Etiology and Antibodies Associated with Paraneoplastic GI Dysmotility

The etiology of paraneoplastic GI dysmotility appears to be immune-mediated – autoimmune, specifically. This is exemplified by the demonstration of onconeural antibodies ( Table 1 ) selectively binding to enteric neurons in the myenteric plexus. An autoimmune etiology of paraneoplastic GI dysmotility is also supported by the common presence of both concomitant paraneoplastic neurological syndromes that are also of suspected autoimmune origin and other autoantibodies (eg, parietal cell and thyroglobulin antibodies), rheumatoid factor, and circulating immune complexes in these patients. An abnormality of external neural control by the autonomic nervous system has also been suggested.

Paraneoplastic syndromes are characterized by an immune response to tumor antigens that are also present in nontumor cells. Apoptosis of tumor cells may expose antigens which then stimulate antibody formation and activate cytotoxic T-cells. Immune destruction of the nontumor cells may then result in symptoms related to loss of normal function. In paraneoplastic GI dysmotility, presumably, tumor antigens elicit an immune response that cross-reacts with enteric or autonomic neural tissue leading to an immune attack directed against both the tumor and the respective nervous system. Consistent with this hypothesis is a study in which mice injected systemically with IgG prepared from serum containing ganglionic-type acetylcholine receptors (AChRs) developed slowed GI transit, urinary retention, and other findings of dysautonomia.

Paraneoplastic syndromes may affect any part of the central and peripheral nervous systems. Histologic abnormalities described in the myenteric plexus in the involved segment(s) of the gut that also support the autoimmune hypothesis include a decrease in the number of ganglion cells, replacement of neurons by Schwann cells and collagen, and a lymphoplasmacytic infiltrate. Smooth muscle cells are typically unaffected. Recently, a loss of interstitial cells of Cajal was demonstrated in a patient with paraneoplastic dysmotility, suggesting that enteric neurons are not the only enteric target of paraneoplastic autoimmunity. Despite these histologic findings and the presence of autoantibodies, the exact role of the antibodies in the pathogenesis of the organ dysfunction remains unclear. It has not been consistently demonstrated, for example, that the onconeural antibodies are themselves pathogenic for neurons, thus leading to the suggestion that these antibodies merely serve as markers of autoimmunity but do not participate in disease pathogenesis. Furthermore, the histologic nature of the underlying malignancy does not always dictate a certain autoantibody formation or specific dysmotility syndrome.

The first and most common autoantibody recognized to be associated with paraneoplastic GI dysmotility is the type 1 anti–neuronal nuclear antibody (ANNA-1) also known as anti-Hu antibody. ANNA-1 recognizes the family of RNA nuclear binding proteins, Hu. These proteins are expressed in the neurons of the central, peripheral, and enteric nervous systems and are most commonly expressed in small cell lung cancer (SCLC) but may also be expressed in multiple other tumor types. Approximately 30% of patients with ANNA-1 autoimmunity have symptoms of GI dysmotility. The presence of ANNA-1 in the serum of SCLC patients has been shown to correlate with limited stage disease, response to chemotherapy, and improved patient survival, further supporting the autoimmune theory. ANNA-2 (anti-Ri) antibodies also exist and have been associated with breast cancer and SCLC but, to date, have not been associated with paraneoplastic GI dysmotility.

The second most commonly reported antibodies in patients with paraneoplastic GI dysmotility target voltage-activated calcium channels. Calcium channels are classified as L, N, P/Q, R, and T channels. P/Q and N type channels are expressed in SCLC and are common targets of autoantibodies in such patients. They regulate acetylcholine release and participate in central and peripheral neurotransmission. Although these antibodies are reported more commonly with other paraneoplastic neurologic syndromes (eg, Lambert-Eaton syndrome), when associated with GI dysmotility, a search for an occult malignancy should be pursued. The N type channel has also been associated with SCLC and retroperitoneal lymphomas. These antibodies may coexist with ANNA-1 but have a weaker association with the eventual finding of a malignancy.

Antibodies directed against neuronal nicotinic acetylcholine receptors are also associated with both idiopathic and paraneoplastic forms of GI dysmotility. Antibodies targeting this protein can disrupt cholinergic synaptic transmission leading to autonomic failure. These antibodies appear to be directly pathogenic as their levels correspond to the severity of the autonomic failure and decrease with clinical improvement.

Purkinje cell cytoplasmic autoantibody, type 1 (PCA-1, aka anti-Yo) targets a neuronal signal transduction protein Cdr. Although defined originally as a marker of paraneoplastic cerebellar degeneration, paraneoplastic GI dysmotility has been present in a small portion of PCA-1 seropositive patients in association with ovarian and breast cancer. Other PCA autoantibodies include PCA-2 and PCA-Tr, which have been associated with SCLC and Hodgkin’s lymphoma, respectively.

