Author’s Accepted Manuscript image

Diagnosis and Management of Solitary Laryngeal

Neurofibromas

Lili Zhang, Juan Jiang, Chengping Hu, Huaping Yang,

Pengbo Deng, Yuanyuan Li

www.elsevier.com/locate/bios

PII: S0002-9629(17)30679-1
DOI: https://doi.org/10.1016/j.amjms.2017.12.005
Reference: AMJMS583
To appear in: The American Journal of the Medical Sciences
Received date: 26 July 2017
Revised date: 15 December 2017
Accepted date: 18 December 2017
Cite this article as: Lili Zhang, Juan Jiang, Chengping Hu, Huaping Yang,
Pengbo Deng and Yuanyuan Li, Diagnosis and Management of Solitary
Laryngeal Neurofibromas, The American Journal of the Medical
Sciences,doi:10.1016/j.amjms.2017.12.005
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 Diagnosis and Management of Solitary Laryngeal Neurofibromas

Lili Zhang1,†, MD, Juan Jiang1,†, MD, Chengping Hu1, MD, Huaping Yang1, MD, Pengbo Deng1, MD

and Yuanyuan Li1, MD

1
Department of Respiratory & Critical Care Medicine, Xiangya Hospital, Central South University,

Changsha 410008, China

Correspondence to:

Yuanyuan Li, MD.

Department of Respiratory Medicine (Department of Respiratory and Critical Care Medicine), Key

Cite of National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South

University.

Email: leeround@csu.edu.cn

Tel: +86-139-7580-6790, Fax: +86-0731-85838261

Address: #87 Xiangya Rd., Kaifu District, Changsha City, Hunan Province, China

Short Title: Solitary Laryngeal Neurofibroma.

†
These authors equally contributed to this work.

All the authors declare no conflicts of interest.

This research was supported by the National Natural Science Foundation of China (81600025).

Key Indexing Terms: solitary neurofibroma; laryngeal neoplasm; asthma.

1
ABSTRACT

Solitary laryngeal neurofibromas are exceedingly rare with only 14 cases reported in the previous

literature. Herein, we reported a case of solitary laryngeal neurofibroma and reviewed all the

published cases of this disease on the clinical manifestations and management options. Patients

with solitary laryngeal neurofibromas can present with a variety of respiratory symptoms.

Immunohistochemical examination of tumor specimen is critical for pathological diagnosis and

complete surgical resection is the optimal therapy. Endoscopic microsurgeries followed by CO2

laser management of the surgical border may be effective on preventing recurrence. Depending

on the location, size and invasiveness of the lesions, the management and prognosis vary among

patients. Long-term follow-up is highlighted due to the possibility of recurrence during a long

period of time after surgery.

INTRODUCTION

Neurofibromas are benign tumors that originate from the peripheral nerve sheath and

predominantly present as solitary or multiple growths on the skin of the chest or abdomen.

Neurofibromas of the larynx are rare and account for only 0.1% of all benign laryngeal tumors[1].

Based on a review of the literature, less than 60 cases of laryngeal neurofibromas have been

published. Most previously reported cases are children with neurofibromatosis (also known as von

Recklinghausen disease)[2], predominantly presenting as multiple tumors. However, solitary

neurofibromas of the larynx are extremely rare, with only 14 cases reported previously in the

English-language literature. In this report, we describe a case of solitary laryngeal neurofibroma

diagnosed and treated at our hospital, and reviewed the related literature on management

options of this disease.

2
CASE PRESENTATION

A 26-year-old woman was admitted with a 5-month history of shortness of breath and

wheezing after exercise. She had no other symptoms (e.g., cough, expectoration, chest pain, chest

tightness or lower limb edema). She was diagnosed with “bronchial asthma” at the primary clinic

and prescribed conventional bronchodilators. Her condition was unchanged until March 14th, 2013

when she developed acute onset of severe respiratory distress after running up a set of stairs and

was sent to the Emergency Department of the local hospital. Cardiopulmonary resuscitation (CPR),

endotracheal intubation and assisted ventilation were performed, and her general condition

gradually improved. She was admitted to the Department of Respiratory Medicine on March 28th,

2013 for further diagnosis and treatment. Her physical examination showed only wheezing and

bilateral rhonchi during the expiratory phase. The patient was a non-smoker and her medical

history was otherwise unremarkable except for a history of occupational exposure to building

construction dusts for 3 years.

