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Purkinje cell cytoplasmic antibody type I (PCA-1-IgG or anti-Yo) seropositivity associates with paraneoplastic cerebellar degeneration (PCD) and is mostly restricted to female patients with müllerian or breast cancers.1–3 PCD presents with nystagmus, dysarthria and trunk and extremity ataxia. PCA-1-IgG is extremely rare in men. Here we report the frequency, clinical characteristics and oncological associations of PCA-1-IgG seropositivity in men and review the literature.
The Mayo Clinic institutional review board approved this study. In the past 30 years, Mayo Clinic’s Neuroimmunology Laboratory identified 650 PCA-1-IgG-seropositive patients3; 8 (1.2%) were men (online supplementary table 1a), with PCA-1-IgG specificity confirmed by western blot with purified human cerebellar degeneration-related protein 2 (CDR2, the PCA-1 antigen; Euroimmun, Lubeck, Germany). Clinical information was obtained for seven by case record review and physician telephone interviews. A PubMed literature search (1990–2015) identified 10 previously published PCA-1-IgG-positive male cases (online supplementary table 1b).
Supplementary file 1
Gastrointestinal adenocarcinoma tissue, from a single patient, was stained using a mouse monoclonal human CDR2-specific IgG (1:100, LifeSpan Biosciences) to detect PCA-1 antigen (figure 1).
A non-smoking man in his 60s, with prostate cancer treated the previous year, presented with melaena and 4 weeks of dizziness, imbalance and incoordination. Examination revealed saccadic overshoots, dysarthria and predominantly left-sided extremity ataxia. Brain MRI and positron emission tomography-computational tomography (PET-CT) were normal. Cerebrospinal fluid (CSF) analysis revealed elevated protein (81 mg/dL; normal <36 mg/dL) and 6 CSF-unique oligoclonal bands (OCBs; normal <5). PCA-1-IgG was detected in serum (1:61,440) and CSF (1:256). An enlarged celiac lymph node detected by PET-CT contained poorly differentiated adenocarcinoma from the gastro-oesophageal junction (tumour grade T3N2M0; figure 1A, B). The tumour tissue had chronic inflammatory cell infiltration with prominent eosinophils; malignant cells were strongly immunoreactive for the CDR2 cerebellar oncoprotein (figure 1D–F). After treatment with carboplatin, paclitaxel and radiation, plus intravenous methylprednisolone, 1 g/dose for 3 days then weekly for 3 weeks, examination revealed interval development of an intermittent involuntary tremor (large amplitude, low frequency) of the left shoulder and torso. After three additional weekly methylprednisolone doses, progressive dysphagia necessitated feeding tube placement. One month later the tumour was resected.
A smoker in his 50s presented with 30 pounds weight loss, dysarthria and dizziness, which progressed within 2 months to walking difficulties and altered mental status. Initial brain MRI was negative; CSF analysis showed elevated protein (98 mg/dL) and 6 CSF-unique OCBs. PCA-1-IgG was detected in serum (1:122,880) and CSF (1:2,048). The patient did not improve with steroid therapy. Oncological evaluation revealed lung nodules and regional lymphadenopathy. PET-CT and biopsy were negative. The patient’s family declined further treatment. Repeat brain MRI showed cerebellar atrophy. Autopsy revealed poorly differentiated large cell lung carcinoma.
A man in his 70s presented with 20 pounds subacute weight loss, nasal tone, dysarthria, spasticity and walking difficulties. Electromyography showed evidence of denervation and axonal sensorimotor polyneuropathy. Brain and spine MRI and chest, abdomen and pelvis CT imaging were unrevealing. PCA-1-IgG was detected in serum (1:61,440). Oncological evaluation revealed a cholangiocarcinoma. The patient did not improve despite treatment with intravenous steroids and immune globulin, and tacrolimus. He died in hospice.
A man in his 60s presented with disequilibrium and dizziness, evolving over 2.5 months to progressive spasticity, weakness and cerebellar ata-xia. Examination revealed dysarthria, limb ataxia and brisk reflexes with crossed adductors; proprioception and vibration sensation were reduced to the knees. Brain MRI showed diffuse atrophy. PCA-1-IgG was detected in serum (1:61,440). Oncological evaluation identified carcinomas of the breast and oesophagus. He progressed rapidly to wheelchair dependence.