Other autoantibodies associated with SCLC include amphiphysin antibody and collapsing response-mediator protein 5 (CRMP-5) antibody. Approximately 20% of patients with the neuronal and glial cytoplasmic autoantibody, CRMP-5, have symptoms of GI dysmotility.

Clinical Presentation of Paraneoplastic GI Dysmotility

Paraneoplastic GI dysmotility has been most commonly seen in association with SCLC, particularly in association with ANNA-1 positivity, but has also been described in relation to tumors of the stomach, esophagus, pancreas, breast, and ovary as well as ganglioneuroblastoma, bronchial carcinoid, retroperitoneal leiomyosarcoma, melanoma, and lymphoma, among others. A synchronous secondary malignancy has been described to occur in up to 13% of ANNA-1 positive SCLC patients. Although active malignancy is usually present at the time of diagnosis of the paraneoplastic GI dysmotility, cases of paraneoplastic motility occurring in patients with a remote history of cancer currently in remission have also been reported.

Paraneoplastic GI dysmotility is often rapidly progressive, leaving the affected patients debilitated in a matter of months. Indeed, a subacute (ie, less than 6 months) progressive clinical course and associated severe disability are highly suggestive of a paraneoplastic etiology to the GI dysmotility. Nevertheless, a slowly progressive course, a relapsing course, or even a benign course does not reliably exclude the diagnosis. Given the rarity of these syndromes, little is known about their overall epidemiology, including gender distribution and age of onset. Some reports suggest that women are more likely to be affected, with a mean age of onset of 66 years. However, a paraneoplastic cause should be considered, particularly in older men, given the generally higher prevalence of motility disorders in younger women. Although patients with paraneoplastic GI dysmotility may present with a dominant symptom suggesting isolated segmental GI involvement, most will have involvement of the entire gut and present with a wide variety of symptoms. In up to 80% of patients these symptoms may precede the diagnosis of the underlying tumor by weeks to years (usually within 6 months); occasionally, the tumor may only be diagnosed at autopsy. Indeed, in one of the larger case series, the GI dysmotility was observed to precede the diagnosis of SCLC by a mean of 8.7 months. Many of these patients also have other neurologic, psychiatric, or chronic pain diagnoses and autoimmune disorders. The main paraneoplastic GI dysmotility syndromes (see Table 1 ) will be briefly described next.

Dysphagia has been described with manometric and barium contrast study findings consistent with achalasia, and diffuse esophageal spasm has also been reported. More common, however, are nonspecific peristaltic abnormalities. Although most cases of pseudoachalasia do not reflect true paraneoplastic dysmotility, a small proportion of these patients have been shown to have no direct tumor involvement of the esophagogastric junction, often with ANNA-1 positivity.

Gastroparesis is a commonly reported paraneoplastic GI syndrome, occurring in 89% of individuals based on gastric emptying scintigraphy. Dilation of the stomach has been noted on radiographic imaging studies and on gross examination at autopsy. Peripheral neuropathy and autonomic dysfunction may accompany gastric involvement. Gastroparesis has been reported to be the most common paraneoplastic GI syndrome associated with ANNA-1 positivity.

Chronic intestinal pseudo-obstruction may be the most common mode of presentation of paraneoplastic dysmotility reported and is certainly the most dramatic. Paraneoplastic intestinal pseudo-obstruction was first suggested in 1975 and is most often reported in association with SCLC and thymoma. The presence of lymphoplasmacytic infiltration of the myenteric plexus and circulating ANNA-1 antibodies are also characteristic findings. Radiographic imaging studies have revealed dilated small bowel and delayed transit through the small bowel. Gastroduodenal and small intestinal manometry studies have demonstrated findings consistent with neuropathy, such as absence of the phase III component of the migrating motor complex, postprandial antral hypomotility, lack of a fed pattern, and uncoordinated, prolonged bursts of phasic activity during both fasting and fed states. Given the rarity of chronic intestinal pseudo-obstruction, a paraneoplastic cause should be considered in any patient who presents with typical features in association with undue weight loss and wasting, particularly when onconeural antibodies are present.

Constipation is a common symptom in paraneoplastic GI dysmotility; however, most will also demonstrate a dilated colon and/or evidence of a more diffuse pseudoobstruction syndrome. An association with ganglionic acetylcholine receptor antibody has been reported in 2 patients with constipation and thymoma and SCLC. Case reports have shown colonic dysmotility and severely slowed colonic transit and infiltration by T and B lymphocytes and plasma cells in the colonic myenteric plexus, in association with both ANNA-1 and antibodies against potassium channels. Pelvic floor dyssynergia has also been reported in 4 patients, of whom 3had ganglionic AChR antibodies and 1 had coexisting voltage-gated potassium channel autoantibodies. Formal evaluations of anorectal and colonic motility have not been performed.