Trigeminal Amyloidoma: A Report of Two Cases and Review of the Literature

Abstract

Cerebral amyloidomas, characterized by localized amyloid deposits in the nervous system in the absence of systemic disease, are rare. These typically consist of immunoglobulin light chain (AL)-type, predominantly lambda. Trigeminal nerve involvement is exceptionally rare with only 21 previously reported cases, three with bilateral disease. We report two additional cases of amyloid localized to Meckel’s cave with secondary involvement of the trigeminal nerves bilaterally, with protein characterization by mass spectrometry. The patients, both females, 39 and 49-years-old, respectively, presented with the insidious onset of progressive trigeminal neuropathy, including pain and numbness with sensory loss, refractory to medical therapy. One patient experienced bilateral symptoms. Magnetic resonance imaging demonstrated abnormal thickening and contrast enhancement along Meckel’s cave bilaterally in both cases. The clinical differential diagnosis included benign neoplasms and inflammatory disorders. At the time of biopsy, the trigeminal nerve was noted to be enlarged and multinodular in one case and associated with abnormal soft tan tissue in the other case. Microscopically, the nerve biopsies showed extensive Congo red-positive amyloid deposits. Liquid chromatography tandem mass spectrometry demonstrated that the amyloid was of (AL)-type in both cases (AL [kappa] in one case and AL [lambda] in the other). After extensive evaluation, there was no evidence of systemic involvement. Both patients received localized radiotherapy for their refractory symptoms. One patient has stable symptomatology and imaging. No follow-up is available for the other patient.

Introduction

Amyloidosis is the abnormal extracellular deposition and aggregation of insoluble misfolded proteins. Amyloidoses are a heterogeneous group of disorders which occur in a variety of clinical settings and involve a range of tissues and organs. Although different proteins with distinct chemical compositions can form amyloid, the proteins' physical structure, characterized by cross-β-pleated sheets forming insoluble fibrils, is uniform across protein types and results in a similar morphologic appearance by histopathology. ¹ Amyloidosis can be generalized, involving multiple organs and tissues, or localized to a single organ. Localized amyloid can rarely form tumor-like deposits termed amyloidomas, most commonly reported in the respiratory and gastrointestinal tracts, skin, urinary bladder, and ocular adnexal structures. ¹

Amyloidomas involving the nervous system are extremely rare ² and typically localize to the periventricular white matter. ^{2 3} The amyloid deposits in the majority of cases are composed of immunoglobulin light chains, predominately lambda-type (AL-lambda). Amyloidomas may also involve the intracranial peripheral nerves, most frequently the trigeminal ganglion, within Meckel's cave. Patients with trigeminal amyloidoma typically present with progressive and sometimes debilitating symptoms of trigeminal neuropathy and nonspecific imaging findings, necessitating biopsy for tissue diagnosis. To date, 21 cases of trigeminal amyloidoma have been reported. Here, we report two additional cases of bilateral trigeminal amyloidomas, with characterization of the amyloid protein by mass spectrometry, and review of the literature.

