Cervical amyloidoma of transthyretin type: a case report and review of literature

Abstract

Background

Amyloidoma is a rare clinical entity characterized by the focal aggregation of amyloid protein within the body, void of systemic involvement. To our knowledge, there have only been 26 reports of cervical amyloidoma to date. Amyloid light chain and beta-2-microglobulin are the most common types, with only three previous reports of transthyretin (ATTR) Amyloidoma.

Case presentation

We report a case of a 71-year-old male who presented with worsening strength and coordination of his upper extremities, right upper-leg pain, unsteady gait, and a reduced range of motion of his neck in all planes. Magnetic resonance imaging revealed a solitary mass compressing the spinal cord at C1-C2. Treatment consisted of cervical decompression and stabilization. Pathological examination confirmed solitary amyloid deposition of ATTR. Postoperative neurological assessment revealed improved balance, gait, hand function, and grip strength. Investigational imaging was ordered 8 months postoperatively revealing no evidence of systemic involvement, confirming the diagnosis of cervical ATTR amyloidoma. A discussion is provided surrounding the published literature of ATTR amyloidoma with description of the typical presentation, management, and outcomes of this rare pathology.

Conclusion

Previous cases and studies indicate clinical signs such as ligamentum of flavum hypertrophy and carpal tunnel syndrome may precede focal ATTR spinal disposition. Outcomes for amyloidoma are generally favourable, as tumour resection prevents irreversible deficits. Patients have a low rate of recurrence with an overall excellent prognosis following resection and stabilization.

Background

Amyloidosis is a disease caused by the aggregation of amyloid which are insoluble fibrils with a cross beta-pleated sheet structure made of an assembly of misfolded and normally soluble proteins [1]. Aggregates deposit in the extracellular spaces of organs and tissues in either a systemic or local fashion [2, 3]. The origin of the term dates to 1854 where it was introduced by Rudolph Virchow when describing a tissue with an abnormal macroscopic appearance. Originally thought to be related to cellulose or starch, later experiments revealed its proteinaceous nature [3].

Amyloidoma is characterized by focal depositions that do not feature systemic involvement. Amyloidomas found in the spine are a rare clinical entity. The first report of cervical amyloidoma was published in 1988 by Dickman et al. and to our knowledge, there have only been 26 reports of amyloidoma identified in the cervical spine [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. We present a case of a 71-year-old patient with transthyretin (ATTR) type cervical amyloidoma and provide a review of literature on amyloidoma involving the cervical spine.

Case presentation

A 71-year-old man presented to his family physician with upper right leg pain. His symptoms progressed with deterioration in his balance and decreased strength and coordination in his upper limbs. Functionally, the patient remarked being clumsy at home, dropping objects on a regular basis, unable to do buttons and/or zippers, and excluded several activities of daily living due to these limitations. The patient had no previous spinal trauma and an unremarkable family history. His previous surgical history included a bilateral hip replacement, tonsillectomy, and carpal tunnel release. A referral was then made to neurosurgery for further management.

Neurological examination revealed an unsteady gait with the inability to heel-to-toe walk and a positive Romberg’s sign. He was unable to sit comfortably and exhibited a reduced range of motion of the neck in all planes. Examination of his upper limbs revealed deficits that were particular to his right side. This included atrophy in the first web space, decreased grip strength (4−/5), poor finger function and reduced sensation. Left arm and hand involvement was present but to a lesser degree. Lower limb involvement included decreased sensation in both feet and in the right L3 dermatome. Reflexes were brisk.

Due to the neurological findings, computed tomography (CT), and nerve conduction study (NCS) were obtained. NCS revealed no abnormal findings while the CT scan showed a mass (28x15x39mm) that compressed the cervical spinal cord at C2.

Magnetic resonance imaging (MRI) was obtained revealing a congenitally narrow cervical spinal canal and significant compression of the spinal cord at C1 and C2 (Fig. 1). Some canal stenosis, in the thoracic and lumbar regions, was present. This was secondary to degenerative changes and ligamentous hypertrophy.