Routine parameters of blood, urine and stool were within normal ranges, erythrocyte

sedimentation rate was 42 mm/hour and tuberculosis antibody (TB-Ab) was negative in serum.

There was no abnormal sign on chest computed tomography images. Pulmonary function test

showed the inspiratory limb of the flow-volume loop was somewhat blunted while the expiratory

limb appeared to be normal (Figure 1), which indicated a variable extra-thoracic airflow

obstruction in this patient. The bronchial provocation test was negative. Flexible fiberoptic

bronchoscopy revealed a pedunculated mass with smooth surface in the supraglottic

interarytenoid region, which was movable to a certain extent; the trachea was normal (Figure 2).

3
 Under general anesthesia, endoscopic laryngeal microsurgery was performed on April 3 rd,

2013; a smooth white neoplasm above the glottis could be seen during surgery. The tumor, which

was tenacious and measured approximately 1.0×0.8×0.6 cm3, was totally removed.

Histopathological examination of the specimen revealed abundant collagen and spindle cells with

elongated nuclei. Immunohistochemistry examination showed that the specimen was positive for

S-100, Bcl-2 and CD34 (Figure 3). The patient was finally diagnosed as having a supraglottic

neurofibroma based on clinical manifestations, bronchoscopy examination and histology findings

from the surgical specimen.

The patient was completely relieved of shortness of breath after the surgery and there was no

postoperative complication. So far, the patient has been in routine follow-up without evidence of

recurrence or additional symptoms.

DISCUSSION AND LITERATURE REVIEW

We conducted a detailed search of the literature in English published before October 2017 in

MEDLINE and PubMed using search criteria “Neurofibroma” AND “larynx” and also manually

searched the cases in relevant references. We thoroughly read either the full texts or the abstracts

and finally included 15 cases of solitary laryngeal neurofibroma (including the present case) in this

review. Clinical information of these patients were retrospectively reviewed, including symptoms,

managements and outcomes. Recent research progresses on this rare disease were also included.

Solitary neurofibromas of the larynx have rarely been reported. Thus, it is necessary to define

the systemic clinical characteristics of this disease, which may help to improve its diagnosis and

management. In this study, we presented a case of solitary laryngeal neurofibroma diagnosed and

treated at our hospital and reviewed all previously published English case reports. A schematic of

4
the general information, clinical manifestation, management and outcomes of these cases is

shown in Table 1. Among the 15 patients with solitary laryngeal neurofibromas (including the

present case), the mean age was 27.1 years old (range from 2 to 78 years), which is considerably

older than that of other cases of neurofibromas that usually occur in the pediatric population and

are commonly associated with neurofibromatosis[3]. The male to female ratio was 4:3, which is

similar to previous reports[4]. However, the literature review by Hisa et al.[5] of Japanese patients

showed that 9 in 10 laryngeal neurofibroma cases were males; this discrepancy might be caused

by ethnicity-based variation. Neurofibromas grow rather slowly, thus patients may be

asymptomatic for years. Symptoms depend on tumor size and location. As shown in Table 1,

patients with solitary laryngeal neurofibromas presented with stridor, hoarseness, wheezing,

snoring, cough or acute respiratory distress, which could be easily misdiagnosed as respiratory

diseases. Among all the cases, the tumor locations included the supraglottic region (7 cases),

subglottic region (5 cases) and vocal cord (3 cases). It has been proposed that neurofibromas arise

from the terminal branch of the superior laryngeal nerve in the submucosal space when located in

subglottis[6, 7] and from the internal branch of the recurrent laryngeal nerve when located in the

supraglottic region[8].

Laryngeal neurofibromas are often associated with neurofibromatosis caused by the biallelic

inactivation of NF1 gene, which is characterized by cafe-au-lait spots. But the etiology of sporadic

laryngeal neurofibromas has remained unknown so far. In the present case, a history of

occupational exposure to building construction dusts for 3 years was noted, indicating that

irritative substances like inorganic dusts might be associated with solitary laryngeal neurofibromas.

