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Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach
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ANL-2634; No. of Pages 6 Auris Nasus Larynx xxx (2019) xxx–xxx Contents lists available at ScienceDirect
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Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach Fumihiko Kuwata a, Masahiro Kikuchi a,*, Masaaki Ishikawa b, Masahiro Tanji c, Tatsunori Sakamoto d, Masaru Yamashita e, Mami Matsunaga a, Koichi Omori a, Takayuki Nakagawa a a
Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan b Department of Otolaryngology-Head and Neck Surgery, Hyogo Prefectual Amagasaki General Medical Center, 2-17-77, Higashi-naniwa-cho, Amagasaki, 660-8550, Japan c Department of Neurosurgery, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan d Department of Otolaryngology-Head and Neck Surgery, Kitano Hospital, 2-4-20, Ogimachi, Kita-ku, Osaka, 530-8480, Japan e Department of Otolaryngology-Head and Neck Surgery, Shizuoka General Hospital, 4-27-1, Kita Ando, Aoi-ku, Shizuoka, 420-8527, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 March 2019 Accepted 1 July 2019 Available online xxx
Objectives: To evaluate long-term olfactory outcomes in patients who underwent pituitary surgery through the endoscopic endonasal transsphenoidal approach (EETSA) by T&T olfactometer. Methods: We retrospectively reviewed 26 patients who underwent pituitary surgery via EETSA. Olfactory function was assessed by T&T olfactometer before and 6 months after surgery. The mean of recognition thresholds for five different odorants was used. The change in the mean recognition threshold values was evaluated in the entire cohort and the subgroup analysis was performed according to the age, sex, past history of pituitary surgery (primary surgery or revision surgery), histopathology (non-functioning adenoma (NFA) or functioning adenoma (FA)), reconstruction procedure (rescue flap or nasoseptal flap), and superior turbinate management (preserved or resected). Results: Of the 26 patients (12 men and 14 women, median age 53 years), 21 patients were newly diagnosed with pituitary gland tumor (16 NFAs, 5 FAs) and the remaining 5 were diagnosed with recurrent pituitary gland tumor (4 NFAs and 1 FA). In the whole cohort, the mean recognition threshold values of T&T olfactometer significantly improved after surgery (P = 0.01). Thirteen out of 26 patients (50%) showed olfactory improvement, whereas only 3 (12%) showed deterioration. In the subgroup analysis, olfactory function outcomes were not significantly different between the subgroups with respect to the age, sex, past history of pituitary surgery, histopathology, reconstruction procedure, or superior turbinate management. The olfactory function tended to worsen in the revision surgery group compared to that in the primary surgery group, but not significantly (P = 0.06). Conclusions: The olfactory function was improved or maintained after pituitary surgery via EETSA in 88% of patients, indicating the benefits of low invasiveness of our surgical treatment. On the other hand, three patients (12%) demonstrated deterioration of olfactory function, suggesting that the risk of postoperative olfactory dysfunction should be informed to patients. © 2019 Elsevier B.V. All rights reserved.
Keywords: Endoscopic endonasal transsphenoidal approach Pituitary adenoma Olfactory function T&T olfactometer
* Corresponding author. E-mail address: [email protected] (M. Kikuchi). https://doi.org/10.1016/j.anl.2019.07.002 0385-8146/© 2019 Elsevier B.V. All rights reserved.
