Rare case: paraneoplastic syndrome affecting peripheral nerves, associated with anti-collapsin-response mediator protein-5 (anti-CRMP5) antibodies, as early manifestation of small cell lung cancer confined to a solitary lymph node without evidence of lung mass on routine CT thorax

Abstract

A 69-year-old woman presented with 9 months history of progressively worsening upper and lower limb weakness leading to reduced functional status. She was diagnosed with peripheral neuropathy (predominantly sensory) initially and had received immunoglobulins and pulsed steroid therapy with no benefit. She was following up with respiratory team for surveillance of hamartoma in left lower lobe. Investigations included a battery of serum samples and tissue samples on two different occasions. Anti-HU and anti-CV2 antibodies were found positive in serum. Sural nerve biopsy raised suspicion of paraneoplastic phenomenon. CT thorax abdomen and pelvis was carried out to identify a primary neoplastic source; however no lesion was identified except for the previously documented hamartoma in the left lower lobe. Positron emission tomography (PET) scan was carried out that identified a single fluorodeoxyglucose (FDG)-avid focus either in the mid oesophagus or in the left para oesophageal region below the left main bronchus. Gastroscopy showed evidence of inflammation only. Bronchoscopy/endobronchial ultrasound (EBUS)-guided lymph node biopsy turned out be small cell lung carcinoma on histological analysis. She was then referred to oncology services, and received 4 cycles of carboplatin/etoposide chemotherapy followed by 30 fractions of radiotherapy. She finished chemotherapeutic treatment without any complications. So far her symptoms have not settled, but not worsening anymore and she continues physiotherapy to regain limb function.

Background

Paraneoplastic neurologic syndromes are an immune mediated phenomenon usually associated with solid cancers. They are usually not caused by metabolic or nutritional deficiency. These can affect the nervous system and finding a cause may be a challenge. One such condition, chronic sensorimotor neuropathy, may occur in cancer patients, most commonly in patients with lung cancer and lymphoma. Paraneoplastic syndrome usually present in advanced disease, well after the diagnosis of malignancy has been made. 10%–15% of patients with solid tumours have been found to have chronic sensorimotor neuropathy.

We report a case of a rare scenario where a patient exhibited the features of paraneoplastic syndrome approximately 9 months before the diagnosis of small cell lung cancer confined to a solitary mediastinal lymph node without involvement of lung tissue. The diagnosis was made on positron emission tomography (PET) CT. Our patient was diagnosed with paraneoplastic syndrome affecting peripheral nerves (anti-collapsin-responsive mediator protein-5 (CRMP5) antibody positive).

Patients with paraneoplastic antibodies to CRMP5 develop a rapidly progressive sensorimotor neuropathy, and are associated with small cell lung carcinoma and thymoma. Electrophysiologically they exhibit axonal pattern. They do not respond to immunotherapy and are usually very disabling.

Case presentation

A 69-year-old woman was referred to medical team from emergency department with progressively worsening upper and lower limb weakness leading to decreased functional status. She was diagnosed with peripheral polyneuropathy predominantly sensory (axonal type) confirmed on nerve conduction studies, and was treated with immunoglobulins and pulsed steroid therapy with no relief from symptoms. She also complained of nausea for a few weeks prior to her presentation. She had a background history of hypertension, hypercholesterolaemia, orthostatic hypotension and mild osteoarthritis. She was diagnosed with a left lower lobe hamartoma in 2012 and was under surveillance for the same. She lived at home with her husband and three daughters and was active smoker up to 12/day and consumed 6 units of alcohol a week. She had a family history of multiple sclerosis (sister).

On examination she had a blood pressure of 108/72 mm Hg, pulse of 99 beats/min. Neurological exam showed reduced hand grip power 4/5 bilaterally, reduced finger abduction and extension 4/5 and proximal lower limb weakness at hip 4/5 on flexion; light touch was intact. There was loss of proprioception and vibration bilaterally in both upper and lower limbs up to level of knees and elbows. Reflexes were absent in both upper and lower limbs.

Investigations

At the time of referral patient had already undergone several investigations to look into the cause of mixed sensory motor neuropathy.

