As an aid in the diagnosis of paraneoplastic neurological autoimmune

disorders related to carcinoma of lung, breast, ovary, thymoma, or

Hodgkin's lymphoma

 

In patients with a history of tobacco use or other lung cancer risk, or if

thymoma is suspected, #83380 "Paraneoplastic Autoantibody Evaluation,

Serum" is also recommended.

Several antineuronal and glial autoantibodies are recognized clinically as

markers of a patient's immune response to specific cancers

(paraneoplastic autoantibodies). Seropositive patients present with

neurologic symptoms and signs in >90% of cases. The cancers are

most commonly small-cell lung carcinoma (SCLC), ovarian (or related

mullerian) carcinoma, breast carcinoma, thymoma, or Hodgkin's

lymphoma. The cancers may be new or recurrent, are usually limited

in metastatic volume, and are often occult by standard imaging

procedures. Detection of the informative marker autoantibodies allows early

diagnosis and treatment of the cancer, which may lessen neurological

morbidity and improve survival.

 

Serum is the preferred specimen for paraneoplastic autoantibodies.

However, cerebrospinal fluid (CSF) results are sometimes positive

when serum results are negative (especially for CRMP-5 and other

inflammatory central nervous system autoimmunity). Additionally,

CSF is more readily interpretable because it generally lacks the interfering

nonorgan-specific antibodies that are common in serum of patients with

cancer. Because neurologists typically perform spinal taps in these

patients, we recommend that CSF be submitted with serum, either for

simultaneous testing or to be held for testing only if serum is negative.

ANTINEURONAL NUCLEAR ANTIBODY-Type 1 (ANNA-1)

      Negative at <1:2

ANTINEURONAL NUCLEAR ANTIBODY-Type 2 (ANNA-2)

      Negative at <1:2

ANTINEURONAL NUCLEAR ANTIBODY-Type 3 (ANNA-3)

      Negative at <1:2

ANTI-GLIAL/NEURONAL NUCLEAR ANTIBODY, Type 1 (AGNA-1)

      Negative at <1:2

PURKINJE CELL CYTOPLASMIC ANTIBODY, Type 1 (PCA-1)

      Negative at <1:2

PURKINJE CELL CYTOPLASMIC ANTIBODY, Type 2 (PCA-2)

      Negative at <1:2

PURKINJE CELL CYTOPLASMIC ANTIBODY, Type Tr (PCA-Tr)

      Negative at <1:2

AMPHIPHYSIN ANTIBODY

      Negative at <1:2

CRMP-5-IgG

      Negative at <1:2

Note:   Titers lower than 1:2 are detectable by recombinant

                CRMP-5 Western blot analysis. CRMP-5 Western blot

                analysis will be done on request on stored spinal fluid (held 4

                weeks). This supplemental testing is recommended in

                cases of chorea, vision loss, cranial neuropathy, and

                myelopathy. Call the Neuroimmunology Laboratory at

                800-533-1710 or 507-266-5700 to request CRMP-5

                Western blot.

     

Neuron-restricted patterns of IgG staining that do not fulfill criteria for

the listed autoantibodies may be reported as "unclassified antineuronal

IgG." If detected, newly identified autoantibody specificities may be

reported. Complex patterns that include non-neuronal elements may be

reported as "uninterpretable."

Antineuronal Nuclear Antibody-Type 1 (ANNA-1 or anti-Hu)

In adults, this autoantibody is found almost exclusively in patients with a

history of tobacco use or passive exposure.

 

Cancer has been found in >90% of seropositive patients identified as

seropositive for ANNA-1 by Mayo Clinic's Neuroimmunology

Laboratory (n=926; female:male = 2:1). SCLC has been found in 83%

of patients. A second malignant neoplasm was found in 13% of patients

positive for ANNA-1 who have SCLC. Therefore, the search for SCLC

should not stop if a non-SCLC tumor is found. ANNA-1 is also a rare

accompaniment of thymoma and neuroblastoma.