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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1. Introduction The traditional surgical approach for pituitary adenoma has been the microscopic endonasal transsphenoidal approach. However, the endoscopic endonasal transsphenoidal approach (EETSA) has become popular in recent years. Compared to the microscopic approach, its outcomes are similar, the complications are fewer, the hospital stay and operating time are shorter, and patient discomfort is reduced [1,2]. As part of EETSA surgery, however, pedicled nasoseptal flap (NSF) [3] and/or its modified nasoseptal “rescue” flap [4,5] are often used for the reconstruction of skull base defects. In addition, resection of the inferior third part of the superior turbinates are sometimes performed to easily access the sphenoid sinus. The olfactory epithelium is located on the cribriform plate, the medial portion of the superior/middle turbinate, and the superior portion of the nasal septum. Considering the location of the olfactory mucosa, the elevation of NSF and/or the resection of superior turbinate may cause an unintended loss or damage of olfactory epithelium. There are few reports [6–9] to evaluate long-term outcomes of olfactory function after pituitary surgery via EETSA, although some authors have reported its short-term outcomes or outcomes evaluated by subjective questionnaire investigation [10–16]. This study aimed to evaluate long-term olfactory outcomes in patients who underwent pituitary surgery via EETSA by using T&T olfactometer. 2. Materials and methods 2.1. Study population From January 2015 to March 2017, 50 patients with pituitary tumors were treated by EETSA at Kyoto University hospital. Twenty-six of them met the eligibility criteria and were enrolled in the study. The inclusion criteria were as follows: patients with newly diagnosed or recurrent pituitary tumor who underwent pituitary surgery via EETSA. The olfactory function was assessed before and 6 months after surgery using T&T olfactometer. The exclusion criteria were as follows: patients with a past history of radiotherapy for pituitary tumor and/or any pituitary surgery within the last 12 months. The study followed the principles of the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of the Graduate School of Medicine, Kyoto University (R1896). 2.2. Endoscopic endonasal approach We routinely use three-handed endonasal trans-sphenoidal approach via binostrils. First, the middle turbinate was lateralized for access to the superior turbinate and sphenoid sinus ostium. Second, the bilateral nasoseptal mucosa was incised horizontally (posterior to anterior) from the sphenoid ostium towards the anterior end of the middle turbinate, and bilateral modified nasoseptal ‘rescue’ flaps were elevated to expose the sphenoid crest [4,5]. Third, the bony structure of the anterior wall of sphenoid sinus between bilateral sphenoid ostia and perpendicular plate of the ethmoid were removed. When a
wide sphenoidotomy was needed for a large tumor, partial resection of the superior turbinate and posterior ethmoidectomy through the superior meatus was additionally performed. For preservation of the olfactory epithelium, the upper two-thirds of the superior turbinate was preserved as much as possible. Finally, after the removal of the intersphenoidal septum and anterior wall of the sellar, the pituitary tumors were extirpated. After tumor removal, the sellar reconstruction is performed according to the degree of intraoperative cerebrospinal fluid (CSF) leak and the size of the sellar defect. Intraoperative CSF leaks were categorized based on Esposito/Kelly classification [17]: Grade 0, no leak observed; Grade 1, small “weeping” CSF leak confirmed by Valsalva maneuver without a visible diaphragmatic defect; Grade 2, moderate leak with definite diaphragmatic defect; or Grade 3, large diaphragmatic and/or dural defect. In general, NSF is used in cases with intraoperative CSF leaks in Grades 2 and 3 by Esposito/Kelly classification [17]. Two days after surgery, patients began to rinse their nose with a saline solution and continued the irrigation for at least 3 months. No specific medication was performed. 2.3. Olfactory function assessment To assess the olfactory function, the Toyota and Takagi (T&T) olfactometer (Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan) was used. The test identifies olfactory detection and each corresponding recognition threshold. Five different odorants were used, and a 10-fold dilution was carried out for each odorant. Four odorants were evaluated at 8 levels ( 2 to 5) and the remaining one odorant was evaluated at 7 levels ( 2 to 4): 0 is the normal olfactory threshold concentration, 5 (or 4) is the highest, and 2 is the lowest. The olfactory function is divided into 5 grades according to the mean values of the five obtained recognition threshold values: mean value 2 1 is normal, 1.2– 2.4 is mild hyposmia, 2.6–4.0 is moderate hyposmia, 4.2–5.4 is severe hyposmia, and >5.6 is anosmia. The test was carried out with low-concentration odorants to high-concentration odorants sequentially (from 2 to 4 or 5). When a patient detected the odor, this concentration was defined as the detection threshold. When a patient identified what kind of odor it was, the concentration was the recognition threshold. Both nostrils were tested simultaneously. Tests were performed twice, before and 6 months after surgery. When the mean threshold value increases/decreases by 1 or more after surgery, the change of olfactory function was defined as deteriorated/improved, respectively. The other cases were defined as stable. 2.4. Evaluation of olfactory function outcomes after surgery The change in the mean recognition threshold values was evaluated in the entire cohort. The subgroup analysis was also performed according to the following factors: age, sex, previous history of pituitary surgery (primary surgery or revision surgery), histopathology (non-functioning adenoma; NFA or functioning adenoma; FA), reconstruction procedure (rescue flap or NSF), and superior turbinate management (preserved or resected).