Clinical Summary

Case 1

A 39-year-old woman, with no significant past medical history, presented with a 13-year history of progressive bilateral facial pain and numbness. Her symptoms began with numbness on the left side of her mouth and progressed to involve her left cheek. She also began to experience electric-type shocks in the left face. Several years later, she began to experience numbness in her right cheek at the angle of her mouth, which progressed to involve the inside of her mouth and gums and part of her tongue and eventually extended into her neck and up to the vertex of the head. She reported shooting pains elicited by touching either side of her face. Her symptoms were refractory to medical therapy which included opioids, corticosteroids, and agents for neuropathic pain, such as gabapentin and carbamazepine. Magnetic resonance imaging (MRI), first performed at the onset of her symptoms, was not available for review but was reportedly unremarkable. Another MRI was performed approximately 9 years later and demonstrated homogeneously enhancing masses involving Meckel's cave bilaterally. A biopsy of the cavernous sinus was performed at another institution and consisted of a small fragment of unremarkable dura and peripheral nerve and was nondiagnostic. At the time of presentation at our institution, physical examination demonstrated severe sensory loss in all three divisions of the trigeminal nerve bilaterally. The strength was normal in the muscles of mastication, and testing of the remainder of the cranial nerves was unremarkable. MRI showed abnormal enhancement and fullness of Meckel's cave bilaterally, with extension into the cavernous sinuses, more evident on the left ( Fig. 1 ). The differential diagnosis included bilateral trigeminal schwannomas or Meckel's cave meningiomas, sarcoidosis, inflammatory pseudotumor, bilateral Tolosa–Hunt syndrome, and much less likely, lymphoma or metastasis considering the very long history. Cerebrospinal fluid analysis and a systemic workup for cancer, inflammatory, or infectious etiologies were unremarkable. She underwent a right middle fossa craniotomy and subtemporal exposure and exploration of right Meckel's cave. Intraoperatively, the dura of the lateral wall of the cavernous sinus was elevated off of V2 and V3 to expose lateral Meckel's cave, which was found to be filled with abnormal soft, tan tissue. Multiple biopsies were taken and sent for pathological analysis.

Fig. 1.

Case 1: Axial T1-weighted ( A ) and coronal ( B ) MRI sequences with fat saturation demonstrating homogenous enhancement with expansion of Meckel's cave and cavernous sinus bilaterally (red arrows). Axial T2-weighted image ( C ) shows Meckel's cave contains abnormal signal (red arrows), which is isointense or slightly hypointense to brain parenchyma bilaterally. Case 2: Postcontrast axial T1- weighted ( D ) and coronal ( E ) MRI sequences with fat saturation demonstrating homogenous enhancement of an infiltrating process within left Meckel's cave and cavernous sinus (red arrows). Axial T1-weighted ( F ) MRI sequence eleven months after radiotherapy shows stable disease in left greater than right Meckel's cave (red arrow). MRI, magnetic resonance imaging.

Case 2

A 49-year-old woman, with no significant past medical history, presented with an 8-year history of progressive left-sided facial pain and numbness, including loss of cornea sensation resulting in a corneal ulcer. Her symptoms began with an unusual sensation on the left side of her nose which evolved to numbness and pain. The symptoms progressed and migrated to her left cheek, forehead, left eye, and chin. She described the pain as burning and tingling in quality, constant in nature, with occasional episodes of paresthesias that lasted minutes to hours, and were not precipitated by tactile stimulus. She later developed right-sided facial numbness. Her symptoms were refractory to medical therapy, which included multiple agents for neuropathic pain. She had been diagnosed with Tolosa–Hunt syndrome but declined treatment with corticosteroids. Physical examination demonstrated severe left greater than right sensory loss in all three divisions of the trigeminal nerve with normal strength in the muscles of mastication. Testing of the remainder of the cranial nerves was unremarkable. MRI showed abnormal enhancement along the lateral margin of the left cavernous sinus and medial margin of the left middle cranial fossa with development of slight enhancement of the lateral margin of right Meckel's cave ( Fig. 1 ). The differential diagnosis was similar to case 1 and included meningioma and a lymphoproliferative or histiocytic process. Cerebrospinal fluid analysis and a systemic workup for cancer, inflammatory, or infectious etiologies were also unremarkable. A left middle cranial fossa craniotomy was performed with subtemporal exposure and biopsy of the left trigeminal nerve at the level of foramen ovale. At the time of surgery, V3 appeared enlarged and multinodular but with no definite separate distinguishable tumor mass.

Materials and Methods

This publication is in compliance with institutional board review requirements.

For special stains, paraffin-embedded tissue was cut at 10 microns for Congo Red.

