American Journal of Otolaryngology–Head and Neck Medicine and Surgery 42 (2021) 102766

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American Journal of Otolaryngology–Head and Neck

Medicine and Surgery
journal homepage: www.elsevier.com/locate/amjoto

Comparison of PPI and combined treatment in the treatment of recurrent

laryngeal contact granuloma
Qian Nie a, b, Jinrang Li a, b, *, **, Shizhen Zou b, Ran Zhang b
a
Anhui Medical University, Hefei, China
b
Department of Otorhinolaryngology Head and Neck Surgery, The Sixth Medical Center of PLA General Hospital, Beijing, China

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To compare the therapeutic effect of PPI and combined treatment in the treatment of patients with
Laryngeal contact granuloma recurrent laryngeal contact granuloma.
Treatment Methods: The clinical data of 299 patients with recurrent laryngeal contact granuloma treated with PPI or
PPI
combined treatment (PPI with glucocorticoid injection into granuloma by the thyroglossal approach) from
Therapeutic effect
February 2013 to June 2019 were analyzed retrospectively. Patients were divided into two subgroups: PPI and
combined treatment. The cure rates, recurrence rates and cure time of the two subgroups were compared and
analyzed separately. Than we can get the optimal treatment of the two treatment in the treatment of recurrent
patients.
Results: In recurrent patients, the cure rate (81.20%) and recurrence rate (3%) of combined treatment were
superior to those of PPI (57.58%) and recurrence rate (12.12%); (P < 0.05). The cure time of PPI was longer than
that of combination therapy (P < 0.001).
Conclusion: The therapeutic effect of combined treatment is better than that of PPI in patients with recurrence. At
the same time, combined treatment is an effective treatment for recurrent granuloma and can be used as a first-
line treatment for recurrent laryngeal contact granuloma.

1. Introduction Aerosol inhalation of triamcinolone acetonide or other hormones has

Selection of treatment for recurrent laryngeal contact granuloma has
been a hot topic for doctors. Patients have significantly decreased
sensitivity to treatment. Regardless of choice of treatment, the thera­
peutic effect was worse than patients treated with initial treatment
[1,2]. For recurrent granuloma, existing treatments include oral PPI;
repeated surgery; surgical treatment combined with botulinum toxin
injection; surgical treatment combined with low dose radiotherapy;
botulinum toxin injection alone etc. [3–6]. Although these treatments
have satisfactory therapeutic effects, most patients suffer from severe
trauma or larger side effects during these treatment, so although the
therapeutic effects were better, clinical applicability were poor. If bot­
ulinum toxin causes loss of voice for at least 3 months, radiation injury
to body etc. Oral PPI had no trauma and less side effects. However, the
therapeutic cycle of oral PPI for recurrent granuloma were significantly
longer than that in patients with initial treatment [2]. The treatment
time of PPI is too long limiting PPI utilization in recurrent patients.
been proved to be superior to PPI in the treatment of laryngeal contact
granuloma [7]. However, long-term aerosol inhalation of corticosteroids
can lead to side effects of fungal infection in the patient’s oral cavity.
Therefore, the application of this treatment is limited. Intraregional
hormone injection ensures local action of hormone while also ensures no
side effects caused by extensive inhalation, so the clinical applicability is
high, which also can be proved by our previous and other research [8,9].
However, there is no study concerned about the therapeutic effect of
combined treatment in recurrent patients. We retrospectively analyzed
our data and compared the two treatments, eventually getting the
optimal treatment for recurrent patients.
2. Materials and methods
2.1. Patient information
From February 2013 to June 2019, 341 patients with recurrence

* Corresponding author at: Anhui Medical University, 230032 Hefei, China.

