Small cell lung cancer with peripheral neuropathy as the first symptom: Two case reports

Abstract

BACKGROUND

Small cell lung cancer (SCLC) is the most malignant type of lung cancer. Even in the latent period and early stage of the tumor, SCLC is prone to produce distant metastases with complex and diverse clinical manifestations. SCLC is most closely related to paraneoplastic syndrome, and some cases present as paraneoplastic peripheral neuropathy (PPN). PPN in SCLC appears early, lacks specificity, and often occurs before diagnosis of the primary tumor. It is easy to be misdiagnosed as a primary disease of the nervous system, leading to missed diagnosis and delayed diagnosis and treatment.

CASE SUMMARY

This paper reports two cases of SCLC with limb weakness as the first symptom. The first symptoms of one patient were rash, limb weakness, and abnormal electromyography. The patient was repeatedly referred to the hospital for limb weakness and rash for > 1 year, during which time, treatment with hormones and immunosuppressants did not lead to significant improvement, and the condition gradually aggravated. The patient was later diagnosed with SCLC, and the dyskinesia did not worsen as the dermatomyositis improved after antineoplastic and hormone therapy. The second case presented with limb numbness and weakness as the first symptom, but the patient did not pay attention to it. Later, the patient was diagnosed with SCLC after facial edema caused by tumor thrombus invading the vein. However, he was diagnosed with extensive SCLC and died 1 year after diagnosis.

CONCLUSION

The two cases had PPN and abnormal electromyography, highlighting its correlation with early clinical indicators of SCLC.

Key Words: Paraneoplastic peripheral neuropathy; Small cell lung cancer; Peripheral neuropathy; Electromyography; Dermatomyositis; Case report

Core Tip: Paraneoplastic peripheral neuropathy is more common in patients with small cell lung cancer (SCLC), but the exact role of peripheral nerve symptoms and electromyography (EMG) in SCLC is still the subject of debate and research. At present, there are few reports of SCLC with peripheral nerve injury as the first symptom and EMG results. This article reports two cases of SCLC with limb numbness and weakness as the initial symptoms, highlighting the potential role of paraneoplastic peripheral nerve status and EMG in SCLC screening and the possible clinical correlation between them.

INTRODUCTION

Lung cancer is the second most common malignancy in the world and has the highest mortality rate, with small cell lung cancer (SCLC) accounting for 15%–20% of all lung cancers[1,2]. SCLC is a poorly differentiated neuroendocrine malignancy with poor prognosis, characterized by high tumor mutation load, short doubling time of tumor cells, easy distant metastasis, and insensitivity to radiotherapy and chemotherapy[3,4]. Lung cancer, especially SCLC, is the most closely related to paraneoplastic syndrome, and often causes paraneoplastic peripheral neuropathy (PPN). Symptoms of neurological damage in PPN appear months or even years before tumor diagnosis, and > 80% of patients with subacute sensory neuropathy are associated with SCLC. PPN of SCLC appears early, lacks specific clinical manifestations, and often appears before the diagnosis of the primary tumor, which is easy to be misdiagnosed as a primary disease of the nervous system, resulting in missed diagnosis, misdiagnosis and delayed diagnosis and treatment of the tumor.

At present, there are few studies on peripheral neuropathy in paraneoplastic syndromes, and most of them are electromyographic manifestations after diagnosis. In electromyographic studies of PPN patients diagnosed with lung cancer or other cancers, PPN often is axonal degeneration, which can be accompanied by Waller’s degeneration and demyelination. In the current literature, PPN has rarely been reported as an initial symptom of SCLC, and it is even rarer to obtain electromyography data before diagnosis and at an early stage. Strengthening the understanding of PPN has important guiding significance in clinical diagnosis of primary tumors. This paper reports two cases of SCLC. The patients were diagnosed with whole body rash, limb soreness and lifting difficulty for 1 year, aggravated for 1 month, and numbness and weakness of limbs for several months, facial edema for > 1 month, ineffective antiallergy treatment, were the first symptoms. The nonrespiratory symptoms were the first symptoms, and the EMG results were positive. PPN as the initial symptom of SCLC is rare. This report highlights the clinical correlation between PPN and SCLC, which is conducive to oncology and neurological research and the diagnosis of SCLC patients.

CASE PRESENTATION

Chief complaints

Case 1: A 74-year-old woman was admitted to hospital with whole body rash, limb soreness and lifting difficulty for 1 year, significantly aggravated for 1 mo. The lifting difficulty was not serious at the beginning and did not affect daily life, but the limbs were only slightly lifted at admission.

