Solitary neurofibroma of the larynx: a diagnostic challenge

Abstract

Solitary neurofibromas of the larynx are extremely rare, with a total of 15 cases described in the literature. Nonetheless, acquaintance with this diagnosis is important, as misdiagnoses can have negative consequences. Presenting symptoms are non-specific and depend on tumour size and location. As well-defined submucosal masses with a broad differential diagnosis, they remain a clinical and radiological challenge. While some characteristics might favour a benign nature and subtle signs might help narrow the differential diagnosis, imaging alone is not sufficient for differentiation and definitive diagnosis requires a biopsy. Complete surgical resection and long-term follow-up is indicated. We share our experience on a case of a solitary laryngeal neurofibroma in a middle-aged woman, presenting with a large well-defined paraglottic lesion.

Background

Neurogenic tumours of the larynx, specifically neurofibromas and schwannomas, are extremely rare, accounting for less than 1% of all benign laryngeal tumours.¹ Laryngeal neurofibromas occur less frequently than schwannomas and are seen in younger patients, especially when associated with neurofibromatosis.^1–3 Little information exists about these tumours in the larynx, most of which is derived from a few existing case reports.^4–15 However, acquaintance with this diagnosis is important, as misdiagnoses can have negative consequences.

Case presentation

A 54-year-old woman was referred to our hospital for investigation of a large supraglottic mass, identified during the workup of longstanding symptoms of progressive dysphonia, dysphagia, globus sensation and, more recently, increasing dyspnoea, which motivated an urgent tracheostomy. Her medical history was relevant for HIV infection, medicated with abacavir/lamivudine/dolutegravir, with low viral load and no history of opportunistic infections; acromegaly in the context of a pituitary tumour, submitted to surgery and radiotherapy 30 years ago (unknown histopathologic diagnosis) and asthma.

Investigations

Laboratory findings revealed negative infectious/inflammatory parameters. HIV1 viral load was <50 copies/mL and neutrophil count was normal. Physical examination found no palpable lymph nodes. Cutaneous and mucosal lesions or other stigmata suggestive of neurofibromatosis were also absent.

Flexible laryngoscopy revealed a large, pale, submucosal mass occupying the whole laryngeal vestibule, apparently originating from the laryngeal surface of the epiglottis and right aryepiglottic fold, precluding the assessment of vocal cord mobility. Imaging was required to better assess the lesion extent and to aid in the differential diagnosis.

Ultrasonography of the neck (figure 1) showed a solid hypoechoic mass with moderate vascularisation on colour Doppler evaluation and with a low resistance capillary pattern.

Figure 1.

Ultrasonography of the neck shows a solid hypoechoic mass with little posterior acoustic enhancement. Colour Doppler evaluation shows moderate central and peripheral vascularisation.

Contrast-enhanced CT scan and MRI of the neck exhibited a large, well-defined, submucosal lesion in the right paraglottic space, causing expansile remodelling of the adjacent structures and collapsing of the supraglottic laryngeal airway. On CT scan (figure 2), a cystic-like appearance with nodular areas of faint heterogeneous contrast enhancement was seen. MRI (figure 3) revealed a heterogeneous T2-weighted (T2W) hyperintense lesion, with multiple ring-like hypointensities and several central areas of nodular and ‘target-like’ enhancement.

Figure 2.

Contrast-enhanced CT scan of the neck: Axial plane reconstructions in soft tissue (A) and bone (B) windows show a large well-defined submucosal lesion in the right paraglottic space, with an overall cystic-like appearance and intralesional nodular areas of faint contrast enhancement (white arrows). Note the remodelling of the right thyroid laminae (dotted arrow) and arytenoid cartilage (short arrow), as well as the enlargement of the thyroarytenoid space (asterixis), with vocal cord fixation.

Figure 3.

MRI of the larynx: (A) Axial T1W, (B) T2W, (C) CE FS (contrast-enhanced fat-suppressed) T1W, (D) sagittal and (E) coronal T2W images. The lesion is hypointense on T1W, heterogeneously hyperintense on T2W, with multiple intralesional ring-like hypointensities (fascicular sign) (arrows in D), central areas of nodular and ‘target-like’ enhancement (dotted arrows in C), as well as thin peripheral linear enhancement. The coronal image (E) nicely shows the paraglottic location and the remodelling of the right thyroid lamina (arrows). T1W, T1 weighted; T2W, T2 weighted.