For immunohistochemistry, the following primary antibodies and dilutions were used: CD3 (Leica clone LN10, 1/250 dilution, Leica Biosystems Newcastle Ltd., Newcastle Upon Tyne, United Kingdom), CD20 (Dako clone L26, 1/300 dilution, Dako Denmark A/S, Glostrup, Denmark), kappa, (Dako rabbit polyclonal, 1/2500 dilution, Dako Denmark A/S, Glostrup, Denmark), and lambda (Dako rabbit polyclonal, 1/3500, Dako Denmark A/S, Glostrup, Denmark).

Liquid chromatography tandem mass spectrometry (LCMS/MS) was performed on peptides extracted from Congo red-positive, microdissected areas of paraffin-embedded nerve specimens as previously described. ⁴

Pathological Findings

Grossly, the specimens consisted of tan-pink soft tissue. Histological sections demonstrated aggregates of amorphous eosinophilic material, consistent with amyloid protein deposition. In the first case, the amyloid infiltrated nerve twigs, ganglia, and dura, creating a mass effect ( Fig. 2 ), and also involved the walls of the microvasculature. In the second case, there was extensive infiltration of the endoneurium ( Fig. 3 ). Amyloid protein was confirmed by positive staining with Congo red and apple-green birefringence on polarization ( Figs. 2 , 3 ). Rare scattered lymphocytes were also identified in the first case, which were CD3-positive but negative for CD20 and kappa and lambda immunoglobulin light chains. No plasma cells were identified in either case. Liquid chromatography tandem mass spectrometry demonstrated a peptide profile consistent with amyloid deposition of the AL (kappa-type) in the first case and AL (lambda-type) in the second case ( Fig. 4 ).

Fig. 2.

Amyloid deposits involving the ganglion ( A, B ). Positive staining and apple-green birefringence with Congo red ( C, D ).

Fig. 3.

Amyloid deposition involving endoneurium ( A, B ). Positive staining and apple-green birefringence with Congo red ( C, D ).

Fig. 4.

Proteomic identification of light chain amyloid in trigeminal nerve amyloid deposits. Congo red-positive deposits were microdissected and analyzed using liquid chromatography with mass spectrometry (LCMS/MS) as described in the Methods. A protein identification report showing the universal amyloid markers (highlighted with blue/gold double stars) and type deterministic markers (highlighted with blue stars). The numbers displayed in green boxes represent the total number of MS/MS spectra matched to the listed protein. Cases 1 and 2 are shown with duplicate independent microdissections and subsequent LCMS/MS analysis. LCMS, liquid chromatography mass spectrometry; MS, mass spectrometry.

Clinical Follow-up

Evaluation for a systemic plasma cell neoplasm, including bone marrow biopsy, flow cytometry, fat aspirate, and urine and serum protein electrophoresis was negative in both cases, and the patients were diagnosed with isolated intracranial amyloidoma. Both patients had persistent intractable pain, refractory to medical therapy. The first patient received gamma knife radiotherapy at another institution and was lost to follow-up. The second patient underwent external beam radiation therapy (20 Gy in 10 fractions) to the left trigeminal nerve approximately 1 month after surgery. Six months after radiation was completed, she was noted to have stable symptoms on the left side of her face. She described worsening symptoms on the right side of her face with tingling and numbness in a V2 distribution below her nose and extending to her upper lip. Repeat MRI 1 year later was essentially unchanged ( Fig. 1 ), and radiotherapy to the right trigeminal nerve is being considered.

Discussion

Trigeminal amyloidoma is an exceptionally rare and diagnostically challenging entity. To date, there have been 23 reported cases of trigeminal amyloidoma, including the two cases reported in this publication ^{3 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20} ( Table 1 ). Cases showed a female predominance, with 15 of 23 cases (65%) occurring in women. Age at diagnosis ranged from 27 to 70 years old (mean of 47 years), and most patients experienced symptoms for several years prior to diagnosis (mean of 7 years). Imaging findings were variable and nonspecific, typically demonstrating mild enlargement of the trigeminal nerve, or a mass-forming lesion within Meckel's cave. Computed tomography was either normal or isodense with homogenous contrast enhancement. On MRI, lesions were typically isointense on T1-weighted images with intense homogenous contrast enhancement, and T2-weighted images were darker than brain parenchyma or heterogeneous (mixed). ¹⁹ Schwannoma or meningioma was most commonly suggested as the preoperative diagnosis. Six of 23 patients (26%), including our two cases, showed bilateral involvement at initial presentation, ^{10 11 19 20} and imaging findings were considered suggestive of an inflammatory or lymphoproliferative process. Intraoperatively, a mass lesion was present in most cases; however, occasionally, as in our second case, no visible mass could be identified.