Case 2: A 70-year-old Chinese man was admitted to hospital with facial edema for > 1 mo.

History of present illness

Case 1: One year ago, the patient presented with patchy skin rash on the frontal face, periorbital region and whole body, accompanied by distension of limbs, which gradually worsened, difficulty in lifting limbs, the degree of which did not affect life, and the rash did not improve after antiallergy treatment. The above symptoms worsened 1 mo ago, with facial edema and inability to walk and hold.

Case 2: One month prior, the patient presented with facial edema, which failed to respond to treatment at the local hospital. Later, the patient went to our hospital for treatment. Chest computed tomography (CT) showed that the anterior superior mediastinum was occupied (about 5.6 cm × 3.2 cm in cross-section) and mediastinal lymph nodes were enlarged. On January 1, 2021, chest enhanced CT (Figure 1) showed multiple mediastinal and bilateral axillary enlargement, fusion of lymph nodes, invasion and narrowing of superior vena cava, and cancerous embolism of the right brachial vein.

Figure 1 Enhanced lung computed tomography of Case 2. A–D: Lung view; E–H: Soft tissue view; I–L: Enhanced soft tissue. The lung texture increased and distorted. The tracheal and bronchial openings were unobtrusive, the hilus of the two lungs were not enlarged, and multiple enlarged lymph nodes were seen in the bilateral axilla, mediastinum and tracheal carina, which were integrated into clusters. The enhanced scan was slightly uneven and enhanced, and venous computed tomography value was about 47 HU. The superior vena cava was invaded, and the enhanced scan revealed a filling defect in the right brachiocephalic vein. Enlarged lymph nodes are marked in orange and cancer embolus is marked in green.

History of past illness

Case 1: The patient had a history of hypertension history of > 10 years.

Case 2: The patient had no previous history of similar conditions.

Personal and family history

The two patients denied any family history of similar conditions.

Physical examination

Case 1: Vital signs were stable and facial edema was mild. Cardiopulmonary examination showed no abnormalities. Muscle tenderness in the extremities was not abnormal. Muscle strength in the extremities was grade 3 near the extremities. Skin tightness and poor elasticity were observed.

Case 2: There were no abnormalities except facial edema.

Laboratory examinations

Case 1: Bronchoscopic diagnosis on April 4, 2023: immunohistochemical results suggested a poorly differentiated neuroendocrine carcinoma (small cell type). Immunohistochemical results showed: thyroid transcription factor 1(+), cytokeratin 7(+), napsin A(), cytokeratin 5/6(), P40(), chromogranin A(+), synaptophysin(+), Ki67(+, 50%), CD56(+).

Case 2: Pathological report of lymph node transbronchial needle aspiration biopsy specimens in group 4R and group 7 on January 18, 2022: a small number of heterogeneous cell nests were significantly compressed and deformed, and immunohistochemical results suggested that it was poorly differentiated neuroendocrine carcinoma (small cell type): thyroid transcription factor 1(+), cytokeratin 7(), napsin A(), cytokeratin 5/6(), P40(), chromogranin A (+), synaptophysin(+), Ki67(+, 40%), CD3(), and CD20().

Imaging examinations

Case 1: Lung CT on April 11, 2023: small nodules in the middle lobe of the right lung. No tumor lesions were observed. Abnormal EMG on April 12, 2023 (Tables 1, 2 and 3): multiple peripheral neuropathies involving axon injury of motor sensory nerve in upper limb. After considering whether the above symptoms were paraneoplastic syndrome, on April 16, 2023 further enhanced lung CT (Figure 2) showed left central lung cancer with left hilar lymph node enlargement.

Figure 2 Enhanced lung computed tomography of Case 1. A–C: Lung view; D–F: Soft tissue view; G–I: Enhanced soft tissue. An irregular soft tissue density shadow with a size of 33 mm × 24 mm was observed at the hilus of the left lung, which showed mild enhancement after enhancement. The bronchial stenosis of the upper lobe of the left lung and pressure of the left upper pulmonary vein were observed. Lymph nodes in the left hilar of the lung were enlarged and enhanced after enhancement. Enlarged lymph nodes are marked in orange and lung cancer is marked in green.

Table 1 Electromyography/evoked potential test report of Case 1, sensory nerve conduction.