** Corresponding author at: Department of Otorhinolaryngology Head and Neck Surgery, The Sixth Medical Center of PLA General Hospital, 100048 Beijing, China.
E-mail address: entljr@sina.com (J. Li).

https://doi.org/10.1016/j.amjoto.2020.102766
Received 10 October 2020;
Available online 22 October 2020
0196-0709/© 2020 Elsevier Inc. All rights reserved.
Q. Nie et al. American Journal of Otolaryngology–Head and Neck Medicine and Surgery 42 (2021) 102766

were diagnosed and treated in the sixth Medical Center of PLA General
Hospital, thirty-two patients lost follow-up. There were 309 cases with
complete data. Inclusion criteria: 1). Diagnosed as laryngeal contact
granuloma (pathological or laryngoscopy); 2). Patients voluntarily
choose treatment and agree to follow-up; 3). There is no contraindica­
tion of the chosen treatment in patients. Exclusion criteria: 1). Granu­
loma after intubation. 2). Large granuloma affect breathing. According
to this standard, 299 patients were selected: conservative treatment: 33
cases: among them 19 cases recurred after surgical treatment; 11 cases
recurred after PPI; 3 cases recurred after voice therapy. And 6 cases
underwent 2 surgeries before treatment; 13 patients underwent 1 sur­
gery and 32 patients undergoing PPI during treatment. combined
treatment: 266 patients: Among them 176 cases recurred after surgical
treatment; 86 recurred after PPI; 4 cases recurred after voice therapy. 3
patients underwent 4 surgeries before treatment; 15 cases underwent 3
surgeries; 53 cases underwent 2 surgeries; 105 cases underwent 1 sur­
gery; and 152 cases undergoing PPI during treatment procedure. We
collected larynx CT of 126 recurred patients among 299 patients (the
rest of the patients did not have larynx CT or the CT results were lost),
and 118 cases of calcification on the lesion side of arytenoid cartilage
(93.65%). The study design has been approved by the Institutional Re­
view Board of The Sixth Medical Center of PLA General Hospital. The
demographic information of patients can be found in Table 1.
2.2. Grouping
neck fully, and one doctor exposed the laryngeal cavity with a
transnasal electronic laryngoscope. Another doctor bent the needle
with triamcinolone acetonide syringe to about 45◦ , pierced back and
downward along the superior notch of thyroid cartilage, approach­
ing the lesion of vocal cord gradually. Injection of triamcinolone
acetonide into the base and interior of granuloma under electronic
laryngoscope. The patient was examined again and triamcinolone
acetonide was injected again if laryngoscope showed that the
laryngeal contact granuloma did not disappear.
2.5. Efficacy evaluation and follow-up
The laryngoscope pictures reexamined every month were compared
with the laryngoscope pictures of the first month and the previous
month, and the size changes of laryngeal contact granuloma were
compared by Image software. Cure: the granuloma disappeared
completely, and there was no recurrence within follow-up period; Sig­
nificant effect: the lesion is reduced by more than 50%, effective: the
lesion volume is reduced by 20% - 50%, ineffective: the lesion is reduced
by less than 20% or increased. In the process of combined treatment and
conservative treatment, the granuloma stopped shrinking or enlarged
for more than 3 months. Recurrence: during the follow-up after cure, the
vocal cord granuloma recurred. The follow-up time of all cases was
12–21 months, and the median follow-up time was 16 months. The
comparison of patients before and after treatment can be seen in Fig. 1.