The patient underwent endoscopic biopsy, which showed a spindle cell mesenchymal tumour with positive S100 antibody staining, compatible with a neurofibroma, along with focal hypercellular regions, that could fall under the category of a schwannoma.

Differential diagnosis

A submucosal laryngeal mass poses a clinical and radiological challenge. It has a broad differential diagnosis, from fairly common malignant lesions such as squamous cell carcinoma to rare benign tumours. In our case, the regular contours of the lesion, smooth remodelling of adjacent structures and lack of locally aggressive features and regional lymphadenopathy favour a benign nature. Nonetheless, imaging characteristics alone are insufficient for such a differentiation and a biopsy is mandatory for the diagnosis.

Benign submucosal laryngeal lesions comprise degenerative/acquired lesions, infectious/inflammatory conditions and rare deposition diseases such as amyloidosis and a wide range of benign tumours, most of which are found in the supraglottic larynx.^{16 17} Besides isolated papilloma and papillomatosis, often related to HPV (human papilloma virus) infection, and lymphovascular lesions, other benign submucosal laryngeal tumours are quite rare and include neurogenic/nerve sheath tumours, solitary fibrous tumour, paraganglioma, chondroma, lipoma, rhabdomyoma and leiomyoma.

Imaging, although usually non-specific, can occasionally make or suggest the diagnosis. This is the case with lipomas, due to their inherent CT density and MR signal intensity following that of fat;^{18 19} non-complicated cystic lesions, which follow the density/signal intensity of fluid, with no contrast enhancement;^{19 20} chondroid tumours, which show the typical ‘ring and arcs’ or ‘amorphous, popcorn-like’ chondroid calcifications^{19 21–23} and vascular tumours/malformations, which show typical patterns of contrast enhancement on CT or MR perfusion studies.^{22 24 25} Dynamic contrast-enhanced MR or CT perfusion studies can nicely show the late time to peak and the slow washout of slow-flow vascular malformations, as well as the arterial-like enhancement of hypervascular lesions, such as paragangliomas.²⁶

In our case, the cystic-like appearance of the lesion on CT scan could have been mistaken for a fluid-filled laryngocele, but the enhancing pattern on the MR study excluded this possibility. While highly suggestive of a benign slow-growing tumour, the imaging features were not specific for any of the above-mentioned diagnoses. However, the lesion was noticeable for the presence of multiple T2W hypointense ring-like structures within the T2-hyperintense background of the tumour, featuring the fascicular sign, often present in neurogenic tumours.²⁷

As a definite diagnosis could not be made based on clinical and imaging findings alone, a biopsy was performed, disclosing a neurogenic tumour.

Treatment

After discussing the different treatment options with the patient, it was decided to perform a laryngoscopy-guided laser resection and postpone open partial laryngectomy for recurrent residual disease when needed. The patient underwent suspension microlaryngoscopy with visualisation of a large pedunculated lesion in the right lateral laryngeal wall, aryepiglottic fold, pyriform sinus and posterolateral pharyngeal wall. ‘Total’ piecemeal resection of the lesion was performed.

Histopathologic evaluation (figure 4) confirmed a loosely arranged spindle cell tumour with a collagenous stroma, composed by cells with wavy ovoid and comma-shaped nuclei. Immunohistochemical analysis showed positive staining for SOX10 (SRY-related HMG box family of transcription factors) and S100. The final pathologic diagnosis was a solitary neurofibroma.

Figure 4.

(A) Macroscopic specimen from a piece meal laryngoscopic resection. Microscopic slides stained with H&E (B) low, (C) medium and (D) high-power magnifications show a loosely arranged mesenchymal spindle cell tumour with a collagenous stroma, composed by cells with wavy ovoid and comma-shaped nuclei. Immunohistochemical analysis showed positive staining for SOX 10 (E) and S100 (not shown).