Nerve/position	Latent period, ms	Amplitude, μV	Conduction velocity, m/s	Distance, mm
L median nerve
Finger 3	3.23	5.8	44	141
Finger 4	3.39	7.8
R median nerve
Finger 3	3.18	5.5	41	130
Finger 4	3.28	4.2
L ulnar nerve
Finger 5	1.93	6.5	60	116
Finger 4	1.98	6.5
R ulnar nerve
Finger 5	1.93	5.3	57	109
Finger 4	2.03	6.9
R nervi suralis
Gastrocnemius	1.93	3.9	49	95
L nervi suralis
Gastrocnemius	2.55	4.3	50	127
R superficial peroneal nerve
Calf	2.19	4.8	46	100
L superficial peroneal nerve
Calf	2.08	4.6	43	90

L: Left; R: Right.

Table 2 Electromyography/evoked potential test report of Case 1, motor nerve conduction.

Nerve/position	Recording position	Latent period, ms	Amplitude, μV	Conduction velocity, m/s	Distance, mm
L median nerve
Wrist	Abductor pollicis brevis muscle	3.8	4.26
Elbow	Abductor pollicis brevis muscle	8.07	4.03	51	217
R median nerve
Wrist	Abductor pollicis brevis muscle	4.01	4.15
Elbow	Abductor pollicis brevis muscle	8.02	3.98	50	200
L ulnar nerve
Wrist	Abductor digiti minimi	2.97	7.24
Below the elbow	Abductor digiti minimi	6.56	6.47	54	195
R ulnar nerve
Wrist	Abductor digiti minimi	2.97	7.58
below the elbow	Abductor digiti minimi	6.77	7.16	53	200
R peroneal nerve
Ankle	Extensor digitorum brevis	3.23	1.06
Under the capitulum of fibula	Extensor digitorum brevis	10.57	0.97	41	300
L peroneal nerve
Ankle	Extensor digitorum brevis	3.44	2.44
Under the capitulum of fibula	Extensor digitorum brevis	10.10	1.95	44	295
R tibial nerve
Ankle	Abductor hallucis	3.59	4.17
Popliteal fossa	Abductor hallucis	12.92	4.15	40	370
L tibial nerve
Ankle	Abductor hallucis	3.59	4.16
Popliteal fossa	Abductor hallucis	12.66	3.05	41	376

L: Left; R: Right.

Table 3 Electromyography/evoked potential test report of Case 1, F-wave.

Nerve	Min M reaction time, ms	Mean M reaction time, ms	Min F reaction time, ms	Mean F reaction time, ms	F-wave occurrence rate, %
L ulnar nerve	2.9	2.9	28.2	28.9	100
R ulnar nerve	2.9	3.0	28.8	29.5	100
R tibial nerve	3.6	3.7	55.0	57.8	100
L tibial nerve	3.8	3.8	53.3	57.2	100

Diagnostic opinion: Electrophysiological findings of multiple peripheral neuropathies involving axonal damage to the motor and sensory nerves of the upper and lower extremities. Bilateral median nerves were damaged at the wrist, and the electrophysiological manifestations of bilateral carpal tunnel syndrome were mild. L: Left; R: Right.

Case 2: On January 1, 2021, chest enhanced CT (Figure 1) showed multiple mediastinal and bilateral axillary enlargement, fusion of lymph nodes, invasion and narrowing of superior vena cava, and cancerous embolism of right brachial vein. No metastatic lesions were found on whole body bone imaging and skull magnetic resonance plain scan + diffusion-weighted imaging.

MULTIDISCIPLINARY EXPERT CONSULTATION

Differential diagnosis: there was no history of diabetes, rheumatoid arthritis, central nervous system related diseases, and heavy alcohol consumption that could cause numbness and weakness. Both patients’ paraneoplastic antibody profile was sent to other institutions, but the data are now lost, but the PPN was evaluated by a specialist.

FINAL DIAGNOSIS

Case 1

The final diagnosis was SCLC (T4N1M0) with PPN.

Case 2

The final diagnosis was SCLC (T4N3M0) with PPN.

TREATMENT

Case 1

Carboplatin injection 450 mg once and etoposide injection 0.1 g for 3 d antitumor therapy, every 3 wk. The chest lesion radiotherapy started on October 2023.

Case 2

Carboplatin injection 400 mg once and etoposide injection 0.12 g for 3 d antitumor therapy, every 3 wk. Radical radiotherapy was performed between February 15 and March 20, 2021. The whole brain preventive radiotherapy was performed on May 17, 2021.