Investigations included viral screening for Hepatitis B, Hepatitis C, HIV, syphilis serology (all negative). Tuberculosis quantiferon negative, immunoglobulins (normal), serum protein electrophoresis (SPEP) showed no evidence of paraproteinaemia, antiganglioside antibodies including anti-GM1 antibody was negative, anti-GQ1B antibody was negative, normal zinc level 9.7 (range 8.0–17.0), normal copper level 17.9 (range 11.0–22.0). Antineutrophil cytoplasmic antibodies (ANCA) was negative, antinuclear antibody (ANA) positive in a speckled pattern with a titre level of 200, anti-double stranded DNA (dsDNA) antibody was negative, anti-Sjögren's-syndrome-related antigen A (anti-SSA/RO) antibody was negative, anti-SSA/LA antibody was negative, anti-centromere antibody was negative, anti-Jo1 antibody was negative, anti-Sm antibody was negative, anti-Sm/ribonucleoprotein (RNP) antibody was negative, anti-Scl-70 antibody was negative, anti-ribosomal P-protein was negative, anti-nucleosome antibody was negative, anti-Pm/Scl antibody was negative. Anti-HU antibody was positive in serum and anti-CV2 antibody (CRMP5) was also detected in serum. Anti-YO and anti-RI antibodies were negative.

In the meantime, neurophysiologic studies were also carried out. Nerve conduction studies commented on the absence of left median, left ulnar, left radial and right sural sensory nerve responses. It was concluded that the main abnormality was the absence of sensory nerve responses. Some of the motor amplitudes were small, with some prolongation of the distal motor latencies, but motor nerve conduction velocity was normal. Therefore, there were no features of a significant, generalised demyelinating neuropathy. This was followed up by electromyography that showed mixed motor and sensory axonal poly neuropathy; no evidence of chronic inflammatory demyelinating polyneuropathy (CIDP) was identified electrophysiologically.

Sural nerve biopsy was carried out to rule out vascular or paraneoplastic phenomenon. Biopsy result highlighted features, on light microscopy and immunohistochemistry, of lymphocytic microvasculitis. Differentials included vasculitic neuropathy and paraneoplastic vasculitic neuropathy. The presence of significant numbers of B cells as well as T cells was a little unusual in the setting of vasculitic neuropathy and was in favour of paraneoplastic aetiology. Overall, the biopsy supported an axonal process; diagnostic features of CIDP were not identified.

By the time all the investigation results were cumulated the most likely diagnosis was paraneoplastic syndrome; however a source had not been identified yet. She underwent CT thorax, abdomen and pelvis to look for a primary neoplasia. The result showed evidence of a well-defined rounded soft tissue density seen in the posterior apical segment of the left lower lobe. It measured about 21 mm (figure 1). It had been documented back as far as 2012 although size had slightly increased (figure 2). It had been previously investigated with a bronchoscopy (the cytology results were negative for malignancy). The mediastinum and hilar structures appeared normal. Internal mammary chain appeared normal. Small focal areas of asymmetry were seen in the left breast (mammography was recommended). There was evidence of emphysematous changes in the lung parenchyma. Impression was of slightly increased reticulation particularly in both upper zones which represented early apical pulmonary fibrosis. There was evidence of partial eventration of the right hemidiaphragm without any suspicious liver lesion. The spleen and pancreas appeared normal. There was some evidence of non-specific thickening of the gastric antrum (gastroscopy was recommended).

Figure 1.

CT thorax (13/08/2012). Solitary left lower lobe pulmonary nodule with pulmonary hamartoma.

Figure 2.

CT thorax (15/08/2018). Stable 1.6×1.6 cm² fat-containing intraparenchymal lesion that represents a pulmonary hamartoma.

We then proceeded with a mammogram to rule out a primary breast lesion; mammogram showed fibrous changes not consistent with breast neoplasia. Gastroscopy was then performed that showed gastritis and duodenitis; the biopsy result from gastric antrum showed antral and pyloric-type gastric mucosa with mild chronic inactive gastritis and moderate reparative-type epithelial regeneration. Stomach body biopsy showed moderate chronic inactive gastritis with focal intestinal metaplasia. No dysplasia was identified.

At this point all investigations pointed to an underlying paraneoplastic process without evidence of primary solid tumour. We decided to perform positron emission tomography scan. It revealed one concerning intensely fluorodeoxyglucose (FDG)-avid focus, which appeared to be either within the mid-oesophagus or a soft tissue mass in the left paraesophageal position, below the left main bronchus (figure 3). It could represent an oesophageal neoplasm or an adjacent metastatic node (further review with endoscopy or endoscopic ultrasound recommended). The subpleural nodule in the left lower lobe was not FDG-avid and could represent a hamartoma or possibly a neurofibroma (figure 4). Ultimately a bronchoscopy was performed, and biopsy samples were taken from the identified lymph node on PET scan. The cytology result showed tumour cells in the cell block that were positive for pancytokeratin MFN116, TTF1, CD56 and synaptophysin and negative for P63. The immunohistochemical profile supported the diagnosis of small cell lung carcinoma.

Figure 3.

Positron emission tomography (PET) CT (05/04/2019). One intensely fluorodeoxyglucose (FDG)-avid focus below left main bronchus representing a metastatic mediastinal node.