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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ANL-2634; No. of Pages 6 F. Kuwata et al. / Auris Nasus Larynx xxx (2019) xxx–xxx Table 1 Patient characteristics (n = 26).
3.2. Surgical approach
Characteristic a
Age Sexb
Past history of pituitary surgeryb Histopathologyb
3
Male Female None Revision NFA GHoma ACTHoma
53.7 12.1 12 (46) 14 (54) 21 (81) 5 (19) 20 (77) 5 (19) 1 (4)
NFA: non-functioning pituitary adenoma. GHoma: growth hormone-secreting pituitary adenoma. ACTHoma: ACTH-secreting pituitary adenoma. a data are presented as mean standard deviation. b data are presented as number (percentage).
2.5. Statistical analysis The mean recognition threshold before and 6 months after surgery for each patient was compared by the Wilcoxon signedrank test. The Fisher’s exact test was used for the subgroup analysis. The level of statistical significance was set at P < 0.05. 3. Results 3.1. Study population Twenty-six patients (12 men, 14 women; median age 53 [range 28–76] years) met the eligibility criteria and were enrolled in the study. The patient characteristics are summarized in Table 1. Of the 26 patients surveyed, 21 patients (81%) were newly diagnosed with pituitary gland tumor (16 NFAs, 5 FAs (4 growth hormone-secreting adenomas and 1 ACTHsecreting adenoma) and the remaining 5 (19%) were diagnosed with recurrent pituitary gland tumor (4 NFAs and 1 FA (growth hormone-secreting adenoma)).
All the patients underwent pituitary adenoma resection using EETAS. Ipsilateral or bilateral resection of the inferior third part of the superior turbinate were performed in 13 cases (50%). There were 18 cases (69%) who had an intraoperative CSF leak; 6 Grade 1, 3 Grade 2, and 9 Grade 3 by Esposito/Kelly classification [17]. NSF was used for the reconstruction in 14 cases. No patients developed postoperative nasal bleeding or CSF leak. 3.3. Olfactory function-Entire cohort T&T olfactometer after surgery was performed 3.0–10.5 months (median, 7.3 months) after surgery. The results of the T&T olfactometer test showed that preoperative recognition threshold values ranged from 0.4 to 5.6 (median, 2.2; Fig. 1). Six patients were normal; 8 patients had mild, 8 had moderate, and 3 had severe hyposmia; and 1 patient had anosmia. In contrast, the postoperative test showed that recognition threshold values were significantly improved (range, 0.2–5.4; median, 1.2, P = 0.01; Fig. 1). Thirteen patients were normal; 8 patients had mild, 4 had moderate, and 1 had severe hyposmia; while no patients had anosmia. Among all patients, 13 (50%), 10 (38%), and 3 (12%) had improved, stable, and deteriorated olfactory functions, respectively (Fig. 1). In short, olfactory function was preserved in 88% of patients. There were three patients whose olfactory function had deteriorated. Their characteristics are summarized in Table 2. Of the three cases, two were revision surgery cases, in which NSF was used for reconstruction. The other was a case with FA (ACTH secreting) with the superior turbinate resection. Obstruction of the olfactory cleft after surgery were not observed in these three cases. 3.4. Olfactory function- subgroup analysis Subgroup analysis of olfactory function after surgery was performed with 6 factors; age, sex, previous history of pituitary
Fig. 1. Olfactory function outcomes after endoscopic transsphenoidal pituitary surgery (all patients, n = 26). Left panel shows the change of recognition threshold values by T&T olfactometer. The threshold values were significantly improved after surgery (P = 0.01). Among all patients, 50%, 38%, and 12% had improved, stable, and deteriorated olfactory functions, respectively (right panel).
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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Table 2 Characteristics of three patients whose olfactory function deteriorated after surgery. Case No.
1 2 3
Age
46 73 57
Sex
Female Male Female
Past history of pituitary surgery
Histopathology
Revision surgery Revision surgery Primary surgery
NFA NFA ACTHoma
Operative procedure
T&T recognition threshold value
Reconstructive procedure
Superior turbinate
Before surgery
6 months after surgery
NSF NSF rescue flap
Preserved Resected Resected
2.6 2.6 0.4
5.3 4 1
NFA: non-functioning pituitary adenoma. ACTHoma: ACTH-secreting pituitary adenoma. NSF: nasoseptal flap.
surgery, histopathology, reconstruction procedure, and superior turbinate management (Table 3). No significant effect on olfactory outcomes was found in all factors. The olfactory function tended to worsen in the revision surgery group compared to the primary surgery group, but the difference was not significant (P = 0.06).
