Acute sensorimotor paraneoplastic neuropathy in a patient with small cell prostate cancer

Abstract

The authors describe a patient with a background of metastatic small cell prostate cancer who presented with a rapidly evolving sensorimotor neuropathy with bulbar features closely resembling Guillain-Barré syndrome, with a good initial response to intravenous immunoglobulins and platinum-based chemotherapy. This represented a likely paraneoplastic manifestation of the patient’s urological malignancy.

Background

Prostate cancer is one of the most common cancers worldwide.¹ These are mostly adenocarcinomas; however, small cell prostate cancer is a rare form of poorly differentiated neuroendocrine carcinoma (figure 1) which can manifest de novo or develop in prostate adenocarcinomas following hormone therapy.^{2 3} Platinum-based chemotherapy is usually the treatment of choice⁴ with an overall poor prognosis given the aggressive nature of the disease.⁵

Figure 1.

Histological images demonstrating sheets of tumour cells with nuclear moulding and brisk mitotic activity on H&E stain (left) and strong positivity for synaptophysin on immunostaining (right), typical of small cell carcinomas.

Rarely neuroendocrine tumours are also associated with paraneoplastic syndromes, with clinical features that are not directly related to the primary disease or its spread.⁶ An even smaller minority develop paraneoplastic neurological syndromes (PNS) as a presumed result of immune-mediated neural damage.⁷

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy which, although not classically recognised as a paraneoplastic syndrome, has been reported to occur in association with malignancy.⁸ To our knowledge, there have been no reported cases of a GBS-like PNS in a patient with a diagnosis of small cell prostate cancer.

Case presentation

A man in his 60s was admitted with a 2-day history of worsening proximal weakness. This was on a background of generalised weakness, predominantly in the upper limbs, with a rapid decline in the days leading up to the admission. The patient also reported a 1-week history of non-bloody diarrhoea shortly before admission but no other infective features.

He had a medical history of spinal stenosis and cervical myelopathy due to disc prolapse requiring an anterior cervical discectomy and fusion. He had been recently diagnosed with a metastatic poorly differentiated small cell prostate cancer (T4N1M1b; Gleason 5+5) presenting with haematuria (figure 2). The patient was a non-smoker, and there was no history of alcohol misuse, with no relevant family history.

Figure 2.

Coronal view of initial CT urinary tract. Diffuse prostate abnormality (1) invading into the bladder (2) with associated bilateral lymphadenopathy (3).

Initial neurological examination revealed proximal weakness in all four limbs with active movement against gravity but not resistance. By the third day of admission, the patient had no movement in his upper limbs and was no longer able to walk, also requiring a nasogastric tube insertion due to difficulty swallowing. Reflexes were present however appeared brisk in his lower limbs with a positive plantar reflex on the right side, which could have been in keeping with his known cervical myelopathy.

In response to the patient’s rapidly progressive weakness and new bulbar features, he was transferred to the high-dependency unit for further monitoring.

Investigations

Basic laboratory investigations were unremarkable, with only a raised thyroxine (free T4 21.8 pmol/L) and decreased thyroid-stimulating hormone (TSH <0.01 mU/L) which was felt to be subclinical hyperthyroidism. While the patient had diarrhoea in the weeks preceding his admission, stool samples had been sent for cultures and these were negative including for Campylobacter species. The main findings on MRI head and spine included cervical stenosis and degenerative changes causing spinal stenosis in the lumbar region, consistent with the patient’s previous history; however, there was no evidence of malignant spinal cord compression or any other pathology that could explain the presentation. Cerebrospinal fluid (CSF) analysis showed no cellularity (white blood cells <5/mm³), no organisms grown, plasma:CSF glucose ratio within normal range (CSF glucose 3.1 mmol/L; serum glucose 4.2 mmol/L) and proteins of 0.22 g/L. The CSF was obtained in the early stages of the presentation, which can be normal in early inflammatory neuropathies.

Given the initial suspicion of a paraneoplastic or immune-mediated neuropathy, neuronal antibodies and a ganglioside screen were sent, including anti-Hu, anti-Yo, anti-Ri, anti-Ma2, anti-CV2, anti-amphiphysin and anti-recoverin antibodies, with only N-methyl-D-aspartate (NMDA) receptor antibodies resulting positive. Nerve conduction studies showed segmental demyelinating sensorimotor polyneuropathy (table 1).

Table 1.