OUTCOME AND FOLLOW-UP

Case 1

On December 20, 2023, whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography/CT imaging (non-dissociation) elevated fluorodeoxyglucose metabolism in the left parahilar nodule, considering lung cancer, lymph node metastasis in the left hilar (Figure 3). On April 7, 2024, head magnetic resonance plain scan, diffusion-weighted imaging and enhancement indicated left cerebellar hemisphere, left occipital lobe metastatic tumor. Compared with the previous MRI, the left frontal lobe was considered as a new metastasis (Figure 4). The patient is still alive, although the metastasis is more than before, but the overall condition is good.

Figure 3 Whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography imaging of Case 1. Diffuse and uneven fluorodeoxyglucose metabolism increased in bilateral deltoid muscles, subscapularis muscles, supraspinatus muscles, posterior intercostal muscles, and left infraspinatus muscle. Localized fluorodeoxyglucose metabolism increased in left lateral femoris muscle, considering the manifestations of dermatomyositis.

Figure 4 Head magnetic resonance scan and enhancement of Case 1. A–C: T1-weighted image; D–F: T1 fluid attenuated inversion recovery; G–I: T2-weighted image; J–L: Diffusion-weighted imaging (DWI). The left cerebellar hemisphere and left occipital lobe showed slightly longer circular T1 and slightly longer T2 signals, and the diffusion on DWI was limited. Patchy high signals were seen in the left frontal bone on DWI, with enhanced and visible intensification, about 22 mm × 14 mm in size; patchy abnormal intensification was seen in the right occipital lobe.

Case 2

This patient had developed numbness and weakness in the extremities several months before the diagnosis and had no previous history of diabetes or lumbar disc herniation. However, the patient did not pay attention. After diagnosis, the numbness and weakness of the limbs were significantly aggravated, and the patient could not walk. On January 18, 2022, EMG showed multiple peripheral nerve damage, sensory nerve accumulation and demyelination damage in upper and lower limbs (Tables 4 and 5). The patient abandoned treatment and died a few days later in January 2022.

Table 4 Electromyography/evoked potential test report from case 2, sensory nerve conduction.

Nerve/position	Latent period, ms	Amplitude, μV	Conduction velocity, m/s	Distance, mm
R median nerve
Finger 3	2.97	5.5	39	117
R ulnar nerve
Finger 5	2.34	5.0	44	103
L nervi suralis
Gastrocnemius	2.19	7.7	32	70
R nervi suralis
Gastrocnemius	2.34	6.0	38	90
R superficial peroneal nerve
Calf	2.34	5.8	36	85
L superficial peroneal nerve
Calf	2.34	5.5	34	80

L: Left; R: Right.

Table 5 Electromyography/evoked potential test report from Case 2, motor nerve conduction.

Nerve/position	Recording position	Latent period, ms	Amplitude, μV	Conduction velocity, m/s	Distance, mm
R median nerve
Wrist	Abductor pollicis brevis muscle	3.33	6.0
Elbow	Abductor pollicis brevis muscle	7.50	5.5	54	225
R ulnar nerve
Wrist	Abductor digiti minimi	2.34	10.2
Below the elbow	Abductor digiti minimi	6.51	9.2	54	225
R peroneal nerve
Ankle	Extensor digitorum brevis	3.23	4.4
Under the capitulum of fibula	Extensor digitorum brevis	9.32	3.6	42	257
L peroneal nerve
Ankle	Extensor digitorum brevis	3.33	2.7
Under the capitulum of fibula	Extensor digitorum brevis	9.74	2.3	41	260
L tibial nerve
Ankle	Abductor hallucis	3.44	12.6
Popliteal fossa	Abductor hallucis	12.24	8.4	40	350
R tibial nerve
Ankle	Abductor hallucis	3.59	14.4
Popliteal fossa	Abductor hallucis	11.82	9.8	42	345

Diagnostic opinion: Electrophysiological changes of multiple peripheral nerve lesions involving the sensory nerves of the upper and lower limbs with demyelinating lesions. L: Left; R: Right.

