Sindromi paraneoplastiche da dismotilità gastrointestinale

Sindromi paraneoplastiche da dismotilità gastrointestinale

Rosario CuomoAOU “Federico II” – Napoli

rcuomo@unina.it

Joint Meeting GISMAD-AIGO-SIED-SIGEDISTURBI DELLA MOTILITA’ GI NELLE

PATOLOGIE SISTEMICHE

Verona, martedì 9 Marzo 2010

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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

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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

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Paraneoplastic syndromes

• General paraneoplastic symptoms• Cutaneous paraneoplastic syndromes• Endocrine paraneoplastic syndromes• GI paraneoplastic syndromesGI paraneoplastic syndromes• Hematologic paraneoplastic syndromes• Neurologic paraneoplastic syndromesNeurologic paraneoplastic syndromes• Renal paraneoplastic syndrome• Rheumatologic paraneoplastic syndromes

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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. 20085

Clinical presentation of a paraneoplastic dysmotility syndrome

• Pseudoachalasia • Paraneoplastic Gastroparesis• Paraneoplastic chronic intestinal

pseudoobstruction• Chronic constipation

Kashyap P and Farrugia G, Gastroenterol Clin North Am. 20086

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

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Enteric Autoantibodies and Gut Motility Disorders

• Antibodies associated with paraneoplastic and idiopathic dysmotility – Type 1 antineuronal nuclear antibody Type 1 antineuronal nuclear antibody (ANNA-1) (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. 20088

Journal of Autoimmunity (1999)9

Autoimmunity Reviews 6 (2007) 162–16810

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

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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 200212

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

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Am J Gastroenterol 2002

Hematoxylin-eosin stain Immunoreactivity of the Kit protein

Metastatic small-cell lung carcinoma cells in the biopsied mediastinal lymphnode

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Am J Gastroenterol 2001;96:373–379

Summary of Patients StudiedSummary of Patients Studied

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Am J Gastroenterol 2001;96:373–379

Results of Manometric and Radiographic Images in Patients With SCLC

Results of Manometric and Radiographic Images in Patients With SCLC

Results of Serological Tests for NeuronalAutoantibodiesResults of Serological Tests for NeuronalAutoantibodies

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Upright plain film of the abdomen demonstrating sitz markers throughout the colon 1 month after

sitz marker ingestion

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.

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, 16–22Neurogastroenterol Motil (2005) 17, 16–2263-year-old woman63-year-old woman 17

Neurogastroenterol Motil (2005) 17, 16–22Neurogastroenterol Motil (2005) 17, 16–22

Lymphoplasmacytic infiltrate is noted in the location of the myenteric plexus.

Lymphoplasmacytic infiltrate is noted in the location of the myenteric plexus.

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J Support Oncol 2007;5:355–363

Pathogenesis of Malignant Gastroparesis in Various Cancer TypesPathogenesis of Malignant Gastroparesis in Various Cancer Types

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J Support Oncol 2007;5:355–363 20

J Support Oncol 2007;5:355–363

Medical Management of Gastroparesis

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J Support Oncol 2007;5:355–363

Enteral tubes for the management of malignant gastroparesis

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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

Kashyap P and Farrugia G, Gastroenterol Clin North Am. 200823

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)

Kashyap P and Farrugia G, Gastroenterol Clin North Am. 200824