ANNA-1 (Anti-Hu)

The most common neuronal autoantibody associated with paraneoplastic dysmotility is the type 1 anti-neuronal nuclear antibody (ANNA-1) . 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. These proteins 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 may express 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 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 remains unclear, because the proteins to which the antibody is directed are not expressed on the cell membrane. Nevertheless, there is some evidence that the antibodies may directly influence motility. A preliminary study in guinea pig ileum has 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 patients with a paraneoplastic gut dysmotility disorder as well as commercial anti-HuD antibodies have been shown to induce apoptosis in a human neuroblastoma cell line (SH-Sy5Y) as well as guinea pig cultured myenteric neurons. It was further demonstrated that the apoptosis was dependent on mitochondria, as evidenced by the specific activation of effector caspase-3 and the cytochrome c–dependent proapoptotic messenger apaf-1 . Mitochondrial dysfunction leading to subsequent neuronal injury is well described and has also been implicated in dorsal root ganglion apoptosis in streptozocin-induced diabetes in rats . Pardi and colleagues 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.

Another nuclear autoantigen associated with disease is Ri, expressed in neurons of the central nervous system, small cell lung cancer, and some breast cancer cells . Formation of type 2 anti-neuronal nuclear antibodies (ANNA-2 or anti-Ri) is far less common than the formation of anti-Hu and is usually associated with neurologic symptoms from midbrain, brain stem, cerebellar, or spinal cord dysfunction . ANNA-2 has not been associated with gastrointestinal dysmotility.

Calcium Channel Antibodies

The second most commonly reported antibodies in patients with paraneoplastic dysmotility target voltage-activated calcium channels. Calcium channels were originally classified based on pharmacology as L, N, P/Q, R, and T channels, a classification still used today. This classification corresponds to the current accepted nomenclature that classifies voltage-gated Ca ²⁺ channels into Ca _v 1.1-Ca _v 1.4 (L-type Ca ²⁺ channels), Ca _v 2.1 (P/Q), Ca _v 2.2 (N), Ca _v 2.3 (R), and Ca _v 3.1-Ca _v 3.3 (T) based on the amino acid sequence of the alpha 1 subunit (the pore-forming 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 . Antibodies to P/Q- and N-type calcium channels are found in some patients with paraneoplastic dysmotility, and their presence should trigger a targeted search for an occult malignancy; however, these antibodies are less frequently found when compared with ANNA-1 antibodies, and their association with the eventual finding of a malignancy in the setting of a gastrointestinal motility disorder is not as strong as for ANNA-1. These antibodies may coexist with ANNA-1.

Nicotinic Acetylcholine Receptors

Another class of autoantibodies associated with gastrointestinal dysmotility is directed against neuronal nicotinic acetylcholine receptors. Antibodies directed toward the extracellular segment of acetylcholine receptor protein in the postsynaptic 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 . Patients with ganglionic receptor blocking antibodies often manifest with symptoms of gastrointestinal dysmotility, abnormal pupillary response, and subacute onset of autonomic neuropathy . This antibody is of use to differentiate autoimmune autonomic neuropathy from degenerative autonomic neuropathy, which is often more insidious and not usually associated with gastrointestinal manifestations. It is important to make this distinction because the diagnosis affects the prognosis and therapy. Degenerative autonomic neuropathy is a slowly progressive disorder, whereas autoimmune autonomic neuropathy can be life threatening and often responds to therapy such as immunomodulators . Neuronal nicotinic acetylcholine receptor antibodies are most likely directly pathogenic because their levels correspond to the severity of autonomic dysfunction, and because a decrease in their level is accompanied by clinical improvement . Symptoms of autonomic failure can also be induced experimentally by passive transfer of antibodies. 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

Purkinje cell cytoplasmic autoantibody, type 1 (PCA-1) (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 . 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 gynecologic or breast carcinoma .

Other Autoantibodies

Antibodies have also been detected against other cytoplasmic antigens such as amphiphysin, present on the cytoplasmic side of the synaptic vesicle membrane . Anti-striational autoantibody targets the skeletal muscle proteins actinin, alpha actin, myosin, titin, and ryanodine receptor . They may be seen in patients with myasthenia gravis associated with thymoma and paraneoplastic neurologic disorders with primary lung cancer but are usually not associated with gastrointestinal dysmotility . Voltage-gated potassium channel autoantibodies have been reported in rare patients with slow transit constipation and in a patient with diarrhea-predominant irritable bowel syndrome . Their significance is currently unknown. Likewise, glutamic acid decarboxylase-65 (GAD) antibodies have been reported in a significant percentage of patients with achalasia, but, again, this finding is currently of uncertain pathogenetic significance .

