Article Text
Abstract
A man in his 50s with metastatic hormone-sensitive prostate cancer, receiving androgen deprivation therapy and abiraterone acetate/prednisone, presented with an uncontrollable ‘Irish brogue’ accent despite no Irish background, consistent with foreign accent syndrome (FAS). He had no neurological examination abnormalities, psychiatric history or MRI of the brain abnormalities at symptom onset. Imaging revealed progression of his prostate cancer, despite undetectable prostate-specific antigen levels. Biopsy confirmed transformation to small cell neuroendocrine prostate cancer (NEPC). Despite chemotherapy, his NEPC progressed resulting in multifocal brain metastases and a likely paraneoplastic ascending paralysis leading to his death. We report FAS as the presenting manifestation of transformation to small cell NEPC, a previously undescribed phenomenon. His presentation was most consistent with an underlying paraneoplastic neurological disorder (PND), despite a negative serum paraneoplastic panel. This report enhances the minimal existing literature on FAS and PNDs associated with transformed NEPC.
- Prostate Cancer
- Neurology
- Immunology
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Background
Neuroendocrine prostate cancer (NEPC) is a relatively rare subset of prostate cancer. It generally presents following treatment with hormonal therapy—particularly potent androgen receptor inhibitors such as abiraterone or enzalutamide—but infrequently can arise de novo.1 2 The prevalence of transformed NEPC among men with lethal metastatic castration-resistant prostate cancer is approximately 20% based on biopsy and autopsy studies.3 4 Phenotypically, it is characterised by low prostate-specific antigen (PSA), increased frequency of visceral metastasis, refractoriness to hormonal therapy and elevated serum markers of neuroendocrine differentiation (eg, carcinoembryonic antigen (CEA), chromogranin A and lactate dehydrogenase (LDH)).2 5 Diagnosis is made histologically with visualisation of small, round, blue cells with characteristic findings including high nuclear to cytoplasmic ratios.6 These cells express at least one of the immunohistochemical markers of neuroendocrine differentiation (synaptophysin, chromogranin, CD56 or neuron-specific enolase) with minimal androgen receptor expression.6–8 Small cell NEPC is often associated with alterations in the tumour suppressor genes (including RB1, TP53 and PTEN), aggressive behaviour and poor prognosis with a median survival of around 19 months, and much shorter in the metastatic setting.6–8
Foreign accent syndrome (FAS) or pseudo-FAS, also called dysprosody, is a rare and complex entity. It is characterised by a consistent change in speech prosody and articulation that leads the listener to perceive the affected speaker to have a foreign accent.9 10 FAS is a clinical diagnosis but can often be attributed to a structural cause, usually in the left hemisphere, and most commonly due to stroke.9 Less common aetiologies recently described include breast cancer with intracranial metastases, a singular left precentral gyrus tumour and anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.9–11 There are documented cases of FAS that cannot be linked to structural or inflammatory causes. These cases are categorised as ‘functional’ or ‘psychogenic’ FAS and are associated with preceding head trauma or a history of psychiatric disease.12 13
Case presentation
A man in his 50s presented with metastatic hormone-sensitive prostate cancer (mHSPC) and received androgen deprivation therapy (ADT), abiraterone acetate/prednisone (AAP) and local radiation therapy to the prostate/pelvis. Twenty months following this diagnosis, he presented with changes in speech pattern and tone.
The patient was diagnosed with T3N1M1 prostate cancer at an outside institution after an elevated screening PSA to 67 ng/mL and a positive digital rectal examination. He was asymptomatic. His prior PSA values ranged from 5 to 6 ng/mL, and he had two prior negative prostate biopsies in the preceding 3 years. Biopsy demonstrated Gleason 4+5=9 grade group 5 adenocarcinoma of the prostate without small cell/NEPC features, and 7/12 cores positive for high-grade disease. Staging CT scan showed enlarged retroperitoneal lymph nodes indicative of de novo metastatic disease but no visceral metastases. Bone scan was without bone metastases. Genomic profiling of his tumour using the Foundation Medicine CDX tissue platform demonstrated RB1 loss, low tumour mutation burden, microsatellite stable disease and a TMPRSS2-ERG fusion, with no actionable mutations. ADT was initiated followed by AAP for low-volume mHSPC. He also completed local radiation therapy to the prostate and pelvis. He had a notable PSA response to treatment with undetectable PSA following the initiation of AAP.
