Introduction
Paraneoplastic syndromes are rare and complex clinical manifestations caused by tumor aberrant production of hormones, cytokines, or autoantibodies, often targeting the nervous system. Among these, paraneoplastic neurological syndromes (PNS) present a unique diagnostic and therapeutic challenge, often preceding the identification of an underlying malignancy. Early recognition of PNS is critical as it can prompt timely investigation and treatment of the associated tumor, potentially improving both neurological and oncological outcomes1–3.
Stiff-person syndrome (SPS) is a rare autoimmune disorder characterized by progressive muscle rigidity, painful spasms, and impaired mobility. It can occur idiopathically or as a paraneoplastic syndrome, associated with autoantibodies targeting synaptic proteins, such as anti-glutamic acid decarboxylase and anti-amphiphysin, the latter being more common in the paraneoplastic form4–6.
Breast cancer is the most common malignancy in women worldwide, encompassing a complex biological and clinical spectrum. While it is primarily associated with older age, a significant subset of cases arises in younger women, under 50 years of age, who fall outside the universal mammographic screening programs in Portugal. In this population, breast cancer often presents delayed diagnosis, more aggressive tumor biology, and distinct psychosocial concerns7,8.
With this article, we share the case of a young woman diagnosed with paraneoplastic SPS secondary to invasive breast carcinoma of no special type (NST). The case highlights the diagnostic complexity of PNS, the therapeutic potential of the cancer treatments, and the importance of a multidisciplinary approach in achieving both tumor control and neurological recovery.
Clinical case
We present the case of a pre-menopausal woman in her forties with a medical history of benign breast disease, having undergone fibroadenoma excision a decade earlier. Her family history was significant for breast cancer in her mother (diagnosed in her thirties), maternal aunt (in her fifties), and maternal cousin (in her forties).
The patient was admitted to the Neurology department following a 3-month history of progressive rigidity, spasms, and pain in her axial muscles and legs. The spasms were spontaneous, intermittent and triggered by sudden movements, unexpected noise or emotional reactions, leading to frequent falls. Upon admission, she was very anxious and unable to walk independently. No urinary retention, gastrointestinal symptoms, or other autonomic alterations were observed.
During hospitalization, symptoms were controlled only with high doses of diazepam and baclofen. A diagnostic workup revealed serologic positivity for anti-amphiphysin antibodies, with no relevant findings on brain computed tomography (CT) or brain and spine magnetic resonance imaging. Thoraco-abdominopelvic CT identified three nodular lesions in the left breast, with the largest measuring 20 mm, and a suspicious ipsilateral axillary lymph node, confirmed by mammographic and ultrasound imaging.
Biopsies of the largest nodule and axillary lymph node revealed invasive carcinoma NST, grade 2. Immunohistochemistry showed estrogen and progesterone receptor expression in over 90% of cells, human epidermal growth factor receptor 2 expression negative (1+), Ki67 proliferation index of 40% (measured in a hot spot). Clinical staging was established as cT1c N1 Mx9. Therefore, a diagnosis of paraneoplastic SPS positive for anti-amphiphysin antibodies was established.
The patient underwent neoadjuvant chemotherapy with anthracyclines, cyclophosphamide, and taxanes, followed by left subcutaneous mastectomy, with immediate reconstruction, and axillary lymph node dissection. Although there was a clinical and radiological response to neoadjuvant treatment, histopathological analysis revealed residual invasive disease (NST), with a pathological staging of ypT1c N1a9. Following surgery, she completed adjuvant radiotherapy and is currently under hormone therapy, adjusted to her pre-menopausal hormonal status, and bisphosphonates10–12. Throughout this time the patient has also performed directed physical rehabilitation, as an adjuvant treatment for her recovery.
Due to her age and family history, genetic testing was performed, revealing no pathogenic variants or variants of unknown significance.
With the initiation of the oncological treatment and physical rehabilitation, the neurological symptoms progressively and significantly improved, allowing for the discontinuation of symptomatic therapy. Nine months after surgery, the patient is pain-free, spasm-free, and has regained full autonomy.
Discussion
Paraneoplastic syndromes are rare manifestations of oncologic diseases, posing significant diagnostic challenges. SPS is a rare neurological condition that requires careful investigation for the possibility of underlying malignancies when presenting in otherwise healthy adults. In this case, there was a discordance between the early-stage breast cancer diagnosis and the severity of the neurological symptoms at presentation, emphasizing the importance of recognizing PNS as a potential indicator of malignancy1–6,13.
It is known that the evolution of the neurological symptoms is strongly dependent on the treatment of the underlying tumor, which can also help to prevent or reduce long-term complications12. Symptomatic management alone often provides only limited relief, as evidenced in this case, where significant improvement was observed only after antineoplastic therapy. The progressive recovery of the patient, leading to in the discontinuation of symptomatic therapy, highlights the importance of integrating oncological and neurological care.
This case also illustrates the diagnostic challenges of PNS as initial manifestations of malignancy, emphasizing the critical role of early tumor detection and multidisciplinary approach, involving oncologists, neurologists, and other health professionals, to optimize patient outcomes and enhance quality of life.
Conclusion
This case highlights the importance of considering paraneoplastic syndromes like stiff-person syndrome as early indicators of malignancy. Significant neurological improvement occurred only after oncological treatment, emphasizing that tumor control is key to symptom resolution. Early recognition, prompt cancer treatment, and a multidisciplinary approach are essential to optimize patient outcomes and restore quality of life.
Funding
No funding was received for this work.
Conflicts of interest
There are no conflicts of interest to declare.
Ethical considerations
Protection of humans and animals. The authors declare that no experiments involving humans or animals were conducted for this research.
Confidentiality, informed consent, and ethical approval. The patient provided informed consent for the publication of clinical information. Care was taken to protect the patient’s confidentiality; all identifying details were omitted or anonymized to ensure privacy.
Declaration on the use of artificial intelligence. The authors declare that no generative artificial intelligence was used in the writing of this manuscript