Fig. 1

Preoperative MRI T2-weighted imaging: sagittal (a) and axial (b) views suggesting a congenitally narrow cervical spinal canal and hypointense mass causing significant spinal cord compression at C1 and C2

A diagnosis of cervical myelopathy secondary to a C2 mass was made. Informed consent for surgery was obtained. Surgical management consisted of decompression of the cervical spinal cord with a posterior cervical fusion of C1-C3. Tissue biopsies were obtained and sent to pathology for investigation.

CT imaging was performed in the early postoperative period which demonstrated no bony or hardware complications. MRI imaging was done 6 months postoperatively (Fig. 2) which illustrated the decompression of the cervical spinal cord. Follow-up clinical examination at that stage found increased grip strength, mobility, and balance with an overall improvement as compared to pre-operative symptomology. He was referred to physiotherapy to aid with rehabilitation.

Fig. 2

Postoperative MRI T2-weighted imaging: sagittal (a) and axial (b) views suggested substantial spinal cord decompression at C1 and C2

Further radiological investigations were obtained to verify that the mass was not secondary to systemic amyloidosis. Results were negative, leading to the confirmation of primary solitary amyloidosis treated with uncomplicated cervical spine surgery.

Furthermore, the patient has been referred to Cardiology and completed a MIBI scan with no evidence of cardiac infiltration. Additional cardiac studies and genetic assessment are planned but have not yet been completed at the time of this report; however, it is suspected the ATTR subtype is non-genetic in nature. The patient is receiving further work-up regarding his lumbar spinal stenosis as it requires treatment.

Pathological findings

Histological examination of the biopsy revealed positive Congo red stained tissue, proof of amyloid deposition [30]. Congo red positive areas were blocked in paraffin and sent for proteomic analysis by mass spectrometry which indicated amyloid deposition of ATTR type.

Discussion and conclusions

Classification of amyloidosis has evolved over the years. Currently, nomenclature consists of beginning with protein A, the amyloid fibril protein, followed by the abbreviated name of the precursor protein. Presently, there are 40 known human amyloid fibril proteins, most of which are exceedingly rare [3]. Of the known proteins, commonly reported amyloidoma types include immunoglobin light chain (AL), serum amyloid A (AA), and β2-microglobulin (Aβ2M); less commonly is the transthyretin type [21, 28]. Most often, reported cases are attributed to either AL or Aβ2M types [2, 21].

AL is a disorder of plasma cells, where lambda or kappa light chains aggregate in focal dispositions and is associated with multiple myeloma patients [31]. AA is often referred to as secondary amyloidosis, as the disease is secondary to longstanding inflammation caused by diseases such as rheumatoid arthritis, chronic osteomyelitis, or Crohn’s Disease [30]. Aβ2M is caused by renal failure in patients with long-standing dialysis who have decreased clearance of the protein A beta-2-microglobulin. Transthyretin functions as a transport protein for thyroxin and retinol and is mainly produced in the liver, whereas small amounts are produced by the choroid plexus. ATTR is commonly categorized as wild-type (ATTRwt) and variant (ATTRv), otherwise defined as the hereditary subtype [32]. Additionally, a third subtype has been reported in patients who receive liver transplants from ATTRv donors, referred to as acquired ATTR amyloidosis [32]. ATTRwt is characterized by normal TTR protein aggregation, while ATTRv is tied to inherited autosomal dominant point mutations [30].

ATTRwt amyloidosis is classically associated with cardiomyopathy in the elderly, more commonly in male patients; however, features of carpal tunnel syndrome and spinal canal stenosis. ATTRv Amyloidosis has been studied within endemic and non-endemic populations which have revealed different clinical features both between endemic and non-endemic populations, as well as between endemic populations such as Sweden compared to Japan and Portugal [32]. Physical manifestations of ATTRv are broad and include neuropathy, cardiomyopathy, oculoleptomeningeal involvement, and potentially myopathy [2, 32, 33]. Acquired ATTR amyloidosis may develop after domino liver transplantation, as the donor’s functioning liver continues to produce ATTRv, and studies have shown the mean duration from transplantation to symptom onset is roughly 8 years [32]. It should be noted that the symptoms differ between the recipient and the donor’s original symptoms. Recipient symptomology tends to focus on sensory, not autonomic symptoms [32].