Sensory nerve conduction studies

Nerve/sites	Latency 2 ms	Latency ms	Amplitude 1–2 µV	Amplitude 2–3 µV	Duration ms	Area µVms	Velocity m/s
R ulnar
Fifth finger	4.10	3.38	0.88	3.9	1.35	1.9
L ulnar
Fifth finger	3.56	3.06	3.0	5.5	2.19	4.0
R superficial peroneal
Lateral leg
Lateral leg	2.94	2.02	8.5	6.1	2.02	7.4	47.7
Lateral leg	2.88	2.10	1.3	6.1	1.94	3.1	48.7

Sensory studies (table 1) returned an asymmetric pattern in the upper limbs (ulnar nerve (figure 3 (i–ii))) and globally reduced responses in the lower limbs (superficial peroneal (iii–iv)). In the upper limbs, motor latencies (table 2) were mildly to moderately prolonged, with partial conduction block which was most severe in the right median nerve (vi). Similarly, peroneal motor studies showed prolonged distal motor latencies, more marked on the left side (vii). F wave minimal latencies (ix) were prolonged throughout into demyelinating range (table 3).

Figure 3.

Nerve conduction tracings for sensory (i–iv) and motor (v–viii) responses, and F wave (ix).

Table 2.

Motor nerve conduction studies

Nerve/sites	Latency ms	Amplitude 1–2 mV	Duration ms	Area mVms	Amplitude 1%–2%	Duration %	Area %	Distance cm	Velocity m/s
R median – abductor pollicis brevis (APB)
Wrist	4.96	6.2	8.52	28.1	100	100	100	8
Elbow	13.23	2.9	12.42	23.1	46.5	146	82.3	25	30.2
L median – APB
Wrist	5.23	5.7	9.04	30.6	100	100	100	8
Post exercise	5.31	5.9	8.08	27.8	105	89.4	90.7
L median – APB
Wrist	5.33	5.2	8.58	27.1	100	100	100	8
R ulnar – abductor digiti minimi (ADM)
Wrist	4.33	3.4	7.27	13.5	100	100	100	8
Post exercise	4.54	3.5	9.08	14.0	102	125	104
R ulnar – ADM
Wrist	4.35	3.4	7.52	14.6	100	100	100	8
Elbow	9.90	2.4	7.75	9.0	68.5	103	61.9	25.5	46.0
L ulnar – ADM
Wrist	3.15	3.4	7.56	13.6	100	100	100	8
Elbow	10.98	1.9	7.17	7.4	55.2	94.8	54.5	24.5	31.3
R peroneal – extensor digitorum brevis (EDB)
Ankle	6.44	1.4	8.73	6.8	100	100	100
Fib head	18.23	0.6	13.04	5.8	40.8	149	85.5	35	29.7
L peroneal – EDB
Ankle	6.67	0.3	6.00	1.1	100	100	100
Fib head	17.44	0.4	5.73	1.2	132	95.5	109	37	34.4

Table 3.

F wave

Nerve	Min F latency ms	Max F latency ms	Range F latency ms	% F	F ratio
R peroneal	83.5	95.3	11.77	36.4	4.05
R tibial	73.5	89.9	16.46	88.9	6.19
L tibial	72.4	85.7	13.33	60	5.97
R median	50.7	55.1	4.43	83.3	3.84
R ulnar	46.1	48.6	2.45	100	3.75
L median	47.2	53.3	6.04	90	3.85
L ulnar	43.1	48.7	5.57	100	5.92

Treatment

The patient was given 5 days of intravenous immunoglobulins (IVIg) with a gradual improvement in his symptoms.

The prostate cancer had only recently been confirmed before the rapid progression of the patient’s neurological symptoms. An urgent oncological review prompted initiation of carboplatin while an inpatient, followed by five cycles of three weekly carboplatin and etoposide with three monthly leuprorelin injections.

Outcome and follow-up

The patient’s weakness continued to improve and at the time of discharge, he was mobilising independently with a walking stick.

He was later reviewed in the neurology clinic after the initial inpatient review. At the time, the patient described a further acute deterioration with progressive weakness in his arms and legs, reduced grip and inability to stand; however, there were no bulbar features. Decreased pinprick sensation was also noted up to his mid-calves. An urgent admission was arranged with a good response to a further 5-day course of IVIg and the patient was discharged on a reducing dose of prednisolone.

In the same period, the patient was admitted twice under urology with urinary sepsis and a new left-sided hydroureteronephrosis, which was managed with a nephrostomy, later replaced by an anterograde ureteric stent. Interval imaging showed extensive left-sided supraclavicular and pelvic adenopathy. Radiotherapy to his pelvis and neck was carried out with repeat imaging showing mixed response to treatment but clearly inclined to disease progression.