Pseudoachalasia

Pseudoachalasia accounts for about 2% to 4% of all cases that have the manometric criteria of incomplete or absent relaxation of the lower esophageal sphincter seen in true achalasia. Most patients with pseudoachalasia have a primary tumor at the gastroesophageal junction . This form of pseudoachalasia is not a form of paraneoplastic dysmotility, because it is usually due to obstruction of the lower esophageal sphincter by the tumor or direct involvement of myenteric plexus with the neoplastic cells. Nevertheless, depletion of ganglion cells in the dorsal nucleus of the vagus nerve as a consequence of neuronal degeneration distant to primary tumor can occur . In a small proportion of patients, there is no evidence of neoplastic involvement of the gastroesophageal junction, but they demonstrate anti-neuronal antibodies, most often ANNA-1 . Liu and colleagues described a case series of 13 patients with pseudoachalasia in which eight patients had direct infiltration of the esophageal wall and involvement of the myenteric plexus. The total number of ganglion cells was normal, and it is unclear how the neoplastic cells altered ganglion cell function. In the same series, they described a patient with small cell lung cancer and lymph node metastasis with achalasia-like symptoms but no radiographic or histologic involvement of the esophagogastric junction. The patient had ANNA-1 antibodies, suggesting a paraneoplastic dysmotility. Histologically, there was complete absence of myenteric ganglion cells and both perineural and intraneural lymphocytic infiltration. Lee and colleagues published a series of 12 cases in which esophageal dysmotility was seen in four patients with small cell lung cancer. Two patients had pseudoachalasia, one had a nonspecific esophageal motility disorder, and one had abnormal manometry but no esophageal symptoms.

Paraneoplastic Gastroparesis

Gastroparesis is characterized by reduced emptying of gastric content, often associated with decreased gastric motility. The presentation of gastroparesis often includes nausea, vomiting of food consumed several hours earlier, bloating, epigastric fullness, and the finding of retained gastric contents on endoscopy. Gastroparesis was reported to be the most common paraneoplastic syndrome associated with ANNA-1 antibodies by Lucchinetti and colleagues . As is true for other paraneoplastic gastrointestinal dysmotilities, paraneoplastic gastroparesis is commonly associated with small cell lung cancer ; however, it has also been reported in association with other tumors, including pancreatic cancer with no other identifiable cause . It has been described in a patient with untreated breast cancer in whom improvement occurred with cisapride and chemotherapy and resulting tumor remission . It is not possible to conclude whether the patient’s symptoms improved with the prokinetic therapy or treatment of the underlying tumor, but it is more than likely that a paraneoplastic dysmotility responds to treatment of the underlying tumor. Gastroparesis has also been reported in a patient with retroperitoneal leiomyosarcoma with no evidence of local invasion or metastasis and resolved completely after resection of the tumor . As described previously, Pardi and colleagues reported a patient with small cell lung cancer with both ANNA-1 and P/Q-type calcium channel antibody with gastroparesis and a disrupted interstitial cell of Cajal network, suggesting that enteric neurons are not the only enteric neural target of the paraneoplastic autoimmunity. Gastroparesis has also been associated with other autoantibodies, including ganglionic acetylcholine receptor antibodies. This finding was observed by Vernino and colleagues in a patient with bladder cancer and also in patients with idiopathic gastroparesis with no known antecedent risk factors and no underlying cancer. These observations strongly suggest that the histologic nature of the underlying malignancy does not always dictate a certain autoantibody formation or specific dysmotility syndrome.