Outcome and follow-up

The tracheostomy tube was removed 3 weeks after surgery. At 1-month follow-up, laryngoscopy (video 1) showed normal airway patency, a slight mucosal bulge at the level of the arytenoid cartilage and false vocal cord and paralysis of the right hemilarynx. The 2-month follow-up MRI (figure 5) revealed a rounded submucosal area of low T2W signal intensity with faint contrast enhancement, most likely corresponding to a tumour residue. In spite of her vocal cord paralysis, the patient has a functional voice and she denies dysphagia, aspiration or dyspnoea. A watchful waiting is under course with a close clinical and quarterly imaging follow-up.

Video 1.

Download video file ^{(2.4MB, mp4)}

DOI: 10.1136/bcr-2020-236682.video01

Figure 5.

Follow-up MRI of the neck 2 months after surgery: (A) Axial T1W, (B) FS (fat-suppressed) T2W and (C) FS CE (fat-suppressed contrast-enhanced) T1W images show thickening of the right aryepiglottic fold with vivid contrast uptake (arrows) and a rounded submucosal area of low T2W signal intensity with faint contrast enhancement at the thyroarytenoid space (dotted arrows in B and C), most likely corresponding to tumour residue. T1W, T1 weighted; T2W, T2 weighted.

Discussion

Neurogenic tumours of the larynx are extremely rare. As elsewhere, they comprise neurofibromas, schwannomas and malignant peripheral nerve sheath tumours (MPNST). They are most often seen in the setting of neurofibromatosis type 1 (NF1) (82% in a paediatric series), followed by NF2 and, finally, isolated solitary tumours.¹⁵ A recent review of the literature found less than 60 cases of laryngeal neurofibromas and only 15 cases with no phakomatosis association.⁶ Therefore, exclusion of neurofibromatosis is mandatory in these patients.

Presenting symptoms are non-specific and depend on tumour size, location and pace of growth. The most common are (in decreasing order): dysphonia, dysphagia, globus sensation, odynophagia, stridor, dyspnoea and a lateral neck lump.^{28 29} Small lesions can be asymptomatic and found incidentally.

On laryngoscopy, neurofibromas present as sessile or pedunculated mucosal bulges impinging on the airway. The most common location is the aryepiglottic fold, followed by the arytenoid, ventricular fold and true vocal cord, accounting for the tumour origin from the terminal plexus of the superior laryngeal nerve.^{3 28} Tumours posteriorly located in the interarytenoid region originate from branches of the recurrent laryngeal nerve (RLN).

Distinguishing the different types of neurogenic tumours is clinically relevant, with implications for patient’s management and prognosis. MPNST require a wide resection and adjuvant radiation therapy and carry a worse prognosis, with higher locoregional recurrence rates and distant metastases, particularly to the lung and bone.³⁰ Around 50% of these tumours occur in the setting of NF1 and may be primary or secondary to the malignant transformation of a neurofibroma.³¹ Compared with schwannomas, neurofibromas have a higher risk of recurrence and of malignant transformation, which is even higher in patients with NF1 (5%–10%).^{3 29}

A longstanding history of progressive symptoms and imaging features of a slowly growing process favour a benign nerve sheath tumour, whereas an acute symptom onset, aggressive imaging features and the presence of lymphadenopathy suggest malignancy. Malignancy can be further corroborated by the presence of restricted diffusion on diffusion-weighted MRI and hypermetabolism on ¹⁸FDG-PET-CT. The presence of a large T2W hyperintense rim, reflecting oedema or infiltration of surrounding tissues, solid peripheral enhancement and intratumoral necrosis, together with a tumour dimension above 4 cm, also suggest malignant degeneration and can discriminate neurofibromas from MPNST with a 61% sensitivity and a 90% specificity.³²