Neurofibromas are divided into plexiform and non-plexiform neurofibromas. Plexiform

neurofibromas are highly invasive and can involve nerve bundles, thus complete surgical removal

5
is difficult[5, 9, 10]
. In this series of patients, only 2 case were demonstrated to be plexiform

neurofibromas[11]. In contrast, non-plexiform neurofibromas behave as a discrete and well-defined

lesion that are amenable to complete surgical excision[12].

Detailed history and physical examination are important steps for the diagnostic work-up of

laryngeal neurofibromas. Direct laryngoscopy, bronchoscopy, neck computed tomography and

magnetic resonance imaging are useful diagnostic tools[13]. Preoperative biopsy is not

recommended due to the submucosal location, firm capsule and high risk of bleeding. Holinger

and Cohen[14] reported excessive bleeding in a case of laryngeal neurofibroma after endoscopic

biopsy. A positive immunohistochemical staining for S-100 protein is helpful to confirm the

diagnosis of neurogenic tumors[15].

Surgery is the optimal therapy for patients with solitary laryngeal neurofibromas. Complete

excision is the key to successful treatment, especially in plexiform neurofibromas with infiltrative

growth pattern, and extended resections should be performed if necessary[2, 5, 8]. Postoperative

complications include hemorrhage, scarring laryngeal stenosis, vocal cord paralysis and

postoperative pulmonary edema[2]. There are several alternative surgical approaches for patients

depending on tumor locations, sizes and subtypes. In this series, laryngeal lesions in most cases

were small-sized tumors with diameters less than 2 cm and could be removed by transoral

endoscopic microsurgery. In contrast, open surgery was also used in several previous cases, as it

provided a better field of vision for complete removal of the mass [2, 8, 16, 17]
; although, this

approach is associated with greater surgical trauma and complications. Apart from open surgery

and conventional microsurgery, CO2 laser has been widely used as a result of a number of

advantages, including high precision, short operation time, fast postoperative recovery and, most

importantly, reduced risk for recurrence due to additional effects of the laser[18]. However, for

6
small-sized tumors, tumor cell nuclei can be easily destroyed by the heat of the laser, making it

difficult to differentiate between benign and malignant lesions[19]. Therefore, we hypothesize that

the best therapeutic strategy for small-sized solitary laryngeal neurofibromas may be

microsurgeries using transoral endoscopy followed by CO2 laser management of the surgical

border, which requires more clinical-based supportive evidence. There is little evidence regarding

the efficacy of systemic chemotherapy or radiotherapy. For benign and slow-growing

neurofibromas, adjuvant radiotherapy and chemotherapy are generally not used due to their

adverse effects.

Postoperative follow-up laryngoscopes are necessary in solitary laryngeal neurofibroma.

Recurrence after complete excision is rare and usually occurs months to years later [20]. Only 2

patients with local recurrence after surgery were identified in this review[17, 19]. However, patients

in this series were only followed for an average of 26.8 months; therefore, it is possible that the

low recurrence rate is caused by the relatively short follow-up period. The risk of late recurrence

emphasizes the importance of long-term follow-up for patients with laryngeal neurofibromas,

particularly because local recurrences seem to carry a higher mortality risk than metastases in

solitary neurofibromas. Meanwhile, subcutaneous neurofibromas, cafe-au-lait spots and

suspected lesions in fundus oculi should be carefully checked during follow-up, as positive results

would suggest the disease has progressed into neurofibromatosis[21]. A second operation should

be performed once recurrence is confirmed.

7
CONCLUSIONS

Solitary laryngeal neurofibromas are rarely reported and easily misdiagnosed with respiratory

diseases. Definite diagnosis relies on histopathological and immunohistochemical examination,

especially on positive S-100 staining. Surgical removal of tumors is the optimal treatment of choice

for neurofibromas. Microsurgeries using transoral endoscopy followed by CO 2 laser management

of the surgical border may be effective to prevent recurrence. Long-term follow-up is

recommended, given that recurrence could develop even several years after surgery.

REFERENCES

[1] Yoshida T, Kuratomi K, Mitsumasu T. Benign neoplasms of the larynx. A 10-year review of
38 patients. Auris Nasus Larynx 1983;10 Suppl:S61-71.

