Case Challenges

Autonomic paraneoplastic syndrome in a patient with small cell lung cancer

A 58-year-old white man was initially evaluated in August 2007 with left-sided chest pain and hemoptysis. His past medical history was significant for colonic polyps and right inguinal hernia repair. He was not on any medications. He had a 60 pack-year smoking history and had quit one year ago. He was in the Army from 1968 to 1970. He was stationed in Vietnam for 15 months and reports probable exposure to Agent Orange during that time. Review of systems was significant for hemoptysis, dyspnea on exertion and dull achy left anterior chest and shoulder pain. He denied any headaches, double vision or blurred vision.

Physical exam was significant for decreased breath sounds at the left upper lobe and right cervical lymph node. His complete blood count and comprehensive metabolic panel were normal. CT scan of the thorax revealed a mass lesion involving the left upper lobe measuring 6.6 cm with encasement of the left pulmonary artery.

The patient underwent a bronchoscopy and the biopsy was consistent with small cell carcinoma (SCLC). PET/CT showed a hypermetabolic mass in the upper lobe of the left lung and the left hilar region with central necrosis and contralateral cervical lymphadenopathy in the high jugular region. CT scan of the head with contrast did not reveal any metastatic disease. Fine-needle aspiration of the right neck node was consistent with metastatic SCLC.

Ramya Varadarajan, MD
Ramya Varadarajan

He received two cycles of cisplatin and etoposide. His CT scan after two cycles showed decrease in the size of the left upper lobe mass, but several new lesions had developed in the left lung. He was then switched to cisplatin and irinotecan with good response and completed five cycles. He also completed radiation to his left lung, mediastinum and right neck for a total of 5,400 cGy in 30 treatments, which he completed in May 2008. This was followed by prophylactic brain radiation of 3,000 cGy in 15 treatments, which he completed in July 2008. He was then followed with periodic CT scans that did not show any evidence of recurrence.

About six months, later the patient started having dysphagia, regurgitation and weight loss, and was evaluated by gastroenterology. Barium swallow showed poor motility, poor emptying and distal esophageal narrowing. Esophageal manometry showed low pressure in the lower esophageal sphincter and aperistalsis in the esophageal body.

He was diagnosed with achalasia and received botox injection at the lower esophageal sphincter without any relief. Surgical treatment (myotomy) was offered, but the patient elected to have a percutaneous endoscopic gastrostomy tube placement instead in September 2009. After this, the patient slowly continued to gain weight; however, in March he was admitted with symptoms of constipation and vomiting, and was subsequently diagnosed with pseudo-obstruction/paralytic ileus.

An anti-Hu antibody done at this time was positive. His current chest/abdomen CT does not show any evidence of recurrence of disease. Currently, he is being managed symptomatically with stool softeners, laxatives and promotility agents.

Case Discussion

Paraneoplastic neurological syndrome occurs in less than 0.1% of SCLC — this excludes syndromes of ectopic hormone production. Paraneoplastic neurological syndrome results from the distant effects of an underlying malignancy and are not related to the local effects of the primary tumor, metastases, side effects of treatment or infections. In most cases, the syndrome antedates the malignancy by a few months. They can present with sensory, motor or autonomic neuropathy. Various antibodies such as VGCC-Ab, Hu-Ab, Yo-Ab, CV2-Ab, Ri-Ab are associated with PNS, defining its subtypes.

More than 80% of patients with high levels of Hu-Ab have SCLC, but this syndrome has also been reported in cancers of the breast, prostate, kidney, bladder, ovary and cervix. The neurologic syndromes seen with Hu-Ab are cerebellar degeneration, limbic encephalitis, opsoclonus-myoclonus, brainstem encephalitis, and less commonly, autonomic failure. Autonomic failure results in orthostatic hypotension, abnormal papillary responses, urinary retention, gastrointestinal paresis, hyperhydrosis, impotence, cardiac arrhythmias and chronic intestinal pseudo-obstruction due to neuronal destruction of the myenteric plexus neurons.

Patients with chronic gastrointestinal pseudo-obstruction present with weight loss, persistent constipation and abdominal obstruction. Some patients present with dysphagia, nausea, vomiting due to esophageal dysmotility or gastroparesis. Radiologic studies show small bowel, colonic or gastric dilation. Esophageal manometry may reveal spasms or achalasia. Antibodies seen in patients with prominent gastrointestinal dysfunction are Hu-Ab or CV2-Ab, and less commonly, nAchR Ab.

