Laboratory Studies
Serum analysis for the presence of onconeural autoantibodies using immunohistochemistry and immunoblotting is the key to diagnosis. Since there is an overlap between the clinical picture of individual paraneoplastic autoantibodies, screening for them using a panel of autoantibodies is appropriate. Lumbar puncture is often indicated, with ample volume of cerebrospinal fluid (CSF) sent for cytologic analysis in addition to the other usual tests. The spinal fluid often reveals a mononuclear pleocytosis, elevated protein, oligoclonal bands, and paraneoplastic onconeural antibodies.
Evidence of another process (eg, diabetes, scleroderma, amyloidosis, thyroid disease) should be considered and excluded by appropriate serologic tests and/or biopsies.
Serological markers of malignancies (eg, CEA, PSA, NSE, CA19-9, AFP, β-HCG, and ProGRP, if available) can help to identify a cancer that is not readily apparent by imaging.
Imaging Studies
If the patient is not known to harbor a malignancy, then chest imaging (eg, high resolution CT scan) is indicated, since small-cell lung cancer is most often the associated tumor. If any abnormalities are seen, then bronchoscopic or transthoracic needle biopsy is usually required. If no tumor is found, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered as it markedly increases the detection rate of malignancy. [42] Imaging of the abdomen, pelvis, and brain is normally indicated to look for a primary tumor or metastasis. Mammography and gynecological ultrasonographic examinations can be of value in women, and testicular ultrasonography in men. If no malignancy is found at presentation, repeating the work-up every 3-6 months is advisable [41] for the first 4 years (or the first 2 years in the case of LEMS). [42]
Other Tests
Electromyography (EMG)/nerve conduction velocity (NCV) studies can identify a neuropathy or defect of neuromuscular transmission if present. Heart rate variability and autonomic skin responses can be performed in most laboratories. More extensive autonomic testing may be helpful to prove autonomic dysfunction in milder cases, although it is usually not necessary.
Histologic Findings
The images below show typical histologic findings from a patient with small-cell lung cancer and autoimmune paraneoplastic autonomic failure. Loss of neurons is evident in autonomic ganglia and dorsal root ganglia, as well as within the CNS. Inflammatory infiltrates are also typical in the vicinity of neuron loss. Similar findings have been reported for autoimmune-mediated paraneoplastic autonomic dysfunction caused by other cancers.
Paraneoplastic autonomic neuropathy. Histopathology of peripheral nerve and sympathetic ganglion from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive anti-HU antibody titer. (a) Peripheral nerve in longitudinal section stained with Luxol fast blue-periodic acid-Schiff (PAS) showing scattered wallerian degeneration (arrowheads). (b) Low-power view of a paravertebral sympathetic ganglion stained with hematoxylin and eosin (H&E). Arrowhead indicates perivascular mononuclear infiltrates. (c) High-power view of the same sympathetic ganglion showing degenerating neurons (single arrowheads) and mononuclear infiltrates (double arrowhead). Magnification bars in a and b indicate 100 mm; c is 50 mm.
Paraneoplastic autonomic neuropathy. Hematoxylin and eosin (H&E)–stained sections from dorsal root ganglion showing the hallmark histopathology of anti-HU disease; a and c are from a healthy patient; b and d are from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive titer of anti-HU antibodies. The arrowheads in b and d indicate degenerating sensory neurons. Also note the interstitial hypercellularity and decreased numbers of neurons in b and d. Magnification bar in b indicates 100 mm and applies also to a. Similarly, the magnification bar in d indicates 50 mm, which also applies to c.
Paraneoplastic autonomic neuropathy. Central nervous system sections from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive titer of anti-HU antibodies stained with hematoxylin and eosin (H&E). (a) Inferior olive showing a cluster of mononuclear cells (arrowhead); (b) hippocampus showing perivascular mononuclear infiltrate (arrowhead); (c) midbrain section showing a vessel encased in a mononuclear infiltrate; (d) ventral horn of the thoracic spinal cord showing clusters of mononuclear cells around degenerating motor neurons (arrowheads). Magnification bars indicate 100 mm. The bar in b applies also to a and the bar in d also applies to c.
The underlying tumor is often heavily infiltrated by inflammatory cells.
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Paraneoplastic autonomic neuropathy. Histopathology of peripheral nerve and sympathetic ganglion from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive anti-HU antibody titer. (a) Peripheral nerve in longitudinal section stained with Luxol fast blue-periodic acid-Schiff (PAS) showing scattered wallerian degeneration (arrowheads). (b) Low-power view of a paravertebral sympathetic ganglion stained with hematoxylin and eosin (H&E). Arrowhead indicates perivascular mononuclear infiltrates. (c) High-power view of the same sympathetic ganglion showing degenerating neurons (single arrowheads) and mononuclear infiltrates (double arrowhead). Magnification bars in a and b indicate 100 mm; c is 50 mm.
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Paraneoplastic autonomic neuropathy. Hematoxylin and eosin (H&E)–stained sections from dorsal root ganglion showing the hallmark histopathology of anti-HU disease; a and c are from a healthy patient; b and d are from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive titer of anti-HU antibodies. The arrowheads in b and d indicate degenerating sensory neurons. Also note the interstitial hypercellularity and decreased numbers of neurons in b and d. Magnification bar in b indicates 100 mm and applies also to a. Similarly, the magnification bar in d indicates 50 mm, which also applies to c.
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Paraneoplastic autonomic neuropathy. Central nervous system sections from a patient with autonomic failure, oat-cell carcinoma of the lung, and positive titer of anti-HU antibodies stained with hematoxylin and eosin (H&E). (a) Inferior olive showing a cluster of mononuclear cells (arrowhead); (b) hippocampus showing perivascular mononuclear infiltrate (arrowhead); (c) midbrain section showing a vessel encased in a mononuclear infiltrate; (d) ventral horn of the thoracic spinal cord showing clusters of mononuclear cells around degenerating motor neurons (arrowheads). Magnification bars indicate 100 mm. The bar in b applies also to a and the bar in d also applies to c.