We divided patients into two subgroups: PPI and combined treat­
ment respectively. We analyzed the cure rate, recurrence rates and cure
time of two subgroups, and the optimal treatment for treating recurrent
laryngeal contact granuloma of the two treatment can be find out.
2.3. Statistical analysis
SPSS16.0 was used for all statistical analysis. For variables, Mann-
Whitney test and Fisher’s Exact test was performed.
We divided patients into two subgroups: PPI and combined treat­
ment, than we analyzed the cure rate, recurrence rates and cure time
between the PPI treatment and the combination treatment group
respectively (a = 0.05).
2.4. Treatment
3. Results
In recurrent patients, the cure rate (81.20%; 216/266) and recur­
rence rate (3%; 8/266) of combined treatment were superior to those of
PPI (57.58%; 19/33) and recurrence rate (12.12%; 4/33); (P < 0.05).
The details of the statistical results are shown in Table 2. The cure time
of PPI (6.79 ± 1.36) was longer than that of combination therapy (4.32
± 1.39) (P < 0.001). Of the 4 patients with recurrence after PPI was
cured, 1 case disappeared during follow-up, 3 cases received combined
treatment, all were cured, there was no recurrence at the last follow-up,
and the minimum follow-up time for 3 cases was 12 months. Among the
8 patients with recurrence after combined treatment, all of them were
treated with combined treatment, 2 cases lost follow-up during the
treatment. 6 cases were cured again, and the minimum follow-up time
for 6 cases was 13 months.

1) Conservative treatment: The patient takes omeprazole 20 mg (or 4. Discussion

equal dose of other PPI), half an hour before meal in the morning and
evening, advises the patient to raise the pillow appropriately, and As our results showed, the cure rate (216/266; 81.20%) and recur­
forbids eating before going to bed, and avoids spicy and irritating rence rate (3%; 8/266) of combined treatment were superior to those of
food in daily life. PPI (57.58%; 19/33) and recurrence rate (12.12%; 4/33); (P < 0.05).
2) Injection of triamcinolone acetonide through thyrohyoid approach: The cure time of PPI (6.79 ± 1.36) was longer than that of combination
After spraying local anesthetic into the throat and nasal cavity, the therapy (4.32 ± 1.39) (P < 0.001).
patient lay in the treatment bed with shoulder pads to expose the As we know, the main cause of laryngeal contact granuloma is LPR
(laryngopharyngeal reflux) [10,11]. It is through chemical factors that
Table 1 damage the mucosa of the vocal cords and eventually lead to granuloma
Basic information of patients. formation. PPI can significantly increase the therapeutic effect of
laryngeal contact granuloma with LPR. Even if patients without LPR
PPI Combination therapy
received PPI, the therapeutic effects were significantly higher [12],
N 33 266 which were not given specific causes in previous studies. Mucosal
Age 42.85 ± 6.72 45.97 ± 8.57
Male 31(93.94%; 31/ 261(98.12%; 261/
integrity is considered to be a key factor in treatment of laryngeal
33) 266) contact granuloma [13]. This is also the majority of reasons for recurrent
Recurrence after surgical 19(57.58%; 19/ 176(66.17%; 176/ patients who recur after surgical treatment. PPI ensures mucosal integ­
treatment 33) 266) rity while also has advantages from etiology therapy which makes it the
Recurrence after voice therapy 11(33.34%; 11/ 86(32.32%; 86/266)
most popular treatment so far. Botulinum toxin has better therapeutic
33)
Recurrence after PPI 3(9.01%; 3/33) 4(1.50%; 4/266) effect on recurrent granuloma in previously studied [5,14]. It is
Cure 19(57.58%; 19/ 216(81.20%; 216/ mentioned in the literature that the treatment of botulinum toxin is to
33) 266) immobilize the bilateral vocal cords, reduce the impact of the vocal
Recurrence after cure 4(12.12%; 4/33) 8(3.00%; 8/266) cords, and give times for the laryngeal contact granuloma to self-healing
Calcification of arytenoid cartilage 16(16/19) 102(102/107)
[15]. Is it enough for the treatment of laryngeal contact granuloma with

2
Q. Nie et al. American Journal of Otolaryngology–Head and Neck Medicine and Surgery 42 (2021) 102766

Fig. 1. Laryngoscopes of treatment process of the patients.