Within 1 year since the initial presentation of his prostate cancer, the patient was admitted to the Oncology ward with worsening weakness and performance status, with further progression of lymphadenopathy on imaging. Management therefore focused on symptom control, with input from the palliative care team, and the patient eventually passed away during the admission (figure 4).

Figure 4.

Timeline of events from initial diagnosis.

Discussion

Due to the rarity and variety in presentation, PNS are particularly challenging to diagnose. Criteria for high-risk phenotypes have been established to aid diagnosis.⁹ In urological malignancies, paraneoplastic processes mostly involve endocrine syndromes, although PNS have also been reported, peripheral polyneuropathy being the most common presentation.⁶ For example, Baird et al described a patient with obstructive uropathy on a background of 6-month history of lower limb peripheral neuropathy who was then diagnosed with small cell prostate cancer with confirmed presence of anti-Hu (ANNA1) antibody, a neuronal antibody typically associated with peripheral neuropathies.¹⁰ Interestingly, this antibody is also frequently found in small cell lung cancer and other neuroendocrine tumours.¹¹

In contrast, the association between GBS and malignancy is still debated as Graus et al do not define it as a paraneoplastic syndrome in the absence of high-risk antibodies.⁹ A number of case reports described GBS in patients with an existing or later diagnosed malignancy^12–25 and a small number of population-based studies have identified an increased risk of cancer in patients who developed GBS.^{8 26 27} Nevertheless, it is not clear whether these findings demonstrate an actual causal link or simply two separate concurrent diagnoses. Due to the rarity of small cell prostate cancer, there is very limited knowledge of its association with GBS or any form of PNS, which is a rare presentation in itself. In the presented case, the degree of suspicion of an underlying PNS was supported by the knowledge of the existing malignancy and heterogeneous neurological features, despite the absence of high-risk antibodies. In fact, the patient only had positive NMDA receptor antibodies. This is an intermediate-risk antibody typically associated with encephalitis and neuropsychiatric features.^{7 9} Its presence was not felt to be significant in our case since it did not correspond to the patient’s presentation.

Management in PNS should focus on oncological treatment;²⁸ however, in our case, this was quite limited given the histology and advanced disease at the time of diagnosis. Immunotherapy is recognised to only provide limited benefit as demonstrated in a multicentre, prospective, clinical study carried out on patients with definite PNS with positive antibodies.²⁹ In our case, the early use of IVIg was prompted by the GBS-like progression of symptoms and bulbar features, with a good response, although transient. This therapeutic outcome is supportive of a likely underlying immune-mediated process. Furthermore, the relapse of the neurological symptoms in correspondence with disease progression, while GBS is a classically monophasic syndrome, points towards a potential association between the patient’s presentation and his cancer, making the diagnosis of an underlying PNS a reasonable hypothesis. Ultimately, treatment was not fully effective; however, the good response to IVIg both in the acute phase and following the relapse 2 months after admission did allow the patient to maintain his quality of life despite the poor prognosis. This highlights the potential reversibility, even if temporary, of severe paraneoplastic neuropathies and the impact it can have on patients who already have a significantly life-limiting disease.

The oncological diagnosis and rapid neurological progression made this a very complex case which required urgent assessment and management. The association between GBS and cancer as a paraneoplastic process is still unclear and, despite the existing criteria, the diagnosis of PNS remains extremely challenging and requires careful assessment of history, clinical features, imaging, neurophysiology and immunologic analysis. Oncological management is recognised as the most effective treatment; however, in our patient, this was limited by the initial staging and aggressive progression of the cancer. The main treatment in GBS involves the use of IVIg and supportive management, with the former being able to provide some benefit also in PNS although this may often have a limited or transient recovery. Nevertheless, the good response demonstrated in this case should encourage active management of similar presentations including consideration of intensive care when appropriate. The authors believe that these therapeutic options should therefore not be precluded just on the basis of a patient’s oncological diagnosis, especially when significant disability can potentially be reversed.

Further studies on small cell prostate cancer and its association with GBS-like neuropathies or other PNS may be beneficial in aiding early recognition and provide additional knowledge of disease progression and response to treatment.

Learning points.

• Small cell prostate cancer is a rare and aggressive neuroendocrine carcinoma which can be associated with paraneoplastic neurological syndromes (PNS).

• Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy which, although not recognised as a PNS, has been reported in conjunction with malignancy.

• Intravenous immunoglobulins (IVIg) are a key element in the management of GBS and can also have some benefits in PNS.

• Patients with a cancer diagnosis, when appropriate, should not be precluded active treatment especially when significant disability can potentially be reversed allowing them to maintain their quality of life as demonstrated by the good response to IVIg presented in our case.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.