Despite the rare occurrence of solitary focal deposits of ATTR along the spinal canal, several studies have investigated the effects of transthyretin amyloidosis in other areas of the human body. ATTRwt disposition has been commonly identified within the ligamentum of flavum (LF) associated with spinal stenosis, the transverse carpal ligament associated with carpal tunnel syndrome (CTS), and endomyocardial tissues affiliated with heart failure [34,35,36]. More recently, studies have shown CTS commonly precedes ATTR amyloidosis [37, 38].

Our patient’s history was significant of carpal tunnel release and radiological assessment revealed compression in both lumbar and thoracic regions due to hypertrophy of the ligaments. To our knowledge, there have been only three previous cases with spinal involvement that have demonstrated a positive or slightly positive result for the transthyretin type [10, 19, 25]. Table 1 illustrates a comparison of the 26 cases identified in our literature review regarding amyloidoma involving the cervical spine.

Table 1 Summary of cervical spine amyloidoma cases within the literature

Previous research has shown that presenting symptoms of cervical amyloidoma most often includes pain, discomfort, subjective weakness, or sensory disturbances. Common physical exam findings include objective weakness, paralysis, and hyperreflexia [21]. MRI imaging often reveals hypointense structures on T1 and T2 images and mostly occupies the epidural space and bone at the C1, C2, C6 and C7 levels [2, 21]. These findings were concurrent with our case and with what has been previously reported in ATTR-specific cases. The differential for C1-C2 pannus is broad and includes primary or metastatic bone tumours, infectious processes, rheumatoid arthritis, calcium pyrophosphate deposition, pigmented villonodular synovitis, gout, osteoarthritis, brown tumour, or amyloidoma [13, 39].

Cervical amyloidoma patients aged ranged from 45 to 86 with an average age of 66 ± 11.9, where 16 patients were male (61.5%) and 10 were female (38.5%). Notably, our patient alongside two other previously reported ATTR cases had a history significant for CTS [19, 25]. As well, the remaining previously published ATTR case report mentioned their patient having prolonged sensory latency of the median nerve [10]. Spinal stenosis due to ligamentous hypertrophy was only reported in the case by Rezania et al. and not described in the remaining ATTR reports [19]. In general, our findings complement previous work and illustrates the potential for CTS and LF hypertrophy to proceed in patients with unknown pannus-like masses compressing the spinal cord, causing neurological deficits on examination.

Medical therapeutics for ATTR have been developed and are classified as transthyretin silencers, stabilizers, and amyloid fibril disruptors/degraders [40]. Such therapeutic agents have been employed to treat cardiac ATTR by targeting various stages of the disease process in hopes of halting progression and possibly reversing aggregation [40]. To date, the mainstay treatment for amyloidoma is surgical excision, with some reports describing the benefits of adjuvant radiotherapy or chemotherapy for patients who were not surgical candidates [2]. A report by Farrell et al. demonstrated improved clinical outcomes for AL cervical amyloidoma using 6 cycles of bortezomib and dexamethasone [8]. Our review revealed no reports describing the use of ATTR-specific therapeutics in the management of spinal amyloidoma. Thus, the real benefits of the treatment of amyloidoma using radiotherapy, chemotherapy, or ATTR-specific therapeutics have not yet been demonstrated or described at all.

Patients diagnosed with localized amyloid deposits have an excellent prognosis due to the lack of systemic involvement and benign tumour-like growth. Interventions most often consist of decompressive surgery with and without fusion depending on the extent of resection [2]. Post-operative outcomes often improve or completely resolve presenting symptoms and are complimented with low reported rates of recurrence and mortality [2, 21]. However, it should be noted that no long-term follow-up reports have been published yet.

In our case, the patient presented with pain, reduced motion, loss of balance, and poor subjective strength which are consistent with common presentations found in previously published literature. Patients with solitary spinal amyloidoma are important to distinguish from other diagnoses due to their favourable outcomes; however, physicians need to maintain clinical suspicion and obtain tissue biopsies to confirm the diagnosis as this is the only proven method of authentication to date. Additionally, CTS and spinal stenosis caused by hypertrophied LF have been attributed to ATTR amyloidosis; hence, patients who develop focal spinal lesions whose history is significant for either or both should maintain clinical suspicion for solitary spinal amyloidoma as these conditions may appear years prior.