Note: The three-line diagram were laryngoscopes of the treatment process of three patients. The first picture in the left column of each row was the laryngoscope
before the injection treatment, the middle was the laryngoscope during the injection treatment, and the rightmost laryngoscopes were the cure picture.

of the perichondrium, it can only give a time window for self-healing,

Table 2
but whether it can self-healing is still a mystery. This may be the
Statistical results.
reason why there were recurrence after conservative treatment. Some
PPI Combination P value OR 95%CI doctors have used hormone aerosol inhalation combined with PPI in the
therapy
treatment of patients with laryngeal contact granuloma, and the thera­
Cure 19 216 0.002 0.314 0.148–0.669 peutic effect is significantly better than that of PPI alone [8]. Aerosol
Uncure 14 50
inhalation of corticosteroids can eliminate mucosal inflammation and
Recurrence 4 8 0.032 4.448 1.262–15.684
Unrecurrence 29 258
enhance the therapeutic effect of PPI. But it is possible to cause oral
fungal infection. The intralesional injection of hormone can not only
Note: OR: Odds ratios; CI: Confidence intervals. eliminate the side effects of hormone on other parts, but also increase
the local drug concentration and enhance the anti-inflammatory effect
recurrence to treat only if etiological treatment and maintain mucous of hormone drugs. Therefore, combined treatment can not only maintain
membrane integrity? Risk factors such as LPR may cause inflammation the advantage of etiological treatment of PPI treatment, but also
to erode cartilage membrane causing inflammation of cartilage mem­ combine the local effects of hormone anti-inflammation and inhibition
brane [16]. In our study, the calcification of arytenoid cartilage on the of granulation tissue proliferation, and eliminate local lesions and
lesion side of laryngeal contact granulomatosis was more than that on cartilage inflammation. The cure rate (81.20%) and recurrence rate
the non-diseased side, indicating the existence of inflammation of (3%) of combined treatment were superior to those of PPI (57.58%) and
arytenoid perichondrium on the diseased side [17] In our study, 126 of recurrence rate (12.12%); (P < 0.05). In a word, combination treatment
the 296 patients with recurrence had calcification arytenoid cartilage in is the optimal treatment.
118 cases (93.65%), indicating that the majority of patients with The cure time of PPI (6.79 ± 1.36) was longer than that of combi­
recurrence with inflammation of the arytenoid cartilage. PPI can only nation therapy (4.32 ± 1.39) (P < 0.001). According to above findings,
make sure that the aggressiveness of risk factors can be reduced from the most recurrent laryngeal granuloma patients have inflammatory of
time of formal treatment, but for the existing lesions and inflammation

