Approach Considerations
Patients with a suspected paraneoplastic disorder should undergo a complete panel of laboratory studies of blood, urine, and cerebrospinal fluid (CSF). Selection of further studies is dictated by the clinical presentation.
Protein electrophoresis of serum and CSF may demonstrate alterations of albumin levels and increased beta-globulins and gamma-globulins. Gamma-globulins are always increased in patients with autoimmune disorders, whether neoplastic or not. Oligoclonal bands are seen frequently on CSF electrophoresis.
Assays for autoantibodies may confirm the paraneoplastic origin of a patient’s condition. Most autoantibodies involved in paraneoplastic syndromes are directed against nervous system structures.
Endoscopy is useful to detect tumors of the respiratory tree and of the digestive tract. It also allows the examiner to obtain biopsy samples. Skin biopsy for histopathologic diagnosis is necessary in patients with facial papules, to distinguish benign lesions from those due to underlying malignancy. [51]
Imaging studies may include whole-body scans for detection of the underlying tumor. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans can detect extremely small tumors and are especially useful for patients with neurologic disorders.
Diagnostic criteria for paraneoplastic neurologic syndromes
In 2021, an international panel of experts published an update to the 2004 criteria for the diagnosis of paraneoplastic neurologic syndromes. Under the updated criteria, neurologic phenotypes are classified as high risk or intermediate risk for cancer, and associated antibodies are classified as high risk (cancer in > 70% of patients with the antibody), intermediate risk (cancer in 30%–70%), and low risk (cancer in < 30%). [52]
The phenotypes associated with high risk for cancer (previously “classical PNS”) are as follows [52] :
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Encephalomyelitis
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Limbic encephalitis
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Rapidly progressive cerebellar syndrome
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Opsoclonus-myoclonus syndrome
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Sensory neuronopathy
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Gastrointestinal pseudo-obstruction (enteric neuropathy)
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Lambert-Eaton myasthenic syndrome
Intermediate-risk phenotypes can occur with or without cancer, follow a rapidly progressive course, and have inflammatory CSF results or an abnormal brain or spine MRI. The panel noted that possible intermediate-risk phenotypes are varied, but the following were the most suggestive:
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Encephalitis
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Brainstem encephalitis
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Morvan syndrome
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Stiff-person syndrome
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Paraneoplastic polyradiculoneuropathies.
The update includes a new clinical scoring system for diagnosis of paraneoplastic neurologic syndrome, the Paraneoplastic (PNS)-Care Score. The PNS-Care Score assesses three factors [52] :
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Phenotype classification
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Associated antibody level
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Presence of cancer
The score ranges from 0 to 10, with the diagnosis categorized based on the score [52] :
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Definite (8-10)
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Probable (6-7)
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Possible (4-5)
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Non-PNS (0-3)
Blood Studies
The complete blood cell count (CBC) may demonstrate anemia. This anemia may be the result of any of several different types of cancer, or it may be the result of different benign conditions. A microscopic study of the white blood cells is helpful for diagnosis of leukemia or lymphoma-related disorders. Hypereosinophilia is frequently observed in patients with Hodgkin lymphoma. A platelet count must be performed in any patient with symptoms of disseminated intravascular coagulation (DIC).
The erythrocyte sedimentation rate (ESR) is usually increased in patients with cancers. However, the ESR is a nonspecific marker for inflammation that is also elevated in a variety of disorders, including infections and rheumatologic disorders.
Blood enzymes may be altered, even in healthy individuals or those who have benign conditions. Increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydryogenase (LDH), and alkaline phosphatase (ALP) are commonly observed in patients with malignancies of the digestive system, as well as in patients with bone or muscle injuries.
Protein electrophoresis of serum may demonstrate alterations of albumin levels and increased beta-globulins and gamma-globulins. Gamma-globulins are always increased in patients with autoimmune disorders, whether neoplastic or not.
Tumor markers are very useful for diagnosis of cancers that are clinically silent, but most markers are not specific for determining the origin of the cancer. For example, carcinoembryonic antigen (CEA) is increased in patients with tumors of the breast, lung, and digestive tract, as well as in patients who are heavy smokers.
Although prostate-specific antigen (PSA) is increased only in patients with prostatic disorders, it is increased in benign disorders (including inflammatory diseases) as well as in prostate cancer. Calculating free PSA as a percentage of total PSA can help differentiate benign from malignant disorders; the higher the percentage of free PSA (a level above 25% is considered normal), the lower the likelihood of cancer.
Autoantibody assays
Many patients with paraneoplastic disorders may have autoantibodies against several tissues of the body. Demonstration of these autoantibodies is very important to confirm the diagnosis of a paraneoplastic syndrome and distinguish it from nonneoplastic forms.
Most known autoantibodies are directed against nervous system structures. Note that there are two systems of nomenclature for onco-neural antibodies in current use: one system designates antibodies by the first two letters of the surname of the patient in whom the antibody was initially discovered, while the other system names antibodies according to their tissue distribution. Such antibodies are screened by indirect immunofluorescence.
Autoantibodies found in paraneoplastic syndromes include the following:
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Anti-Hu (previously called antineuronal nuclear antibody 1 or ANNA-1) is an autoantibody detected in the serum of patients with paraneoplastic subacute sensory neuronopathy and/or encephalomyelitis
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Anti-Ri (previously called antineuronal nuclear antibody 2 or ANNA-2) may be present in patients with opsoclonus/myoclonus syndrome
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Antibodies directed against amphiphysin (a synaptic vesicle protein) have been detected in the serum of patients with the paraneoplastic form of stiff man syndrome [53]
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The antineuronal antibodies Ma1 and Ma2 (also called anti-Ta) are members of a novel but expanding family of brain-specific or testis-specific proteins; while Ma1 is not found in association with any one type of tumor, Ma2 seems to be associated strongly with testicular cancer
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The anti-Yo or anti-Purkinje cell antibody 1 (APCA-1) has been detected in patients with paraneoplastic cerebellar degeneration
Imaging Studies
Any possible imaging study may be useful to detect the primary tumor in patients with paraneoplastic disorders, including the following:
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Computed tomography (CT) and magnetic resonance image (MRI) scanning of the whole body allow detection of the site and the extension of the underlying primary tumor and its metastases, if present
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Scintigraphy may be useful in patients with endocrine disorders related to a hormone-producing tumor
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Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scanning may be performed to evaluate patients with neurologic disorders; these examinations allow differentiation of paraneoplastic and nonparaneoplastic neurologic disorders; fluoro-deoxyglucose-PET (FDG-PET) scanning can visualize tumors as small as 6-8 mm anywhere in the body and may be positive when chest radiography and CT are negative [40]
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Vatankulu and colleagues examined the accuracy of FDG-PET/CT and paraneoplastic antibodies in diagnosing cancer in a retrospective study of 42 patients with paraneoplastic neurologic syndromes. PET/CT had 85.71% sensitivity, 100% specificity, 100% positive predictive value,and 97.22% negative predictive value for the detection of tumors, and was accurate in detecting underlying malignancy regardless of the presence of paraneoplastic antibodies. [54]
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Kristensen and colleagues examined the clinical value of FDG-PET/CT in suspected paraneoplastic syndromes in a retrospective analysis of 137 patients.FDG-PET/CT had 75% sensitivity, 82% sepecificity, 29% positive predictive value, and 97% negative predictive value for ruling out paraneoplastic syndromes. [55]