[2] Masip MJ, Esteban E, Alberto C, et al. Laryngeal involvement in pediatric

neurofibromatosis: a case report and review of the literature. Pediatr Radiol 1996;26(7):488-92.

[3] Stanley RJ, Scheithauer BW, Weiland LH, et al. Neural and neuroendocrine tumors of the
larynx. Ann Otol Rhinol Laryngol 1987;96(6):630-8.

[4] Supance JS, Quenelle DJ, Crissman J. Endolaryngeal neurofibromas. Otolaryngology and
head and neck surgery 1980;88(1):74-8.

[5] Hisa Y, Tatemoto K, DeJima K, et al. Laser vestibulectomy for endolaryngeal neurofibroma.
Otolaryngol Head Neck Surg 1995;113(4):459-61.

[6] Maisel RH, Ogura JH. Neurofibromatosis with laryngeal involvement. Laryngoscope
1974;84(1):132-40.

[7] Jafek BW, Stern FA. Neurofibroma of the larynx occurring with Von Recklinghausen disease.
Report of a case. Arch Otolaryngol 1973;98(2):77-9.

[8] Fukuda I, Ogasawara H, Kumoi T, et al. Subglottic neurofibroma in a child. Int J Pediatr
Otorhinolaryngol 1987;14(2-3):161-70.

[9] Pulli RS, Coniglio JU. Subglottic nerve sheath tumor in a pediatric patient: case report and
literature review. Head Neck 1997;19(5):440-4.

[10] Martin DS, Stith J, Awwad EE, et al. MR in neurofibromatosis of the larynx. AJNR Am J
Neuroradiol 1995;16(3):503-6.

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[11] Ejnell H, Jarund M, Bailey M, et al. Airway obstruction in children due to plexiform
neurofibroma of the larynx. J Laryngol Otol 1996;110(11):1065-68.

[12] Greinwald J, Derkay CS, Schechter GL. Management of massive head and neck
neurofibromas in children. Am J Otolaryngol 1996;17(2):136-42.

[13] Yucel EA, Guldiken Y, Ozdemir M, et al. Plexiform neurofibroma of the larynx in a child. J
Laryngol Otol 2002;116(1):49-51.

[14] Holinger PH, Cohen LL. Neurofibromatosis (von Reckling-hause's disease) with involvement
of the larynx. Report of a case. Laryngoscope 1950;60:193-6.

[15] Puri R, Berry S, Srivastava G. Solitary neurofibroma of the larynx. Otolaryngol Head Neck
Surg 1997;117(6):713-4.

[16] Bagwell CE. CO2 laser excision of pediatric airway lesions. J Pediatr Surg 1990;25(11):1152-
6.

[17] Gstottner M, Galvan O, Gschwendtner A, et al. Solitary subglottic neurofibroma: a report

of an unusual manifestation. Eur Arch Otorhinolaryngol 2005;262(9):705-7.

[18] Moussali N, Belmoukari S, Elmahfoudi H, et al. [An uncommon cause of dyspnea in

children. Plexiform neurofibroma of the larynx]. Arch Pediatr 2013;20(6):629-32.

[19] Supance JS, Quenelle DJ, Crissman J. Endolaryngeal neurofibroma. Otolaryngol Head Neck
Surg 1980;88:74-8.

[20] Liu J, Wong CF, Lim F, et al. Glottic Neurofibroma in an Elderly Patient: A Case Report. J
Voice 2013;27(5):644-6.

[21] Chen YW, Fang TJ, Li HY. A solitary laryngeal neurofibroma ina pediatric patient. Chang
Gung Med J 2004;27(12):930-3.

[22] Chinn SB, Collar RM, McHugh JB, et al. Pediatric laryngeal neurofibroma: Case report and
review of the literature. Int J Pediatr Otorhi 2014;78(1):142-7.

[23] Setabutr D, Perez MR, Truong MT, et al. Neurofibromatosis of the larynx causing stridor
and sleep apnea. Am J Otolaryng 2014;35(5):631-5.

[24] Son HY, Shim HS, Kim JP, et al. Synchronous plexiform neurofibroma in the arytenoids and
neurofibroma in the parapharynx in a patient with non-neurofibromatosis: a case report. J Med
Case Rep 2013;7:15-20.