Paraneoplastic Chronic Intestinal Pseudo-Obstruction

Chronic intestinal pseudo-obstruction is defined as recurrent episodes or persistent symptoms of bowel obstruction in the absence of mechanical obstruction. Most cases of chronic intestinal pseudo-obstruction are due to primary defects in the contractile apparatus (nerves, interstitial cells of Cajal, smooth muscle cells) of the gut or are secondary to an infiltrating disease such as amyloidosis or scleroderma . Paraneoplastic intestinal pseudo-obstruction is most often reported in cases with small cell lung cancer and thymoma and is usually associated with the presence of circulating ANNA-1 antibodies . There have also been several case reports of patients with pseudo-obstruction with other primary cancers. Chronic intestinal pseudo-obstruction along with achalasia, gastroparesis, and constipation was reported in a patient with metastasizing bronchial carcinoid . Intestinal pseudo-obstruction associated with lymphoplasmacytic infiltration of the myenteric plexus and the presence of ANNA-1 antibodies was found in a patient about 1.5 years after removal of a paravertebral ganglioneuroblastoma . Viallard and colleagues reported a case of colonic dysmotility associated with antibodies against voltage-gated potassium channels in a patient with invasive thymoma and acquired neuromyotonia, which improved after plasmapheresis.

As discussed previously, Lee and colleagues published a case series of 12 patients in which chronic intestinal dysmotility and acute colonic pseudo-obstruction were observed in patients with cancer and ANNA-1, PCA-1, or anti–N-type calcium channel antibodies. All of the patients with small cell lung cancer had ANNA-1 antibodies, a patient with ovarian cancer was positive for PCA-1 antibody, and a patient with lymphoma had N-type calcium channel antibody. Histologically, the ANNA-1 antibodies in these patients were reactive with both nucleus and cytoplasm, as opposed to the findings in cases of idiopathic colonic pseudo-obstruction, in which a predominant cytoplasmic staining has been observed. Interestingly, in this study, the investigators observed that the gastrointestinal dysmotility preceded the small cell lung cancer by a mean period of 8.7 months, whereas in the patients who had other malignancies, antibodies were found after the tumor diagnosis. These data suggest that the diagnosis of new onset gut dysmotility accompanied by the presence of ANNA-1 antibodies should prompt a search for occult small cell lung cancer. Even if the initial screen is negative, vigilance should be maintained in the subsequent years. It was also observed that the patients with colonic pseudo-obstruction and small cell lung cancer often had additional disease, including peripheral, sensorimotor, or autonomic neuropathies, cerebellar degeneration, or encephalopathy.

Chronic Constipation

Chronic constipation without accompanying pseudo-obstruction is not a common presentation of a paraneoplastic syndrome. Vernino and colleagues reported constipation in two patients with ganglionic acetylcholine receptor antibody associated with thymoma and small cell lung cancer.

Pseudoachalasia

Pseudoachalasia accounts for about 2% to 4% of all cases that have the manometric criteria of incomplete or absent relaxation of the lower esophageal sphincter seen in true achalasia. Most patients with pseudoachalasia have a primary tumor at the gastroesophageal junction . This form of pseudoachalasia is not a form of paraneoplastic dysmotility, because it is usually due to obstruction of the lower esophageal sphincter by the tumor or direct involvement of myenteric plexus with the neoplastic cells. Nevertheless, depletion of ganglion cells in the dorsal nucleus of the vagus nerve as a consequence of neuronal degeneration distant to primary tumor can occur . In a small proportion of patients, there is no evidence of neoplastic involvement of the gastroesophageal junction, but they demonstrate anti-neuronal antibodies, most often ANNA-1 . Liu and colleagues described a case series of 13 patients with pseudoachalasia in which eight patients had direct infiltration of the esophageal wall and involvement of the myenteric plexus. The total number of ganglion cells was normal, and it is unclear how the neoplastic cells altered ganglion cell function. In the same series, they described a patient with small cell lung cancer and lymph node metastasis with achalasia-like symptoms but no radiographic or histologic involvement of the esophagogastric junction. The patient had ANNA-1 antibodies, suggesting a paraneoplastic dysmotility. Histologically, there was complete absence of myenteric ganglion cells and both perineural and intraneural lymphocytic infiltration. Lee and colleagues published a series of 12 cases in which esophageal dysmotility was seen in four patients with small cell lung cancer. Two patients had pseudoachalasia, one had a nonspecific esophageal motility disorder, and one had abnormal manometry but no esophageal symptoms.