The pathogenesis of PNS is poorly understood. One of the plausible mechanisms is autoimmunity. Studies have shown tumor-associated antigens in the surface of human SCLC cells, but not on normal lung tissue, which cross-react with normal nervous system tissue. The severity of most PNS is probably due to early and irreversible destruction of neuronal structures by inflammatory processes. Hu-Ab is detected using immunohistochemistry or western blot analysis, and has a high sensitivity and specificity. Although higher titers are more likely to be associated with a PNS, there was no correlation between the Hu-Ab titers and neurologic outcome, tumor evolution or treatment. Graus et al has shown that the presence of Hu-Ab at the time of diagnosis of SCLC is a strong and independent predictor of complete response to treatment and longer survival.

The course of the disease is usually not regressive, except in rare cases of limbic encephalitis. Death is mainly due to cardiovascular, collapse or respiratory failure secondary to autonomic dysfunction, rather than to widespread metastasis.

Management of patients with SCLC and PNS is associated with a poor outcome. Clinical improvement has not been seen with the use of steroids, plasmapheresis or IVIg, except in a few case reports. Most of the patients who have improvement after immunosuppressive treatment had exclusive involvement of the peripheral nervous system with sensory neuropathy. Early treatment of SCLC with chemotherapeutic agents may stabilize, but not improve, the symptoms of PNS. If the antibody is identified early during the course of the disease, immunosuppression with plasmapheresis along with the treatment of SCLC can be considered. Supportive treatment such as prokinetic agents, nutritional supplements, and alternative route of nutrition such as percutaneous endoscopic gastrostomy tube placement remains the mainstay of therapy in the later stages.

It has been suggested that in patients presenting with unexplained neurological symptoms paraneoplastic antibody testing may aid in the early diagnosis of underlying malignancy.

Ramya Varadarajan, MD, is a Medical Oncology Fellow at Roswell Park Cancer Institute, Buffalo, N.Y., and is a member of the HemOnc Today Editorial Board.

A 58-year-old white man was initially evaluated in August 2007 with left-sided chest pain and hemoptysis. His past medical history was significant for colonic polyps and right inguinal hernia repair. He was not on any medications. He had a 60 pack-year smoking history and had quit one year ago. He was in the Army from 1968 to 1970. He was stationed in Vietnam for 15 months and reports probable exposure to Agent Orange during that time. Review of systems was significant for hemoptysis, dyspnea on exertion and dull achy left anterior chest and shoulder pain. He denied any headaches, double vision or blurred vision.

Physical exam was significant for decreased breath sounds at the left upper lobe and right cervical lymph node. His complete blood count and comprehensive metabolic panel were normal. CT scan of the thorax revealed a mass lesion involving the left upper lobe measuring 6.6 cm with encasement of the left pulmonary artery.

The patient underwent a bronchoscopy and the biopsy was consistent with small cell carcinoma (SCLC). PET/CT showed a hypermetabolic mass in the upper lobe of the left lung and the left hilar region with central necrosis and contralateral cervical lymphadenopathy in the high jugular region. CT scan of the head with contrast did not reveal any metastatic disease. Fine-needle aspiration of the right neck node was consistent with metastatic SCLC.

Ramya Varadarajan, MD
Ramya Varadarajan

He received two cycles of cisplatin and etoposide. His CT scan after two cycles showed decrease in the size of the left upper lobe mass, but several new lesions had developed in the left lung. He was then switched to cisplatin and irinotecan with good response and completed five cycles. He also completed radiation to his left lung, mediastinum and right neck for a total of 5,400 cGy in 30 treatments, which he completed in May 2008. This was followed by prophylactic brain radiation of 3,000 cGy in 15 treatments, which he completed in July 2008. He was then followed with periodic CT scans that did not show any evidence of recurrence.

About six months, later the patient started having dysphagia, regurgitation and weight loss, and was evaluated by gastroenterology. Barium swallow showed poor motility, poor emptying and distal esophageal narrowing. Esophageal manometry showed low pressure in the lower esophageal sphincter and aperistalsis in the esophageal body.