Approximately 20 months following his diagnosis of mHSPC, he presented to an outside institution reporting notable speech changes from his typical speech pattern (online supplemental file 1) to a consistent ‘Irish brogue’ accent (online supplemental file 2). The patient had never been to Ireland and had never previously spoken in an Irish accent, though he had Irish family/friends and had lived in England briefly in his 20s. His accent was uncontrollable, present in all settings and gradually became persistent. He did not have any known head trauma, psychiatric conditions or psychosocial stressors prior to his speech changes. He reported unintentional weight loss but denied other symptoms. His examination was without any neurological or psychiatric abnormalities. MRI of the brain was normal. CT of the abdomen/pelvis demonstrated a new cluster of right pelvic lymph nodes above the bladder but was otherwise stable. PSA was undetectable, and he continued treatment with ADT and AAP. He was diagnosed with FAS and referred to neurology. Formal neurological evaluation was never completed at that time.
Supplemental material
Supplemental material
Because of his progressive prostate cancer, he was referred to an established care with our institution 3 months later. He was still consistently speaking in the ‘Irish brogue’ accent. He was also experiencing new dysuria, lower abdominal discomfort and intermittent right leg pain. His examination was notable for mild lower abdominal tenderness but no other abnormalities.
Investigations
Upon establishing care at our institution, contrasted CT of the chest/abdomen/pelvis demonstrated marked progression with a large pelvic soft tissue mass (figure 1), bulky lymph node disease, and metastatic disease to the liver and bone. Liver metastases were 2–3 cm in size and multiple. A bone scan revealed increased tracer activity in the mid-shaft of the right femur and the posterolateral right approximate eighth rib concerning for osseous metastatic disease. Blood tests showed undetectable PSA, elevated serum CEA (183.8 ng/mL; reference ≤2.5 ng/mL) and elevated chromogranin A (103 ng/mL; reference <93 ng/mL), but his serum LDH was normal. His evidence of progression on imaging in the setting of undetectable PSA and elevated serum neuroendocrine markers raised concern for transformation to NEPC. Biopsy of the pelvic mass confirmed the diagnosis of small cell NEPC (figure 2). Mayo Clinic serum paraneoplastic panel was sent due to his persistent FAS but returned negative (figure 3).
Outcome and follow-up
Following the diagnosis of NEPC, AAP was discontinued, and the patient was started on docetaxel and carboplatin with palliative radiation therapy for his painful metastatic right femur lesion. After two cycles of docetaxel and carboplatin, he presented to an outside hospital with a debilitating ascending muscle flaccid paralysis involving his legs and eventually arms, most concerning for Guillain-Barre or Lambert-Eaton syndrome, for which he was given intravenous immunoglobulin. Lumbar puncture at that time was notable for elevated cerebrospinal fluid (CSF) protein (161 mg/dL) and normal glucose (157 mg/dL) without white or red blood cells. No paraneoplastic or other studies were obtained. He was also found to have multiple supratentorial and infratentorial lesions on brain MRI consistent with intracranial metastatic disease (figure 4). Due to his rapid clinical deterioration and disease progression despite chemotherapy, he transitioned to home hospice care and died shortly thereafter. Figure 5 outlines this patient’s course from initial presentation to his death. His Irish brogue-like accent was maintained until his death.
Differential diagnosis
The differential diagnosis for the aetiology of the patient’s FAS included structural (metastasis or stroke), psychogenic/functional and paraneoplastic neurological disorder (PND). Supporting evidence was ultimately most indicative of a PND as the underlying driver of his FAS.
Paraneoplastic syndromes are systemic symptoms caused by the presence of an underlying neoplasm through hormonal, immune-mediated or unknown mechanisms.14 Though rare overall, they are more commonly associated with prostate cancer than other urological malignancies, excluding renal cell carcinoma.14 15 Endocrine syndromes such as Cushing’s syndrome and syndrome of inappropriate antidiuretic hormone secretion are most frequently described in NEPC and known to be more common in NEPC than in conventional prostate adenocarcinoma.6 Immune-mediated PNDs including Lambert-Eaton, limbic encephalitis, encephalomyelitis, cerebellar degeneration and brain stem encephalitis have been more rarely described both in neuroendocrine and conventional prostate cancer.14 16
Our patient’s serum paraneoplastic panel was negative 7 months after his initial presentation with dysprosody. However, a PND cannot be excluded because no paraneoplastic panel was obtained at symptom onset and no CSF paraneoplastic panel was completed. There are no known paraneoplastic antibodies associated with an isolated FAS in the absence of other signs of encephalomyelitis. A review by Storstein et al identified 37 cases of paraneoplastic neurological syndromes in association with prostate cancer, most of which were found to have associated anti-Hu antibodies. Six patients had no specific autoantibodies isolated, supporting the possibility of a yet uncharacterised autoantibody in our patient’s case.16 Paraneoplastic syndromes additionally have a known association with disease progression in prostate cancer, and this patient’s FAS coincided with his progression.16 17 Further, the ascending paralysis he developed prior to his death is also suspicious for a PND.