Paraneoplastic Gastroparesis

Gastroparesis is characterized by reduced emptying of gastric content, often associated with decreased gastric motility. The presentation of gastroparesis often includes nausea, vomiting of food consumed several hours earlier, bloating, epigastric fullness, and the finding of retained gastric contents on endoscopy. Gastroparesis was reported to be the most common paraneoplastic syndrome associated with ANNA-1 antibodies by Lucchinetti and colleagues . As is true for other paraneoplastic gastrointestinal dysmotilities, paraneoplastic gastroparesis is commonly associated with small cell lung cancer ; however, it has also been reported in association with other tumors, including pancreatic cancer with no other identifiable cause . It has been described in a patient with untreated breast cancer in whom improvement occurred with cisapride and chemotherapy and resulting tumor remission . It is not possible to conclude whether the patient’s symptoms improved with the prokinetic therapy or treatment of the underlying tumor, but it is more than likely that a paraneoplastic dysmotility responds to treatment of the underlying tumor. Gastroparesis has also been reported in a patient with retroperitoneal leiomyosarcoma with no evidence of local invasion or metastasis and resolved completely after resection of the tumor . As described previously, Pardi and colleagues reported a patient with small cell lung cancer with both ANNA-1 and P/Q-type calcium channel antibody with gastroparesis and a disrupted interstitial cell of Cajal network, suggesting that enteric neurons are not the only enteric neural target of the paraneoplastic autoimmunity. Gastroparesis has also been associated with other autoantibodies, including ganglionic acetylcholine receptor antibodies. This finding was observed by Vernino and colleagues in a patient with bladder cancer and also in patients with idiopathic gastroparesis with no known antecedent risk factors and no underlying cancer. These observations strongly suggest that the histologic nature of the underlying malignancy does not always dictate a certain autoantibody formation or specific dysmotility syndrome.

Paraneoplastic Chronic Intestinal Pseudo-Obstruction

Chronic intestinal pseudo-obstruction is defined as recurrent episodes or persistent symptoms of bowel obstruction in the absence of mechanical obstruction. Most cases of chronic intestinal pseudo-obstruction are due to primary defects in the contractile apparatus (nerves, interstitial cells of Cajal, smooth muscle cells) of the gut or are secondary to an infiltrating disease such as amyloidosis or scleroderma . Paraneoplastic intestinal pseudo-obstruction is most often reported in cases with small cell lung cancer and thymoma and is usually associated with the presence of circulating ANNA-1 antibodies . There have also been several case reports of patients with pseudo-obstruction with other primary cancers. Chronic intestinal pseudo-obstruction along with achalasia, gastroparesis, and constipation was reported in a patient with metastasizing bronchial carcinoid . Intestinal pseudo-obstruction associated with lymphoplasmacytic infiltration of the myenteric plexus and the presence of ANNA-1 antibodies was found in a patient about 1.5 years after removal of a paravertebral ganglioneuroblastoma . Viallard and colleagues reported a case of colonic dysmotility associated with antibodies against voltage-gated potassium channels in a patient with invasive thymoma and acquired neuromyotonia, which improved after plasmapheresis.

As discussed previously, Lee and colleagues published a case series of 12 patients in which chronic intestinal dysmotility and acute colonic pseudo-obstruction were observed in patients with cancer and ANNA-1, PCA-1, or anti–N-type calcium channel antibodies. All of the patients with small cell lung cancer had ANNA-1 antibodies, a patient with ovarian cancer was positive for PCA-1 antibody, and a patient with lymphoma had N-type calcium channel antibody. Histologically, the ANNA-1 antibodies in these patients were reactive with both nucleus and cytoplasm, as opposed to the findings in cases of idiopathic colonic pseudo-obstruction, in which a predominant cytoplasmic staining has been observed. Interestingly, in this study, the investigators observed that the gastrointestinal dysmotility preceded the small cell lung cancer by a mean period of 8.7 months, whereas in the patients who had other malignancies, antibodies were found after the tumor diagnosis. These data suggest that the diagnosis of new onset gut dysmotility accompanied by the presence of ANNA-1 antibodies should prompt a search for occult small cell lung cancer. Even if the initial screen is negative, vigilance should be maintained in the subsequent years. It was also observed that the patients with colonic pseudo-obstruction and small cell lung cancer often had additional disease, including peripheral, sensorimotor, or autonomic neuropathies, cerebellar degeneration, or encephalopathy.

Chronic Constipation

Chronic constipation without accompanying pseudo-obstruction is not a common presentation of a paraneoplastic syndrome. Vernino and colleagues reported constipation in two patients with ganglionic acetylcholine receptor antibody associated with thymoma and small cell lung cancer.