3
Q. Nie et al. American Journal of Otolaryngology–Head and Neck Medicine and Surgery 42 (2021) 102766

cartilage membrane. While 93.65% patients with recurrence have References

calcification of cricoarytenoid cartilage in our study. Local hormone
injection can obviously relieve cartilage inflammation in recurrent pa­ [1] Hong-Gang D, He-Juan J, Chun-Quan Z, et al. Surgery and proton pump inhibitors
for treatment of vocal process granulomas. Eur Arch Otorhinolaryngol 2013;270
tients and promote inflammation recovery, so the cure time for com­ (11):2921–6. https://doi.org/10.1007/s00405-013-2527-8.
bined treatment is shorter. 19 recurrent patients cured by PPI were [2] Lee SW, Hong HJ, Choi SH, et al. Comparison of treatment modalities for contact
followed up 4 cases recurred more than those in combined treatment. granuloma: a nationwide multicenter study. The Laryngocopes 2014;124(5):
1187–91. https://doi.org/10.1002/lary.24470.
Inflammatory therapy should be paid attention to by patients with [3] Ylitalo R. Lindestad PA. A retrospective study of contact granuloma. The
recurrent patients. Laryngocopes 1999;109(3):433–6. https://doi.org/10.1097/00005537-
199903000-00017.
[4] Yongli Song, Li Shi, Yu Zhao, et al. Surgical removal followed by radiotherapy for
5. Limitations refractory vocal process granuloma. J Voice 2012;26(5):666e1–5. https://doi.org/
10.1016/j.jvoice.2011.08.004.
There is a significant difference in the number of people between the [5] Yilmaz T, Süslü N, Atay G, et al. Recurrent contact granuloma: experience with
excision and botulinum toxin injection. JAMA otolaryngology. Head Neck Surg
two subgroups of combination treatment and PPI in our data, which may
2013;139(6):579–83. https://doi.org/10.1001/jamaoto.2013.3186.
cause an offset. [6] Hirano S, Kojima H, Tateya I, et al. Fiberoptic laryngeal surgery for vocal process
granuloma. Annals of Otology, Rhinology & Laryngology 2002;111(9):789–93.
6. Conclusion https://doi.org/10.1177/000348940211100905.
[7] Hillel AT, Lin LM, Samlan R, et al. Inhaled triamcinolone with proton pump
inhibitor for treatment of vocal process granulomas: a series of 67 granulomas.
Combined treatment can be used as the preferred therapy for gran­ Annals of Otology, Rhinology & Laryngology 2010;119(5):325–30. https://doi.
uloma with recurrence. org/10.1177/000348941011900509.
[8] Tian SY, Li JR, Li KL, et al. Treatment of laryngeal contact granuloma via
glucocorticoid injection into granuloma by the thyrohyoid approach. J. Audiology
Funding and Speech Pathology 2017;25(1):70–2. https://doi.org/10.3969/j.issn.1006-
7299.2017.01.017.
[9] Wang CT, Lai MS, Lo WC, et al. Intralesional steroid injection:an alternative
None. treatment option for vocal process granuloma in ten patients. Clin Otolaryngol
2013;38(1):77–81. https://doi.org/10.1111/coa.12021.
Ethical approval [10] Ylitalo R, Lindestad PA. Laryngeal finding in patients with contact granuloma:a
long time follow-up study. Acta Otolaryngal 2000;120(5):655–9. https://doi.org/
10.1080/000164800750000504.
This article does not contain any studies with human participants or [11] Reiter R, Heyduck A, Seufferlein T, et al. Laryngopharyngeal reflux.
animals performed by any of the authors. Larygorhinologie 2018;97(4):238–45. https://doi.org/10.1055/s-0044-100794.
[12] Wani MK, Gayle E, et al. Laryngeal contact granuloma. The Laryngocopes 1999;
109(10):1589–93. https://doi.org/10.1097/00005537-199910000-00008.
Informed consent [13] Sun GB, Sun N, Tang HH, et al. Zinc sulfate therapy of vocal process granuloma.
Eur Arch Otorhinolaryngol 2012;269(9):2087–90. https://doi.org/10.1007/
Informed consent was obtained from all individual participants s00405-012-1971-1.
[14] Orloff LA, Goldman SN. Vocal fold granuloma: successful treatment with
included in the study. botulinum toxin. Otolarybgol Head Neck Sury 1999;121(4):410–3. https://doi.
org/10.1016/S0194-5998(99)70230-5.
Pledge statement [15] Karkos PD, George M, Van Der Veen J, et al. Vocal process granulomas: a
systematic review of treatment. Ann Otol Rhinol Laryngol 2014;123(5):314–20.
https://doi.org/10.1177/0003489414525921.
This paper has not been submitted to any another journal. [16] Shoffel-Havakuk H, Halperin D, Yosef L, et al. Lesions of the posterior glottis:
clinical and pathologic considerations and treatment outcome. J Voice 2014;28(2):
263e1–8. https://doi.org/10.1016/j.jvoice.2013.08.013.
Declaration of competing interest [17] Li JR, Tian SY, Zou SZ, et al. CT study of the arytenoid cartilage in patients with
laryngeal contact granuloma. Otolaryngology-head and neck surgery 2017;157(6):
None. 1013–6. https://doi.org/10.1177/0194599817721153.