Structural causes were thought to be unlikely given his initial negative MRI of the brain. Though central nervous system parenchymal metastases are rare from both typical prostate adenocarcinoma and NEPC, his repeat brain MRI about 8 months later did reveal multiple intracranial metastases, coinciding with his progressive NEPC and liver metastases despite multiagent chemotherapy.18 It is plausible that he could have had micro-metastatic disease undetectable on his initial imaging; however, it seems improbable that his FAS was due to lesions that small. Psychogenic FAS was also considered, but this patient had no history of psychiatric disease, head trauma or known psychosocial stressor prior to the onset of his speech changes making this aetiology less likely.
Discussion
There are only two other reports in the literature of FAS in patients with malignancy. In 2009, Abel et al reported a woman in her 60s with breast cancer who developed FAS and other neurological abnormalities attributed to multiple intracranial metastases.10 The second case in 2011 reported by Tomasino et al described a woman in her 50s with seizures and FAS secondary to a singular circumscribed tumour of the left precentral gyrus.11 To our knowledge, this is the first case of FAS described in a patient with prostate cancer and the third described in a patient with malignancy.
This patient presented with a ‘classic’ constellation of findings for transformation to small cell NEPC, including progressive disease with visceral metastasis, undetectable PSA, evidence of elevation in serum neuroendocrine markers and tumour, and genomic profile with RB1 loss that accompanied his TMPRSS2-ERG translocation, consistent with a prostate cancer adenocarcinoma primary. His transformation to small cell NEPC coincided with the emergence of an ‘Irish brogue’ accent and subsequent diagnosis of FAS in the setting of potent androgen receptor blockade, which may have promoted lineage plasticity and transformation to NEPC.
No structural or psychogenic aetiology of his FAS was identified. The concurrence of his speech changes and his clinical progression, as well as the paralytic syndrome he developed at the end of his life, are suggestive of a PND associated with his small cell NEPC. In a review of paraneoplastic syndromes associated with prostate cancer, Hong et al found that about 20% of these syndromes were the heralding symptom of progression to castration-resistant disease.15 Additionally, there are multiple cases in the literature describing PNDs, particularly Lambert-Eaton syndrome, as the presenting symptoms of patients with transformation small cell NEPC.17
This unusual presentation highlights the importance of additional literature on FAS and PNDs associated with prostate cancer to improve understanding of the links between these rare syndromes and clinical trajectory.
Learning points
Though rare, paraneoplastic syndromes can manifest with a variety of systemic symptoms and have known associations with prostate cancer, particularly neuroendocrine prostate cancer (NEPC)/small cell transition. These syndromes are important to recognise as they can be the presenting feature of progression of or transformation to NEPC.
Foreign accent syndrome (FAS) is a rare and complex entity with multiple aetiologies. Clinical context and thorough evaluation can suggest certain causes, even when definitive diagnostics are not obtained.
Additional reports characterising FAS and paraneoplastic neurological disorders associated with prostate cancer are needed to further understand the possible links between these rare syndromes, clinical trajectory and disease progression.
Ethics statements
Patient consent for publication
Acknowledgments
We would like to acknowledge Gina Sotolongo for her contribution to this report by obtaining the histopathology images.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @ABroderickMD, @AarmstrongDuke
Contributors AB drafted and revised the case report and gathered/analysed all of the patient information together. MKL gathered data about the patient, helped with the overall conception of the report and critically revised the report. NS cared for the patient, acquired additional data and information about the patient, and critically revised the report. AA cared for the patient, contributed to the conception/design of the report, and drafted and critically revised the report.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests In the last 36 months, AA is disclosing institutional grant funding (to Duke University) from Pfizer, Astellas, Bayer, Dendreon, Genentech/Roche, Merck, BMS, Amgen, AstraZeneca, Celgene, Forma, Janssen, NIH, DOD, and PCF/Movember; and consulting/advisor relationships with Pfizer, Astellas, Bayer, Dendreon, Genentech/Roche, Merck, BMS, AstraZeneca, Forma, Janssen, Myovant, Exelixis and Exact sciences. There are no other competing interests to disclose.
Provenance and peer review Not commissioned; externally peer reviewed.
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