Table 1. Summary of clinical characteristics and amyloid subtype.

Reference	Age (y)/gender	Laterality	Symptoms	Duration	Location	Amyloid subtype
3	46/M	Right	V2 numbness	10 y	Trigeminal ganglion	AL-type (lambda), IHC
3	36/F	Left	Facial pain, numbness	9 y	Trigeminal ganglion	AL-type (lambda), IHC, ISH
3	31/M	Right	V1–V3 sensory loss	4 y	Trigeminal ganglion	AL-type (lambda), IHC, ISH
5	42/M	Right	Facial pain, numbness	11 y	Trigeminal ganglion to V2–V3	N/A
6	58/F	Right	V1–V3 pain, numbness, motor weakness	7 years	Meckel's cave	N/A
7	54/F	Left	V1–V3 numbness	4 y	Trigeminal ganglion	N/A
8	59/M	Right	V2–V3 numbness	18 mo	Trigeminal ganglion, lower portion	N/A
9	32/F	Left	V2–V3 pain, numbness, motor weakness	10 y	Meckel's cave	AL-type (lambda), IHC, immunocytochemistry
9	49/F	Left	V1–V3 pain, numbness	10 y	Meckel's cave to V2–V3	AL-type (lambda), IHC, immunocytochemistry
9	45/F	Left	V1–V3 pain, numbness	10 y	Meckel's cave	AL-type (lambda), IHC, immunocytochemistry
10	49/F	Left	Left facial numbness, motor weakness	4 y	Cavernous sinus	Equivocal immunocytochemistry
11	34/M	Bilateral	V1–V3 numbness, microbial keratitis	5 y	Bilateral trigeminal ganglia	N/A
12	46/F	Right	V2–V3 pain, numbness	1 y	Meckel's cave to V1–V2	N/A
13	41/F	Left	V2–V3 numbness	Not defined	Meckel's cave	AL-type (lambda), IHC
14	62/M	Left	Chronic trigeminal neuralgia	Not defined	Meckel's cave	AL-type (lambda) and transthyretin, IHC
15	64/M	Right	V2–V3 numbness	9 mo	Cavernous sinus into Meckel's cave and along V2–V3	AL-type (lambda), IHC
16	32/F	Right	V1–V3 pain, numbness	3 y	Cavernous sinus into Meckel's cave and foramen ovale	AL-type (lambda), IHC
17	27/F	Right	Painless eye proptosis	2 y	Cavernous sinus, Meckel's cave, infratemporal fossa, orbit, cerebellopontine angle cistern	AL-type (kappa and lambda), IHC
18	62/F	Right	V1–V3 pain, numbness	1.5 y	Meckel's cave to V2–V3	non-amyloid-A-type, potassium permanganate
19	57/F	Bilateral	V1–V3 pain, numbness	3 y	Bilateral Meckel's cave	AL-type (lambda), IHC
20	45/M	Bilateral	V1–V3 numbness, motor weakness	25 y	Bilateral Meckel's cave	AL-type (lambda), IHC
Case 1	39/F	Bilateral	V2–V3 pain, numbness	13 y	Bilateral Meckel's cave	AL-type (kappa), LCMS
Case 2	49/F	Bilateral	Left V1–V3 pain, numbness, right V1-V2 numbness	8 y	Bilateral Meckel's cave	AL-type (lambda), LCMS

Abbreviations: F, female; IHC, immunohistochemistry; ISH, in situ hybridization; LCMS, liquid chromatography mass spectrometry; M, male; N/A, not available; y, years.