 

The most common presentation of patients seropositive for ANNA-1

is peripheral neuropathy (sensory > sensorimotor > autonomic >

motor), but they can exhibit any element of an encephalomyeloradiculo-

pathy; 12% present with gastrointestinal dysmotility (gastroparesis,

pseudo-obstruction, esophageal achalasia, pyloric stenosis, or anal spasm).

 

ANNA-1 has been identified in children with acquired cerebellar ataxia,

encephalopathy, or intestinal pseudoobstruction. Peripheral neuro-

blastomas are sometimes identifiable.

 

Antineuronal Nuclear Antibody-Type 2 (ANNA-2 or anti-Ri)

ANNA-2 is a rare paraneoplastic autoantibody. It is a marker of breast

carcinoma and SCLC. It has been reported most often in postmenopausal

women. In the Mayo Clinic Neuroimmunology Laboratory's prospective

experience, 32% of ANNA-2-positive patients have been male.

 

Seropositive patients often present with signs of midbrain, brain stem,

cerebellar, or spinal cord dysfunction. Ocular opsoclonus-myoclonus or

jaw spasm may be prominent. Sensorimotor neuropathy is sometimes seen.

 

Of 28 patients originally identified in Mayo Clinic's Neuroimmunology

Laboratory as seropositive for ANNA-2, and followed up clinically, 24 had

evidence of active cancer:  histologically proven lung carcinoma (10),

chest imaging abnormality consistent with lung cancer (3), histologically

proven breast carcinoma (9), recurrent uterine cervical carcinoma (1), and

bladder carcinoma.(1) Continued surveillance increased the cancer

detection frequency. A majority improved neurologically after

immunomodulatory or tumor-directed therapy.

 

For patients with a clinically unexplained neurologic disorder, detection

of ANNA-2 in serum or CSF identifies the neurologic problem as auto-

immune and almost certainly paraneoplastic, targets the search for

underlying malignancy (breast, lung, or gynecologic), and leads to early

treatment of cancer and consideration of immunosuppressant therapy.

 

Treatment of the cancer associated with ANNA-2 can lead to stabilization

and even striking improvement of the neurologic disorder and progressive

reduction of the autoantibody titer.

 

Antineuronal Nuclear Antibody-Type 3 (ANNA-3)

A positive result confirms that a patient's subacute neurological

disorder has an autoimmune basis and has a 90% predictive value

for an aerodigestive carcinoma, usually SCLC, that is new or recurrent

and confined to the chest. Fifteen percent of patients who are eventually

proven to have small-cell carcinoma have an unrelated and often more

obvious cancer, either coexisting or in the past.

 

ANNA-3 has not yet been encountered in patients with lung carcinoma

without a neurological accompaniment (n=100), or with other cancers

(n=300), or in healthy subjects (n=100).

 

Purkinje Cell Cytoplasmic Antibody-Type 1 (PCA-1 or

anti-Yo)

This autoantibody is found almost exclusively in women (<1% men) and is

a marker of an immune response initiated by ovarian carcinoma, a related

mullerian neoplasm, or breast carcinoma.

 

Seropositive patients usually present with a prominent subacute

cerebellar ataxia with variable elements of encephalomyeloradiculo-

pathy. In Mayo Clinic Neuroimmunology Laboratory's prospective

experience with 260 patients seropositive for PCA-1: a carcinoma

was found in 90% of seropositive patients (ovarian or other mullerian

or breast); >90% of patients presented with cerebellar ataxia; 5%

presented with sensorimotor or motor or autonomic neuropathy, and of

these, all had a pelvic neoplasm consistent with mullerian carcinoma.

 

PCA-1 autoantibody has not been found in any healthy subject.

It is rarely found in patients with neurologic diseases (including

cerebellar disorders) without gynecologic or breast cancer. The

ovarian cancers are typically limited in metastatic spread and may

not be detected by imaging procedures. If mammography is negative,

regardless of CA125 elevation, exploratory laparotomy is advisable

(as for a "second look" in management of ovarian carcinoma). Breast

carcinoma may coexist with a mullerian cancer. PCA-1 autoantibody is

rarely found in patients with gynecologic cancer without neurologic

dysfunction (<2%).  

 

PCA-1 is rarely found in male patients (<1%) and not, in Mayo Clinic's

experience, in paraneoplastic cerebellar degeneration associated

with lung cancer.