Preoperative distinction between schwannoma and neurofibroma is much less reliable, since their clinical and imaging features overlap: well-defined lesions, isointense to hypointense on T1-weighted (T1W) sequences and hyperintense on T2W sequences, with gadolinium enhancement.¹⁹ Several imaging signs have been investigated in their ability to discriminate neurofibromas from schwannomas, including: distribution along the major nerve axis, the entering and exiting nerve sign, the target sign, the fascicular sign, the T2W hyperintense rim sign and the presence of intratumoral cysts.²⁷ Whereas neurofibromas tend to grow concentrically along the fibres of the parent nerve, schwannomas grow eccentrically. This bears practical importance to the surgeon, as neurofibroma excision often requires sacrifice of the parent nerve.¹ Although both tumour types can show a target sign (central area with low signal intensity on T2W and intense contrast enhancement on postgadolinium T1W images, surrounded by a peripheral rim of T2W hyperintensity with little contrast enhancement), it is more commonly seen in neurofibromas. On histology, it correlates with the tumour arrangement in fascicular bundles with a central fibro-collagenous core surrounded by myxomatous tissue. In schwannomas, the histological correlate of this sign is a core of hypercellular tissue composed of spindle cells (Antoni A-type tissue), surrounded by myxoid hypocellular stroma (Antoni B-type tissue). On the other hand, intratumoral cysts and the T2W hyperintense rim sign (consisting of compressed neighbouring tissue) are more commonly seen in schwannomas compared with neurofibromas.²⁷

Not uncommonly, endoscopic biopsies are insufficient for diagnosis due to error sampling of peritumoral inflammatory tissue, potentially delaying the diagnosis and treatment.

On histopathology, neurofibromas are non-encapsulated WHO grade I tumours originating from perineural fibrocytes, composed by spindle Schwann cells entangled with axons and collagen fibres, differing from schwannomas, which grow extrinsically to nerve bundles.³³ According to their growth pattern, they are classified into: solitary—a single well-delineated mass; diffuse—a diffusely infiltrating lesion and plexiform—reflecting a poorly localised infiltrative growth, often extending into surrounding tissues and resembling a ‘bag or worms’. The latter is almost exclusively seen in patients with NF1 and carries the highest risk of malignant degeneration (5%-10%).³³ Malignant transformation in non-plexiform neurofibromas is negligible. Microscopically, neurofibromas are further classified into benign, atypical or malignant (MPNST) according to their cellularity, mitotic count, presence of necrosis and cellular pleomorphism.

On immunohistochemical analysis, both neurofibromas and schwannomas show positivity for S100, SOX 10, CD34 and GFAP. Whereas schwannomas only show peripheral staining with neurofilament, neurofibromas show internal staining of the entrapped axons within the lesion.³³

Surgical excision is the treatment of choice in laryngeal neurofibromas. Endoscopic surgery is associated with a better functional result and lower incidence of RLN palsy but carries a higher recurrence rate. Open surgery (via lateral thyrotomy, lateral pharyngotomy or laryngofissure) affords a lower recurrence rate but at the risk of worse functional outcome, with a higher rate of RLN palsy. For small tumours, minimally invasive endoscopic procedures (endoscopic laser excision) are preferred to preserve laryngeal function. Larger tumours can be managed either by a conservative approach, if the patient is paucisymptomatic, or a partial endoscopic resection followed by close follow-up or open surgery. Currently, subtotal resection with repeated endoscopic laser excision to control residual disease has been preferred, in an attempt to better preserve laryngeal function and to avoid surgical complications, such as scarring, vocal cord paralysis and aspiration. These treatment options should be thoroughly discussed with the patient, as the risk for recurrence is not negligible. For the same reason, long term follow-up is recommended.

Postoperatively, it may be difficult to distinguish residual tumour from granulation scar tissue, both on clinical and imaging grounds. A postoperative baseline imaging study, using the same technique, should be obtained to facilitate the interpretation of further follow-up studies.

In our case, a conservative endoscopic approach was decided with a close follow-up of the residual disease.

Learning points.

• Submucosal laryngeal masses have a broad differential diagnosis and remain a clinical and radiological challenge.

• While some characteristics might favour a benign nature, clinical and imaging findings alone are not specific and a definitive diagnosis requires histopathology.

• Although extremely rare in this location, neurogenic tumours should be considered in the presence of a well-defined laryngeal submucosal lesion.

• Complete surgical resection is the treatment of choice and, when not achieved, long-term follow-up of residual disease is indicated.