An ex-smoker in his 50s presented with vertigo, dysarthria, diplopia, ataxia and nystagmus developing subacutely over 3 weeks. He had a history of resected hard breast masses 15 years earlier; no histopathological information was available. Examination revealed ataxia and nystagmus. PCA-1-IgG was detected in serum (1:7,680) and CSF (1:512). After plasmapheresis, severe nystagmus was noted, he could not feed himself and required a walker to ambulate.
An ex-smoker in his 70s presented with a 4-week history of dysarthria, cerebellar ataxia, anorexia and 30 pounds weight loss. PCA-1-IgG was detected in serum(1:61,440). Oncological evaluation revealed metastatic gastric carcinoma. The patient died.
An ex-smoker in his 60s presented with nausea, vertigo, vertical diplopia and subacute ataxia. Brain MRI was normal. CT chest showed an oesophageal mass. PET-CT demonstrated hypermetabolic foci in oesophagus and lymph nodes (iliac, abdomen and chest). CSF showed 50 WBC/μL (normal <6/ µL; 99% lymphocytes) and elevated protein (54 mg/dL). PCA-1-IgG was detected in serum (1:7680) and CSF (1:128). Biopsied tumour tissue revealed metastatic oesophageal adenocarcinoma. Response to 5 days’ intravenous immune globulin and methylprednisolone was minimal.
Gastrointestinal carcinomas were identified in five of seven (71%) PCA-1-IgG-positive men with available history. Patient #1’s tumour stained positive for PCA-1-IgG’s antigen, CDR2 (figure 1). When combined with 10 literature-reported male cases (online supplementary table 1b), 10/17 patients (59%) had gastrointestinal cancers: 3 gastric, 6 oesophageal and 1 cholangiocarcinoma. In prior case series describing 55, 16 and 83 PCA-1-IgG-positive women with PCD,1–3 1 patient (0.6%) had a history of colon cancer,3 and none had an upper gastrointestinal malignancy (ie, oesophagus, stomach or biliary tree). This finding has important implications for PCA-1-IgG-seropositive men. Because gastrointestinal tumours may not be well visualised on CT or PET imaging, oesophagogastroduodenoscopy, colonoscopy and potentially abdominal ultrasound are recommended in the oncological evaluation.
In prior series of PCA-1-IgG-seropositive female patients,1–3 breast and müllerian tumours, typically adenocarcinomas, accounted for 88%–95% of associated tumours. In this study, available histopathology for three of the tumours found in six PCA-1-IgG-seropositive male patients revealed two oesophageal adenocarcinomas and one large cell lung cancer. The other reported tumours in this study, cholangiocarcinoma, gastric, breast, oesophageal and prostate cancers were likely also adenocarcinomas. Adenocarcinomas accounted for 9/10 (90%) of cancers identified in previously reported PCA-1-IgG-seropositive men (online supplementary table 1b); the 10th patient had a large cell lung carcinoma.
Overall, PCA-1-IgG seropositivity is strongly associated with adenocarcinomas, particularly of the upper gastrointestinal tract in men.
The authors thank Jessica Sagen for her assistance in coordinating data and Mary Curtis for her administrative assistance.
Contributors JJL, VAL and SJP: study concept and design. JJL and SJP: drafting of the manuscript. SJP: study supervision. All authors: acquisition, analysis or interpretation of data; critical revision of the manuscript for important intellectual content.
Funding SJP has provided consultation to Alexion Pharmaceuticals, Medimmune and Chugai Pharma USA, but has received no personal fees or personal compensation for these consulting activities. All compensation for consulting activities is paid directly to Mayo Clinic. SJP has received research support from Alexion, Medimmune and Grifols. AMcK received research support from and has consulted for Euroimmun, Medimmune and Grifols, but has not received personal compensation. CFL has received funding support from Biogen, Novartis, Mallinkrodt and shares in royalties from marketing kits for detecting AQP4 autoantibody. BP has received compensation for consulting from Novartis. BP is currently employed by Biogen.
Competing interests None declared.
Ethics approval Mayo Clinic Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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