Neurol Sci DOI 10.1007/s10072-015-2113-5
LETTER TO THE EDITOR
Paraneoplastic cerebellar degeneration with anti-CV2/CRMP5 antibodies and prostate adenocarcinoma A. Aliprandi • A. Terruzzi • A. Rigamonti • E. Bazzigaluppi • L. Tremolizzo • C. Ferrarese A. Salmaggi
•
Received: 27 October 2014 / Accepted: 10 February 2015 Ó Springer-Verlag Italia 2015
Dear Sir, An 80-year-old male patient, with no relevant previous family and medical history was admitted to our unit for progressive dysarthria, limb and gait ataxia developed during the previous 10 months. Mild axonal sensorimotor polyneuropathy was also present. Brain MR scan disclosed marked shrinkage of the cerebellum and slight atrophy of supratentorial structures. Lumbar puncture and blood tests were not informative. Prostate specific antigen (PSA) was 1220 ng/mL (normal values \4000 ng/mL) and increased values were shown for neuron-specific enolase (NSE, 25.7 lg/L, normal range: 0–12.5; reconfirmed at a subsequent determination); CYFRA 21-1 was negative. A positive title of anti-CV2/CMRP5 antibodies was found in serum samples in two separate occasions by combining indirect immunofluorescence (IFI) and immunoblot techniques (Fig. 1). Serum anti-Hu, -Yo, -Ri, -amphiphysin, and -GAD65 were negative. Total-body FDG-PET scan showed marked hypermetabolism of the prostatic gland. A biopsy detected an adenocarcinoma with no evidence of extracapsular dissemination (Gleason score 3/3). The A. Aliprandi A. Terruzzi A. Rigamonti A. Salmaggi (&) Neurology-Stroke Unit Division, Department of Neuroscience, ‘‘A. Manzoni’’ Hospital, Lecco, Italy e-mail: [email protected] E. Bazzigaluppi Laboraf Autoimmunity Laboratory, ‘‘San Raffaele’’ Hospital Scientific Institute, Milan, Italy L. Tremolizzo C. Ferrarese Neurology Unit, ‘‘San Gerardo’’ Hospital, Monza, Italy L. Tremolizzo C. Ferrarese DCMT and Neuro-MI, University of Milano-Bicocca, Milan, Italy
patient was started on bicalutamide and tamoxifen. Intravenous immunoglobulins (IVIG, 0.4 g/kg/die for 5 days) were then administered with an initial favorable response that eventually disappeared despite a second trial 3 months later. Nine months later ataxia was still severe (Klockgether’s score 27/35, worst items trunk and gait ataxia) [1]. Most of the antibodies found associated with paraneoplastic cerebellar degeneration (PCD) are directed against intracellular antigens either widely expressed in several neuronal types (ANNA), or specifically in Purkinje cells (e.g., PCA-2) [2]. Anti-CV2, also known as antiCRMP5 (Collapsin Response Mediator Protein 5) was initially reported in a patient with cerebellar ataxia, uveitis and peripheral neuropathy associated to breast/undifferentiated carcinoma [3]. A case series of 37 anti-CV2-positive patients was subsequently compared to 324 patients with a positive titre for anti-Hu, with higher rates of cerebellar ataxia and uveo/retinal involvement and lower rates of peripheral neuropathy in the former group with respect to the latter [4]; chorea and myasthenic syndromes were recorded only in the anti-CV2 group, while limbic encephalitis was equally present in the two groups. SCLC was the most frequent cancer in both groups of patients, while malignant thymoma was represented only in the antiCV2 positive group. Interestingly, prostate adenocarcinoma was not reported, while the much more aggressive small cell prostate carcinoma (SCPC) was reported without overt differences between the two groups [4]. Apart from PCD, anti-CV2 has been strongly associated to peripheral neuropathy, as was found for our patient [5]. Paraneoplastic diseases have been reported in association with prostate adenocarcinoma and PCD is listed among possible presentations, implying that this site should be always included in the search for occult malignancies [6]. Furthermore, the possibility of either finding SCPC
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Neurol Sci Fig. 1 a A pattern suggestive for anti-CV2 (cytoplasmic staining with nuclear sparing) was obtained at the indirect immunofluorescence (IFI) performed with our patient’s serum on primate cerebellum (Inova Diagnostics, San Diego); the estimated titre was 1:500. b Subsequent immunoblot verification (Ravo Diagnostika) of anti-CV2 isolated presence in serum obtained from the proband in two separate occasions (lanes 3–4); serum dilution 1:2000
islets within an adenocarcinoma surrounding, or of facing an histodiagnostic dilemma should not be forgotten, since the prostate represents the most common extrapulmonary site for small cell neuroendocrine carcinomas. Besides the histological exam, the much faster progression rate of SCPC definitely is not compatible with the clinical history of our patient. Also the possibility of the presence of more than one tumour should not be rejected, since, for example, anti-CV2 paraneoplastic presentation associated to prostatic adenocarcinoma has been afterwards found to imply a concurrent SCLC [7]. Notably, PCD may occur many years before cancer detection [6] and we can not exclude that elevated NSE serum levels in our patient might predate the discovery of a SCLC or a malignant thymoma [8]. This issue might be of relevance since, to our knowledge, antiCV2-related PCD has never been clearly associated before to a non-metastatic prostatic adenocarcinoma, at least if considering IFI screening results. Conceivably, a definite demonstration of the proposed association would come only from experiments showing the expression of the CV2 antigen on biopsy tissue obtained from our patient. However, we could not run these experiments and the evidence behind the present report, albeit highly plausible, remains at the moment circumstantial. Even when high titres of serum antibodies are reported, anti-CV2 is found in the CSF about half of the times [9]; one single patient presenting with SCPC associated to cerebellar degeneration and sensory neuronopathy with serum anti-CV2 (titre: 1:1000) plus anti-Hu had no trace of anti-CV2 in the CSF [9]. Our patient did not display CSF anomalies, and the presence of oligoclonal bands was excluded [10]; however, anti-CV2 antibody testing in CSF was not performed. Furthermore, our patient did not have other paraneoplastic syndrome autoantibodies in serum, while the concomitant finding of several antibodies is not infrequent [10].
