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
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.
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
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.
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
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
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