 

Purkinje Cell Cytoplasmic Antibody-Type 2 (PCA-2)

A positive value (at 1:2 dilution or higher) is consistent with

neurological autoimmunity, and justifies a thorough search for

a lung cancer, particularly SCLC. The cancers are usually limited in

metastasis. An extra-pulmonary primary small-cell carcinoma (eg,

skin, breast, larynx, cervix, prostate) should be considered.

 

PCA-2 is found in <2% of patients with uncomplicated SCLC.

 

Purkinje Cell Cytoplasmic Antibody Tr (PCA-Tr)

A positive value (at 1:2 dilution or higher) is consistent with

neurological autoimmunity and justifies a search for Hodgkin's

lymphoma. PCA-Tr has not yet been identified in any other

context.

 

Seropositive patients usually have Hodgkin's lymphoma and

present with subacute cerebellar ataxia.

 

Amphiphysin

A positive result is consistent with neurologic autoimmunity, usually

related to breast carcinoma or SCLC.

 

CRMP-5-IgG

Detection of IgG autoantibodies specific for the neuronal cytoplasmic

antigen CRMP-5 in a patient's serum or CSF confirms that the patient's

subacute neurological disorder has an autoimmune basis and has 75%

to 80% predictive value for SCLC or thymoma(1)

 

CRMP-5-IgG titers generally fall after the neoplasm is treated,

and a rising titer is indicative of tumor persistence or recurrence.

 

Anti-Glial/Neuronal Nuclear Antibody, Type 1 (AGNA-1)

AGNA-1 is recognized clinically as marker of a patient's immune

response to a lung cancer that is usually not obvious, but is manifest

as an autoimmune neurological disorder. AGNA-1 is an lgG marker of

an immune response to cancer (usually a SCLC) in patients presenting

with a subacute, generally multifocal, paraneoplastic neurological

disorder.(8-9)

Not recommended as a general screening test for cancer.

 

Seronegativity does not exclude malignancy.

1.   Lucchinetti CF, Kimmel DW, Lennon VA:  Paraneoplastic and

      oncological profiles of patients seropositive for type 1 anti-

      neuronal nuclear antibody. Neurology 1998;50:652-657

 

 2. Pittock SJ, Lucchinetti CF, Lennon VA: Anti-neuronal nuclear

      autoantibody type 2: paraneoplastic accompaniments. Ann Neurol

      2003;53(5):580-587

 

3.   Chan KH, Vernino S, Lennon VA:  ANNA-3 anti-neuronal nuclear

      antibody: marker of lung cancer-related autoimmunity. Ann Neurol

      2001 September;50(3):301-311

 

4.   Hetzel DJ, Stanhope CR, O'Neill BP, Lennon VA:  Gynecologic

      cancer in patients with subacute cerebellar degeneration predicted

      by anti-purkinje cell antibodies and limited in metastatic volume.

      Mayo Clin Proc 1990;65:1558-1563

 

5.   Vernino S, Lennon VA:  New Purkinje cell antibody (PCA-2):  marker

      of lung cancer-related neurological autoimmunity. Ann Neurol 2000

      March;47(3):297-305

 

6.  Pittock SJ, Lucchinetti CF, Parisi JE, et al: Amphiphysin autoimmunity:

     paraneoplastic accompaniments. Ann Neurol 2005;58(1):96-107

 

7.   Yu Z, Kryzer TJ, Griesmann GE, et al:  CRMP-5 neuronal autoantibody:

      marker of lung cancer and thymoma-related autoimmunity. Ann Neurol

      2001 February;49(2):146-154

 

8.  Graus F, Vincent A, Pozo-Rosich P, et al:  Anti-glial nuclear antibody:

      marker of lung cancer-related paraneoplastic neurological syndromes.

      J Neuroimmunol 2005;154(1-2):166-171

 

9,  Lachance D, Kryzer TJ, Pittock SJ, et al:  Anti-neuronal nuclear

      antibody type 4 (ANNA-4), a novel paraneoplastic marker of small-

      cell lung carcinoma (SCLC). Neurology 2006;66 (Suppl2):A340