123
In our case the treatment with IVIG initially showed modest efficacy, albeit the patient eventually remained markedly impaired despite both, (a) the second trial, and (b) the absence of clinical progression of the underlying prostatic malignancy. This might be not surprising, and has been documented by a previous report of two cycles of IVIG administered to a patient affected by PCD associated to squamous cell carcinoma of the tongue; in this latter case the initially high anti-CV2 CSF positive titre decreased following treatment in absence of significant clinical improvement [11]. Long-duration, possibly irreversible, neuronal tissue damage and failure to eradicate the abnormal cellular activity presumably generating molecular mimicry might be likely explanations. In conclusion we report here a case of PCD/peripheral neuropathy presumably due to anti-CV2 antibodies, with the unique evidence of a prostatic adenocarcinoma without other malignancies or extra-prostatic localizations despite of a quite long follow-up period. Hence, we further suggest that prostate cancers should be always considered when facing such clinical presentations and we conclude extending the borders of the of anti-CV2 associated spectrum. Conflict of interest
None.
References 1. Klockgether T, Schroth G, Diener HC, Dichgans J (1990) Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 53:297–305 2. Greenlee JE, Clawson SA, Hill KE, Dechet CB, Carlson NG (2010) Antineuronal autoantibodies in paraneoplastic cerebellar degeneration associated with adenocarcinoma of the prostate. J Neurol Sci 291:74–78 3. Antoine JC, Honnorat J, Vocanson C, Koenig F, Aguera M, Belin MF, Michel D (1993) Posterior uveitis, paraneoplastic
Neurol Sci
4.
5.
6.
7.
encephalomyelitis and auto-antibodies reacting with developmental protein of brain and retina. J Neurol Sci 117:215–223 Honnorat J, Cartalat-Carel S, Ricard D, Camdessanche JP, Carpentier AF, Rogemond V, Chapuis F, Aguera M, Decullier E, Duchemin AM, Graus F, Antoine JC (2009) Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 80:412–416 Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini G, Euronetwork PNS (2010) Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 67:330–335 Hong MK, Kong J, Namdarian B, Longano A, Grummet J, Hovens CM, Costello AJ, Corcoran NM (2010) Paraneoplastic syndromes in prostate cancer. Nat Rev Urol 7:681–692 Ritzenthaler T, Verret JM, Honnorat J (2010) Paraneoplastic chorea and behavioral disorders in a patient with anti-CV2/
8.
9.
10.
11.