Figure 4.

CT thorax/positron emission tomography (PET) CT. Subpleural nodule in left lower lobe is not fluorodeoxyglucose (FDG)-avid, noted in previous studies, and represents a hamartoma or a neurofibroma.

Differential diagnosis

Patient was admitted for workup of mixed peripheral neuropathy predominantly sensory. Differentials included metabolic causes such as diabetes mellitus, hypothyroididsm/hyperthyroidism, vitamin b12/folate deficiency and vasculitic cause including rheumatoid arthritis and infective causes including Lyme’s disease, HIV and syphilis and paraneoplastic syndrome affecting peripheral nerves.¹

All possible metabolic causes were ruled out except for vitamin b12 as a possible cause of symptoms. However, even after supplementation and achieving normal vitamin b12 levels symptoms were deteriorating rapidly.

Sural nerve biopsy narrowed our differential to two possible diagnoses. These included peripheral neuropathy secondary to vasculitis or paraneoplastic phenomenon. ANA was weakly positive with a titre of 200; however this was found to be of no clinical significance in isolation as no other feature or evidence of active vasculitis was identified and non-pathogenic weakly positive ANA titres have been found to be increasingly prevalent with age. In addition, sural nerve biopsy was more in favour of paraneoplastic phenomenon. Autoantibodies, anti-HU and anti-CV2 antibody (CRMP5) were detected in serum raising the suspicion of paraneoplastic syndrome with underlying solid malignancy. Routine CT scans did not show any evidence of systemic malignancy; PET CT and mediastinal biopsy were used to confirm a diagnosis of small cell lung carcinoma confined to only a solitary lymph node.

Treatment

Patient was referred to oncology services following discussions in multidisciplinary team meeting between respiratory, radiology and oncology services. She was started on carboplatin/etoposide regimen chemotherapy and received weekly chemotherapy for 4 weeks. This was followed by 30 fractions of radiotherapy. She finished her chemotherapy/radiotherapy without any complications.

She is due to attend radiation oncology services in the coming weeks to assess the need for preventative radiotherapy to her brain.

In terms of further investigations she is due to undergo CT thorax, abdomen and pelvis to assess resolution of primary lesion and to rule out presence of distant metastasis. Later in the year she will be undergoing a repeat PET CT scan to assess resolution of small cell lung carcinoma.

From a functional status viewpoint, she was referred to physiotherapy team for support with ongoing weakness and functional deterioration secondary to sensory/motor neuropathy. She continues to mobilise with a Zimmer frame and continues to see physiotherapy team and has so far made little progress in terms of regaining function. Her symptoms have worsened to an extent that she has lost dexterity in her hands and feels uncomfortable holding a cup of tea. Also, she has made adjustments at home to help her move around the house. She continues to perform various physiotherapy exercises at home and will attend a physiotherapist in near future to ascertain future rehab goals.

Outcome and follow-up

Her symptoms worsened during treatment phase (chemotherapy); however she has now settled to the level that was prior to treatment. Physiotherapy has so far not made any difference in her functional status.

She attended weekly chemotherapy sessions, finished four cycles and then received 30 fractions of radiotherapy. After completion of treatment she will now attend oncology outpatient clinic on a monthly basis initially and then on a 3-month basis. She is due to attend radiation oncology services for assessment of possible preventative radiotherapy to brain.

She will also be followed up in respiratory outpatient clinic yearly for surveillance of left lower lobe hamartoma.

Discussion

We present a rare case of paraneoplastic syndrome associated with small cell lung carcinoma confined to a solitary lymph node (T0 N2 M0) without involvement of lung tissue. Neurological symptoms appeared almost a year before the diagnosis of small cell lung carcinoma was made, as it is rare presentation but could be earliest symptom of cancer itself in few patients.²

Paraneoplastic syndromes affecting neurological system include number of disorders. These are caused by processes other than physical or metabolic involvement from tumour and not explained by any other reason for neurological disorder.³ Any part of neurological system can be affected from cerebral cortex to neuromuscular junction, leading to clinical syndromes of encephalitis to peripheral neuropathies.

