphnode 14

15. Am J Gastroenterol 2001;96:373–379 Summary of Patients Studied 15

16. Am J Gastroenterol 2001;96:373–379 Results of Manometric and Radiographic Images in Patients With SCLC Results of Serological Tests for Neuronal Autoantibodies Results of Serological Tests for Neuronal Autoantibodies 16

17. Upright plain film of the abdomen demonstrating sitz markers throughout the colon 1 month after sitz marker ingestion Supine film of the abdomen taken 1 year after the film shown in Fig 1. Extensive distention of the colon with stool is noted. Nineteen stiz markers ingested a year previously are retained. A gastrostomy tube is present. Neurogastroenterol Motil (2005) 17, 16–22 63-year-old woman 17

18. Neurogastroenterol Motil (2005) 17, 16–22 Lymphoplasmacytic infiltrate is noted in the location of the myenteric plexus. 18

19. J Support Oncol 2007;5:355–363 Pathogenesis of Malignant Gastroparesis in Various Cancer Types 19

20. J Support Oncol 2007;5:355–363 20

21. J Support Oncol 2007;5:355–363 Medical Management of Gastroparesis 21

22. J Support Oncol 2007;5:355–363 Enteral tubes for the management of malignant gastroparesis 22

23. Management algorithm for paraneoplastic dysmotility Insufficient evidence to recommend a paraneoplastic antibody profile on every patient with new onset of a gut motility disorder The presence of significant weight loss, a rapid onset of the disease, a past or present smoking history should prompt to consider testing for the presence of autoantibodies ANNA-1 positivity: start with a CT chest and if negative follow up with a PET scan and directed biopsies of any suspicious lymph nodes or masses if indicated (SCLC 13%) The presence of other autoantibodies without concomitant ANNA-1 positivity is less likely to predict the presence of a malignancy Insufficient evidence to recommend a paraneoplastic antibody profile on every patient with new onset of a gut motility disorder The presence of significant weight loss, a rapid onset of the disease, a past or present smoking history should prompt to consider testing for the presence of autoantibodies ANNA-1 positivity: start with a CT chest and if negative follow up with a PET scan and directed biopsies of any suspicious lymph nodes or masses if indicated (SCLC 13%) The presence of other autoantibodies without concomitant ANNA-1 positivity is less likely to predict the presence of a malignancy Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008 23

24. 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) Kashyap P and Farrugia G, Gastroenterol Clin North Am. 2008 24