CRMP5 antibodies and two different tumors. Rev Neurol (Paris) 166:90–95 Simonelli M, Banna GL, Santoro A (2009) Thymoma associated with myasthenia and autonomic anti-Hu paraneoplastic neuropathy. Tumori 95:243–247 Rogemond V, Honnorat J (2000) Anti-CV2 autoantibodies and paraneoplastic neurological syndromes. Clin Rev Allergy Immunol 19:51–59 Stich O, Rauer S (2007) Antigen-specific oligoclonal bands in cerebrospinal fluid and serum from patients with anti-amphiphysin- and anti-CV2/CRMP5 associated paraneoplastic neurological syndromes. Eur J Neurol 14:650–653 Saloustros E, Zaganas I, Mavridis M, Vamvakas L, Plaitakis A, Georgoulias V, Mavroudis D (2010) Anti-CV2 associated cerebellar degeneration after complete response to chemoradiation of head and neck carcinoma. J Neurooncol 97:291–294
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LETTER TO THE EDITOR
Paraneoplastic cerebellar degeneration with anti-CV2/CRMP5 antibodies and prostate adenocarcinoma A. Aliprandi • A. Terruzzi • A. Rigamonti • E. Bazzigaluppi • L. Tremolizzo • C. Ferrarese A. Salmaggi
•
Received: 27 October 2014 / Accepted: 10 February 2015 Ó Springer-Verlag Italia 2015
Dear Sir, An 80-year-old male patient, with no relevant previous family and medical history was admitted to our unit for progressive dysarthria, limb and gait ataxia developed during the previous 10 months. Mild axonal sensorimotor polyneuropathy was also present. Brain MR scan disclosed marked shrinkage of the cerebellum and slight atrophy of supratentorial structures. Lumbar puncture and blood tests were not informative. Prostate specific antigen (PSA) was 1220 ng/mL (normal values \4000 ng/mL) and increased values were shown for neuron-specific enolase (NSE, 25.7 lg/L, normal range: 0–12.5; reconfirmed at a subsequent determination); CYFRA 21-1 was negative. A positive title of anti-CV2/CMRP5 antibodies was found in serum samples in two separate occasions by combining indirect immunofluorescence (IFI) and immunoblot techniques (Fig. 1). Serum anti-Hu, -Yo, -Ri, -amphiphysin, and -GAD65 were negative. Total-body FDG-PET scan showed marked hypermetabolism of the prostatic gland. A biopsy detected an adenocarcinoma with no evidence of extracapsular dissemination (Gleason score 3/3). The A. Aliprandi A. Terruzzi A. Rigamonti A. Salmaggi (&) Neurology-Stroke Unit Division, Department of Neuroscience, ‘‘A. Manzoni’’ Hospital, Lecco, Italy e-mail: [email protected] E. Bazzigaluppi Laboraf Autoimmunity Laboratory, ‘‘San Raffaele’’ Hospital Scientific Institute, Milan, Italy L. Tremolizzo C. Ferrarese Neurology Unit, ‘‘San Gerardo’’ Hospital, Monza, Italy L. Tremolizzo C. Ferrarese DCMT and Neuro-MI, University of Milano-Bicocca, Milan, Italy
patient was started on bicalutamide and tamoxifen. Intravenous immunoglobulins (IVIG, 0.4 g/kg/die for 5 days) were then administered with an initial favorable response that eventually disappeared despite a second trial 3 months later. Nine months later ataxia was still severe (Klockgether’s score 27/35, worst items trunk and gait ataxia) [1]. Most of the antibodies found associated with paraneoplastic cerebellar degeneration (PCD) are directed against intracellular antigens either widely expressed in several neuronal types (ANNA), or specifically in Purkinje cells (e.g., PCA-2) [2]. Anti-CV2, also known as antiCRMP5 (Collapsin Response Mediator Protein 5) was initially reported in a patient with cerebellar ataxia, uveitis and peripheral neuropathy associated to breast/undifferentiated carcinoma [3]. A case series of 37 anti-CV2-positive patients was subsequently compared to 324 patients with a positive titre for anti-Hu, with higher rates of cerebellar ataxia and uveo/retinal involvement and lower rates of peripheral neuropathy in the former group with respect to the latter [4]; chorea and myasthenic syndromes were recorded only in the anti-CV2 group, while limbic encephalitis was equally present in the two groups. SCLC was the most frequent cancer in both groups of patients, while malignant thymoma was represented only in the antiCV2 positive group. Interestingly, prostate adenocarcinoma was not reported, while the much more aggressive small cell prostate carcinoma (SCPC) was reported without overt differences between the two groups [4]. Apart from PCD, anti-CV2 has been strongly associated to peripheral neuropathy, as was found for our patient [5]. Paraneoplastic diseases have been reported in association with prostate adenocarcinoma and PCD is listed among possible presentations, implying that this site should be always included in the search for occult malignancies [6]. Furthermore, the possibility of either finding SCPC
123
Neurol Sci Fig. 1 a A pattern suggestive for anti-CV2 (cytoplasmic staining with nuclear sparing) was obtained at the indirect immunofluorescence (IFI) performed with our patient’s serum on primate cerebellum (Inova Diagnostics, San Diego); the estimated titre was 1:500. b Subsequent immunoblot verification (Ravo Diagnostika) of anti-CV2 isolated presence in serum obtained from the proband in two separate occasions (lanes 3–4); serum dilution 1:2000
islets within an adenocarcinoma surrounding, or of facing an histodiagnostic dilemma should not be forgotten, since the prostate represents the most common extrapulmonary site for small cell neuroendocrine carcinomas. Besides the histological exam, the much faster progression rate of SCPC definitely is not compatible with the clinical history of our patient. Also the possibility of the presence of more than one tumour should not be rejected, since, for example, anti-CV2 paraneoplastic presentation associated to prostatic adenocarcinoma has been afterwards found to imply a concurrent SCLC [7]. Notably, PCD may occur many years before cancer detection [6] and we can not exclude that elevated NSE serum levels in our patient might predate the discovery of a SCLC or a malignant thymoma [8]. This issue might be of relevance since, to our knowledge, antiCV2-related PCD has never been clearly associated before to a non-metastatic prostatic adenocarcinoma, at least if considering IFI screening results. Conceivably, a definite demonstration of the proposed association would come only from experiments showing the expression of the CV2 antigen on biopsy tissue obtained from our patient. However, we could not run these experiments and the evidence behind the present report, albeit highly plausible, remains at the moment circumstantial. Even when high titres of serum antibodies are reported, anti-CV2 is found in the CSF about half of the times [9]; one single patient presenting with SCPC associated to cerebellar degeneration and sensory neuronopathy with serum anti-CV2 (titre: 1:1000) plus anti-Hu had no trace of anti-CV2 in the CSF [9]. Our patient did not display CSF anomalies, and the presence of oligoclonal bands was excluded [10]; however, anti-CV2 antibody testing in CSF was not performed. Furthermore, our patient did not have other paraneoplastic syndrome autoantibodies in serum, while the concomitant finding of several antibodies is not infrequent [10].