Anti-neuronal antibodies are important in diagnosing small cell lung carcinoma. Specific types of paraneoplastic syndromes are associated with specific cancers and autoimmunity plays its role; hence specific pathogenic antibodies are associated with specific cancers as they are developed from cross reactivity to tumour antigens. Anti-Hu antibody is associated with peripheral sensory neuropathy secondary to small cell lung cancer, breast and ovary lymphoma.⁴ PET CT has proven beneficial in identifying suspected small cell lung cancer in association with paraneoplastic syndrome, which is difficult to diagnose on normal CT.⁵

Paraneoplastic antigens are either found in cytoplasm (anti-Yo) or the nucleus (anti-CRMP5). It is believed that autoimmunity leads to neuronal damage and related symptoms. When antigens are located on the cell surface, immune modulating treatments are found to be effective in treating and sometime reversing the symptoms.⁶ While in cases when antigen is intracellular they do not respond to immune modulating treatment and treatment aims at treating underlying malignancy, as in our case.⁶ In latter cases successful treatment of primary malignancy halts worsening of symptoms and paraneoplastic syndrome but significant improvement is not identified in majority of patients.

Patient’s perspective.

I first noticed itching sensation in my back moving all the way down to my legs. That is how it all started as far as I can remember. Itching sensation was too much for me to handle and before I could do anything about it, the sensation changed and I started feeling pins and needles in my legs and then in my hands. At first i thought it was my arthritis giving me trouble but soon i noticed that my balance was not right and the power in my fingers and hands had decreased. That was very worrying for me as I had no answers. I was referred to a neurologist who performed different blood tests. I was told that vitamin b12 levels in my body were low and that may have been the cause of my symptoms, it was first important bit of information I had received at the time. I felt relieved and thought that once I took supplements maybe my symptoms would settle. However that did not happen and I lost more and more function of my hands and power in the legs continued to deteriorate. I then had nerve conduction studies to find out the nature of the weakness and loss of sensation. My neurologist told me the result but it did not make me feel any different as my symptoms were no better.

Then I had immunoglobulin infusions with little to no effect followed by steroid therapy, all in vain as far as I was concerned. I had very little use of my hands and I couldn’t walk straight and had to use a frame to walk, it was all very frustrating. I guess if there was a diagnosis made at that point maybe I would have been in a more positive state of mind. I must say that the level of communication was excellent even though there was no definite diagnosis. I was satisfied with the efforts put in by all the teams.

My neurologist then requested all the blood tests known to man, he mentioned a couple of fancy blood tests and told me the results might help getting to a diagnosis. At that point I was very frustrated and exhausted and also scared as it had been going on for almost a year at that point. I was told that a biopsy would be necessary to reach a diagnosis. Any time some one mentions biopsy it just means that something serious is going on, anyways I consented to it as it was the only way to get some sort of clarity about the whole situation. The result of biopsy narrowed down the search for a possible diagnosis, however I was again asked to undergo a PET scan, I had never heard of that scan before and did not know what to expect at the time. Once the result of the scan was out only then did I realise how grave the situation was, I was told that there was a small node in my chest that looked suspicious for cancer. As much as I was hoping to avoid something like that it became my reality. I underwent a camera test to get a tissue sample again, this time into my lungs. The results took a life time to get, or at least that is how long it felt to me but I was sort of thankful that a diagnosis was imminent. Finally I was informed that it was a form of lung cancer but only limited to a small node in my chest and not in my lung. I had a long discussion with my doctors about results of all the tests and what it meant for future in terms of management. One of my daughters kind of knew that something was not right all along. For my part, I guess I was just staying positive and hoping for the best.

From there on everything happened really quickly and now that I think about it I don’t think I got a chance to really think about or rather be overwhelmed by the whole cancer situation. I was just relieved that a diagnosis was made and treatment was initiated promptly even though it took a long time to get to a diagnosis. Sometimes I wonder why it took so long to get to a diagnosis but I have been told that normally my condition presents in a totally reverse order so I don’t know if this is good or bad in terms of prognosis.

I was offered chemotherapy; I have to say it was not a pleasant experience as I felt very exhausted and drained throughout the whole process. Then I received radiotherapy, that too was not a pleasant experience but by that time I was in a more positive state of mind and was determined to get through it. My family has been a great source of inspiration for me. The support and care I enjoyed has been overwhelming.

My symptoms have not improved so far and now I am thinking of attending a physiotherapist regularly to set future rehabilitation goals. I understand that the road to recovery is long but I have never been more positive about my health, so I know I will overcome all this.

Learning points.

• Paraneoplastic syndrome can be present prior to the appearance of a primary solid tumour. As rare as it is, it should be considered as a potential cause of peripheral neuropathy especially if common causes are ruled out.

• Even a solitary lymph node with malignant cells is enough to cause a severe and debilitating form of paraneoplastic syndrome affecting peripheral nerves.

• Treatment should be initiated promptly as only treating the cause may relieve symptoms.

• Multidisciplinary approach is essential in long-term management; the role of physiotherapy is vital and realistic rehab goals should be set.

• The significance of positron emission tomography (PET) scan in the setting of peripheral neuropathy, with no identifiable cause, is highlighted in this rare case.

Ethics statements

Patient consent for publication

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