He was diagnosed with achalasia and received botox injection at the lower esophageal sphincter without any relief. Surgical treatment (myotomy) was offered, but the patient elected to have a percutaneous endoscopic gastrostomy tube placement instead in September 2009. After this, the patient slowly continued to gain weight; however, in March he was admitted with symptoms of constipation and vomiting, and was subsequently diagnosed with pseudo-obstruction/paralytic ileus.

An anti-Hu antibody done at this time was positive. His current chest/abdomen CT does not show any evidence of recurrence of disease. Currently, he is being managed symptomatically with stool softeners, laxatives and promotility agents.

Case Discussion

Paraneoplastic neurological syndrome occurs in less than 0.1% of SCLC — this excludes syndromes of ectopic hormone production. Paraneoplastic neurological syndrome results from the distant effects of an underlying malignancy and are not related to the local effects of the primary tumor, metastases, side effects of treatment or infections. In most cases, the syndrome antedates the malignancy by a few months. They can present with sensory, motor or autonomic neuropathy. Various antibodies such as VGCC-Ab, Hu-Ab, Yo-Ab, CV2-Ab, Ri-Ab are associated with PNS, defining its subtypes.

More than 80% of patients with high levels of Hu-Ab have SCLC, but this syndrome has also been reported in cancers of the breast, prostate, kidney, bladder, ovary and cervix. The neurologic syndromes seen with Hu-Ab are cerebellar degeneration, limbic encephalitis, opsoclonus-myoclonus, brainstem encephalitis, and less commonly, autonomic failure. Autonomic failure results in orthostatic hypotension, abnormal papillary responses, urinary retention, gastrointestinal paresis, hyperhydrosis, impotence, cardiac arrhythmias and chronic intestinal pseudo-obstruction due to neuronal destruction of the myenteric plexus neurons.

Patients with chronic gastrointestinal pseudo-obstruction present with weight loss, persistent constipation and abdominal obstruction. Some patients present with dysphagia, nausea, vomiting due to esophageal dysmotility or gastroparesis. Radiologic studies show small bowel, colonic or gastric dilation. Esophageal manometry may reveal spasms or achalasia. Antibodies seen in patients with prominent gastrointestinal dysfunction are Hu-Ab or CV2-Ab, and less commonly, nAchR Ab.

The pathogenesis of PNS is poorly understood. One of the plausible mechanisms is autoimmunity. Studies have shown tumor-associated antigens in the surface of human SCLC cells, but not on normal lung tissue, which cross-react with normal nervous system tissue. The severity of most PNS is probably due to early and irreversible destruction of neuronal structures by inflammatory processes. Hu-Ab is detected using immunohistochemistry or western blot analysis, and has a high sensitivity and specificity. Although higher titers are more likely to be associated with a PNS, there was no correlation between the Hu-Ab titers and neurologic outcome, tumor evolution or treatment. Graus et al has shown that the presence of Hu-Ab at the time of diagnosis of SCLC is a strong and independent predictor of complete response to treatment and longer survival.

The course of the disease is usually not regressive, except in rare cases of limbic encephalitis. Death is mainly due to cardiovascular, collapse or respiratory failure secondary to autonomic dysfunction, rather than to widespread metastasis.

Management of patients with SCLC and PNS is associated with a poor outcome. Clinical improvement has not been seen with the use of steroids, plasmapheresis or IVIg, except in a few case reports. Most of the patients who have improvement after immunosuppressive treatment had exclusive involvement of the peripheral nervous system with sensory neuropathy. Early treatment of SCLC with chemotherapeutic agents may stabilize, but not improve, the symptoms of PNS. If the antibody is identified early during the course of the disease, immunosuppression with plasmapheresis along with the treatment of SCLC can be considered. Supportive treatment such as prokinetic agents, nutritional supplements, and alternative route of nutrition such as percutaneous endoscopic gastrostomy tube placement remains the mainstay of therapy in the later stages.

It has been suggested that in patients presenting with unexplained neurological symptoms paraneoplastic antibody testing may aid in the early diagnosis of underlying malignancy.

Ramya Varadarajan, MD, is a Medical Oncology Fellow at Roswell Park Cancer Institute, Buffalo, N.Y., and is a member of the HemOnc Today Editorial Board.