123
In our case the treatment with IVIG initially showed modest efficacy, albeit the patient eventually remained markedly impaired despite both, (a) the second trial, and (b) the absence of clinical progression of the underlying prostatic malignancy. This might be not surprising, and has been documented by a previous report of two cycles of IVIG administered to a patient affected by PCD associated to squamous cell carcinoma of the tongue; in this latter case the initially high anti-CV2 CSF positive titre decreased following treatment in absence of significant clinical improvement [11]. Long-duration, possibly irreversible, neuronal tissue damage and failure to eradicate the abnormal cellular activity presumably generating molecular mimicry might be likely explanations. In conclusion we report here a case of PCD/peripheral neuropathy presumably due to anti-CV2 antibodies, with the unique evidence of a prostatic adenocarcinoma without other malignancies or extra-prostatic localizations despite of a quite long follow-up period. Hence, we further suggest that prostate cancers should be always considered when facing such clinical presentations and we conclude extending the borders of the of anti-CV2 associated spectrum. Conflict of interest
None.
References 1. Klockgether T, Schroth G, Diener HC, Dichgans J (1990) Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 53:297–305 2. Greenlee JE, Clawson SA, Hill KE, Dechet CB, Carlson NG (2010) Antineuronal autoantibodies in paraneoplastic cerebellar degeneration associated with adenocarcinoma of the prostate. J Neurol Sci 291:74–78 3. Antoine JC, Honnorat J, Vocanson C, Koenig F, Aguera M, Belin MF, Michel D (1993) Posterior uveitis, paraneoplastic
Neurol Sci
4.
5.
6.
7.
encephalomyelitis and auto-antibodies reacting with developmental protein of brain and retina. J Neurol Sci 117:215–223 Honnorat J, Cartalat-Carel S, Ricard D, Camdessanche JP, Carpentier AF, Rogemond V, Chapuis F, Aguera M, Decullier E, Duchemin AM, Graus F, Antoine JC (2009) Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 80:412–416 Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini G, Euronetwork PNS (2010) Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 67:330–335 Hong MK, Kong J, Namdarian B, Longano A, Grummet J, Hovens CM, Costello AJ, Corcoran NM (2010) Paraneoplastic syndromes in prostate cancer. Nat Rev Urol 7:681–692 Ritzenthaler T, Verret JM, Honnorat J (2010) Paraneoplastic chorea and behavioral disorders in a patient with anti-CV2/
8.
9.
10.
11.
CRMP5 antibodies and two different tumors. Rev Neurol (Paris) 166:90–95 Simonelli M, Banna GL, Santoro A (2009) Thymoma associated with myasthenia and autonomic anti-Hu paraneoplastic neuropathy. Tumori 95:243–247 Rogemond V, Honnorat J (2000) Anti-CV2 autoantibodies and paraneoplastic neurological syndromes. Clin Rev Allergy Immunol 19:51–59 Stich O, Rauer S (2007) Antigen-specific oligoclonal bands in cerebrospinal fluid and serum from patients with anti-amphiphysin- and anti-CV2/CRMP5 associated paraneoplastic neurological syndromes. Eur J Neurol 14:650–653 Saloustros E, Zaganas I, Mavridis M, Vamvakas L, Plaitakis A, Georgoulias V, Mavroudis D (2010) Anti-CV2 associated cerebellar degeneration after complete response to chemoradiation of head and neck carcinoma. J Neurooncol 97:291–294
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