DISCUSSION

SCLC is the most malignant subtype of lung cancer[5,6]. PPN of SCLC appears early, lacks specific clinical manifestations, and often appears before the diagnosis of the primary tumor, which is easy to be misdiagnosed as a primary disease of the nervous system, resulting in missed diagnosis of the tumor[7,8]. The incidence of PPN is high in paraneoplastic syndrome of the nervous system. EMG plays an important role in the diagnosis of PPN. Analysis of nerve electrophysiological characteristics is helpful to distinguish from peripheral neuropathy caused by other causes, and can provide an objective basis for early clinical diagnosis. PPN is seen in a variety of tumors; the most common of which is lung cancer, especially SCLC[9], which starts with subacute onset. The clinical manifestations are numbness, pain, paresthesia, limb weakness, and muscular atrophy at the distal extremity, which progress rapidly, and sensory disorders are more prominent. According to neuro-electrophysiological characteristics, it can be divided into axon injury type, demyelinating type, axon injury type and demyelinating co-existing type.

Prior to the diagnosis of SCLC, both patients presented with clinical manifestations of peripheral nerve injury. Case 1 presented with whole body rash, limb soreness and lifting difficulty, and SCLC was found earlier than in case 2. After antitumor treatment, the patient’s disease progressed but currently has a survival time of 18 mo and she is still alive. After antitumor therapy combined with hormone therapy, dermatomyositis and limb weakness were improved and controlled to a certain extent, which increased the survival. Dermatomyositis has also been shown to be a manifestation of a paraneoplastic syndrome, and the excellent response to treatment in this patient supports this view. Therefore, for patients with unexplained limb numbness and weakness and poor treatment effect of dermatomyositis, we can improve the EMG examination. If the patient has multiple peripheral nerve injury, we can further screen for lung cancer, especially SCLC, to improve the early detection of SCLC and paraneoplastic neuropathy, and improve prognosis. On January 1, 2021, due to facial edema for 1 mo, lung CT examination at the outpatient department of our hospital showed a mediastinal mass. After hospitalization, the patient was diagnosed with SCLC and mediastinal lymph node enlargement. The antitumor treatment after diagnosis was not effective, and the disease progressed rapidly, and the patient died 1 year later. The symptoms of limb numbness and weakness in the above two patients were earlier than those of rash and facial edema, but both of them were treated for rash and facial edema, while limb numbness and weakness were ignored. Improving the diagnosis, treatment and screening of patients with limb numbness and weakness, and improving the understanding of the clinical correlation between PPN and SCLC may help early diagnosis of SCLC and improve the prognosis of patients.

PPN is characterized by a lack of specificity in clinical manifestations and low incidence, and the symptoms of peripheral nerve damage usually appear before the diagnosis of the primary tumor, which is easy to be missed or misdiagnosed. Analysis of neuro-electrophysiological characteristics is helpful to distinguish peripheral neuropathy caused by other causes, and can provide an objective basis for early clinical diagnosis. Before diagnosis, Case 1 had facial and body rash, limb soreness and difficulty lifting. Studies have shown that one-third of patients with dermatomyositis develop cancer, and dermatomyositis in the first symptom in more than half the patients, and nearly half are diagnosed with dermatomyositis and malignant tumors at the same time[10]. Most malignancies are found after diagnosis of dermatomyositis, which was also found in our two cases. Some studies have shown that dermatomyositis patients with facial malignant erythema may be complicated by malignant tumors[11,12]. Case 1 in this study had facial rash and PPN, and the dermatomyositis improved with the clinical treatment of lung cancer, further indicating that the dermatomyositis and limb weakness in this case were manifestations of paraneoplastic syndrome. Treatment options for SCLC depend on the stage of the disease. Limited-stage SCLC is considered a curable disease, and current treatments can significantly improve median overall survival[13]. However, only a small percentage of patients with SCLC are diagnosed at the limited stage. It is necessary to screen for malignant tumors in patients diagnosed with dermatomyositis in order to improve the rate of early detection, diagnosis and treatment.

CONCLUSION

SCLC is the most malignant subtype of lung cancer. PPN of SCLC appears early, lacks specific clinical manifestations, and often appears before the diagnosis of the primary tumor, which is easy to be misdiagnosed as a primary disease of the nervous system, resulting in missed diagnosis of the tumor. Among paraneoplastic neurological syndromes, the incidence of PPN is high. EMG plays an important role in the diagnosis of PPN. It is suggested that more patients with unexplained limb numbness and weakness and risk factors of lung cancer should be further screened by enhanced CT and other examinations for lung cancer, especially SCLC, in order to achieve early detection and diagnosis. Routine EMG screening in patients with suspected SCLC can improve the early detection of PPN and may affect the prognosis of patients.