Amyloidomas are often indeterminate on radiographic imaging, and definitive diagnosis requires histopathology. Lesions demonstrate Congo red-positive, amorphous eosinophilic material, typically with absent to minimal associated lymphoplasmacytic inflammatory infiltrate. Similar to intracerebral amyloidomas, the majority of trigeminal amyloidomas are reported to be AL (lambda)-type. Amyloid subtyping was performed in 15 of 23 reported cases, most by immunohistochemistry, and 12 were reported to be AL-lambda, one AL-kappa, one mixed AL-kappa/AL-lambda, and one mixed AL-lambda/transthyretin. However, due to technical limitations, amyloid typing by immunohistochemistry has poor specificity, and thus the amyloid type in these cases may not have been definitively established. ^{4 21 22} Our first case illustrates this point: immunohistochemistry was negative for kappa or lambda, while amyloid typing by mass spectrometry was consistent with AL (kappa)-type amyloid.

The etiology of cerebral amyloidomas is not well understood. Consistent with previous reports, extensive evaluation of our patients for an underlying plasma or B-cell dyscrasia failed to identify any evidence of a systemic disorder at diagnosis. Although most reported cases had limited long-term follow-up, no patients subsequently developed a systemic lymphoproliferative disorder or systemic amyloidosis. However, several studies have identified clonal B-cell populations within intracerebral amyloidomas, ^{2 3} including one trigeminal amyloidoma. ³ This has led to the hypothesis that amyloidomas may be the manifestation of an exhausted extramedullary plasmacytoma or low-grade B-cell lymphoma with plasmacytic differentiation, such as localized mucosa-associated lymphoid tissue lymphoma, overtaken by amyloid deposits. ^{23 24} The mass spectrometry results further support the clonal etiology in these cases even in the setting of localized disease and the lack of a clonal B-cell or plasma cell population.

There is no consensus regarding treatment for trigeminal amyloidoma. Treatment modalities have included resection, biopsy with observation, colchicine, and radiation therapy. When resection was achieved, the majority of patients experienced resolution of pain symptoms; however, extensive resection usually requires removing the nerve and ganglion, resulting in worsening anesthesia, with possible risk of anesthesia dolorosa, and loss of motor function. ¹⁶ The optimal treatment strategy for bilateral disease is unclear. As the presumed etiology is a localized clonal plasma cell or B-cell population, focal radiotherapy may be of benefit as plasma cells are radiosensitive. ²⁵ Focal radiotherapy applied to a cerebral amyloidoma (AL [lambda]-type) not amenable to resection resulted in stable symptoms and imaging at 18 months. ²⁴ The patient in that study was treated with fractionated radiation therapy to 30.6 Gy at 1.8 Gy per fraction. ²⁴ Both of our reported cases were treated with focal radiotherapy. The first case was treated elsewhere with single fraction stereotactic radiosurgery and, unfortunately, lost to follow-up. The second patient was treated with radiotherapy to the left side to 20 Gy and had stable symptoms with adequate pain control and imaging at 1 year follow-up. The optimal radiation dose is not well defined. When possible, tumor resection with preservation of the nerve seems to have the greatest opportunity for improvement in symptoms; however, when this is not achievable, radiotherapy may have a role in preventing symptom progression.

Conclusion

In summary, we report two cases of trigeminal amyloidoma with bilateral involvement. Upon review of the literature, resection without nerve compromise results in the best outcome when possible. When not possible, localized radiotherapy or radiosurgery may have a role, although the optimal dose has not been determined. No known recurrences have been reported, suggesting an indolent course with no association with systemic B-cell dyscrasia or systemic amyloidosis. Although rare, trigeminal amyloidomas should be considered in the differential diagnosis of trigeminal neuropathy with contrast-enhancing lesions on imaging. Identification of amyloid should prompt characterization, ideally by mass spectrometry to determine the subtype and etiology. If a light chain-type is detected, systemic amyloidosis should be excluded before diagnosing an amyloidoma.