[25] Nakahira M, Nakatani H, Sawada S, et al. Neurofibroma of the Larynx in

Neurofibromatosis. Arch Otolaryngol Head Neck Surg 2001;127(3):325-8.

[26] Tanaka H, Patel U, Coniglio JU, et al. Solitary subglottic neurofibroma: MR findings. AJNR
Am J Neuroradiol 1997;18(9):1726-8.

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[27] Fisher GE, Odess JS. Solitary neurofibroma of the larynx; report of two cases. Laryngoscope
1949;59(12):1345-9.

FIGURE LEGENDS

FIGURE 1. Pulmonary function test. The flow-volume loop shows a blunted inspiratory limb (red

arrow).

FIGURE 2. Preoperative bronchoscopy. Left, a pedunculated lesion with smooth surface is located

in supraglottic interarytenoid region (black arrow). Right, the trachea is normal.

FIGURE 3. Histological and immunohistochemical examinations of surgical specimen. A,

hematoxylin and eosin staining shows the tumor cell nuclei are generally elongated and abundant

collagen is produced. B, C and D, spindle cells are stained positive with S-100, Bcl-2 and CD34 in

immunohistochemistry, respectively.

10
11
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13
 Table 1. Clinical information of cases included in this study
Time to Characteri- Follow- Tumor
Year First Author Pt. Symptoms Location Size (cm) Treatment Status SC
dx (m) stic up time size (ml)
present shortness of breath,
2017 26F 6 SpG 0.6×0.8×1.0 Encap Endos MicroS NR NA 50 0.48
case wheezing
[22] CO2 laser,
2014 Chinn 8M asymptomatic 0 SpG UR Uncap NR NA 18 UR
Endos MicroS
CO2 laser,
2014 Setabutr[23] 2M stridor, sleep apnea UR UR Uncap NR NA 12 UR
aryepiglottic Endos MicroS
[24] Respiratory left left vocal
2013 Son 56F UR 2.0×1.3 Uncap CO2 laser NR 24 UR
distress, sleep arytenoids cord
[20] hoarseness, right vocal
2013 Liu 78M 1 0.8×0.6 Encap Endos MicroS NR NA 6 0.21
odynophagia fold
[17
Gstottner CO2 laser, R after
2005 ] 35M exertional dyspnea 6 SbG 1.8×1.5×2.0 Encap NA 60 4.8
Endos MicroS 4y
[21] CO2 laser,
2004 Chen 4F stridor 24 SpG 2×2 Encap NR NA 48 6
Endos MicroS
Nd-YAG laser,
2001 Nakahira[25] 44M abnormal sensation 3 3.5×2.0×1.5 Encap NR NA 12 UR
aryepiglottic Endos MicroS
biopsy,
1997 Tanaka[26] 12F stridor 2 SbG 1.2×0.7 Uncap NR NA UR 0.84
CO2 laser
[9]
1997 Pulli 12F wheezing, dyspnea 2 SbG 0.8×0.5×1.2 Encap CO2 laser NR NA 5 0.48
snoring, lateral
[11]
1996 Ejnell 7 obstructive sleep 7 SbG 3.0×2.0×1.0 Uncap pharyngotomy, NR NA 24 6
apnea peroperative
[5]
1995 Hisa 23F hoarseness 1 SpG 1.5×1.1×0.9 Encap CO2 laser vestibulectomy NR NA 24 1.5

[8]
1987 Fukuda 2.5M stridor 2 SbG 2.0×1.0×0.7 Encap Open S NR NA 24 2.1

[27] cup-type laryngeal

peduncul-
1949 Fisher 75M dyspnea, cough 180 SpG 0.4×0.5×0.6 NR NA 60 0.12
ated forceps
hoarseness, dry cup-type laryngeal
1949 Fisher[27] 23M 1 SpG 0.7×0.3 Uncap NR NA 7 0.1
cough forceps
Abbreviations: SN, serial number; Pt, patient; dx, diagnosis; M, male; F, female; UR, unrecorded; R, recurrence; NR, no recurrence; NA, no surgery
complication; S, surgery; MicroS, microsurgery; EndoS, Endoscopic; SC; surgery complications; Encap, encapsuled; Uncap, uncapsuled; SpG, supraglottic; SbG,