4. Discussion The current study was conducted to evaluate long-term olfactory outcomes in patients who underwent pituitary surgery via EETSA. T&T olfactometer, which is the Japanese standard olfactory test, was used to assess olfactory function. Exceeding our expectations, the mean recognition threshold values of T&T olfactometer were significantly improved after EETSA (P = 0.01). Regarding olfactory function, 50% showed improvement and 38% exhibited the maintenance of olfactory function. In the subgroup analysis, the olfactory function outcomes were not significantly different between the subgroups with respect to age, sex, past history of pituitary surgery, histopathology, reconstruction procedure, and superior turbinate management. These results indicated the low invasiveness of our surgical management for the olfactory system.
Considering the location of the olfactory mucosa, the elevation of NSF and/or the resection of superior turbinate may cause an unintended loss or damage of olfactory epithelia during pituitary surgery via EETSA. However, the impact of those surgical procedures on olfactory function is still controversial. Some authors have shown that postoperative olfactory dysfunction is associated with NSF-based skull base reconstruction [14,18,19], whereas there are other contradicting reports [8,9,11]. These contradicting outcomes may be due to several confounding factors, including different pathologies, different surgical approaches, different surgical skills, and differences in postoperative care and in the method of evaluating olfactory function [11]. Kim et al. [20] reported that coagulation and cutting mode electrocautery caused olfactory epithelial loss up to 76.9% and 55.8%, respectively, whereas a cold knife resulted in only 20% epithelial loss; therefore, they recommended the use of a cold knife in making superior nasal septum incision to reduce tissue damage with better olfactory outcomes. Hong et al. [21] also recommended the use of a cold knife when elevating nasoseptal rescue flaps, which are considered less likely to cause olfactory disruption than NSFs, to retain olfactory function during surgery. On the other hand, the recent study showed that there are differences in no short-term (3-month) or long-term (12-month) olfactory outcomes between a cold knife and monopolar cautery [9]. We
Table 3 Subgroup analysis of olfactory function after surgery. Olfactory function after surgery
Characteristic
Age, n (%) Sex, n (%) Past history of pituitary surgery, n (%) Histopathology, n (%) Reconstruction procedure, n (%) Superior turbinate management, n (%)
60 <60 Male Female Primary Revision NFA FA Rescue flap Nasoseptal flap Preserved Resected
P value
Improved
Stable
Deteriorated
(n = 13)
(n = 10)
(n = 3)
7 (44) 6 (60) 4 (33) 9 (64) 12 (57) 1 (20) 9 (45) 4 (66) 9 (64) 4 (33) 7 (54) 6 (46)
7 3 7 3 8 2 9 1 4 6 5 5
2 1 1 2 1 2 2 1 1 2 1 2
(44) (30) (58) (22) (38) (40) (45) (17) (29) (50) (38) (38)
(12) (10) (9) (14) (5) (40) (10) (17) (7) (17) (8) (16)
0.71 0.15 0.06 0.45 0.28 0.81
NFA: non-functioning pituitary adenoma. FA: functioning pituitary adenoma.
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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found that the cutting-mode monopolar electrocautery is useful for reducing bleeding during the elevation of NSF or rescue flap, and its use is also safe for olfactory function if only used with low-power output. In addition, the location of the incision lines for flaps may also be important for preservation of olfaction. Similar to our results, several authors have reported improvement of nasal symptoms or olfactory function after pituitary surgery via EETSA. Hart et al. [22] evaluated postoperative olfactory function using the University of Pennsylvania Smell Identification Test (UPSIT) at 3 months after surgery and showed that 7% of patients (3 of 45) experienced improvement of greater than 25% in UPSIT scores after surgery. Zimmer and Shah [10] evaluated postoperative short-term quality-of-life (QOL) outcomes using Sinonasal Outcome Test-22 (SNOT-22) at 1 and 3 months for patients who underwent resection of the inferior third of the superior turbinates as part of pituitary surgery, and they concluded that SNOT scores were comparable between preoperative and 1-month testing. However, the scores were significantly improved at 3 months. Harvey et al. [6] assessed postoperative long-term QOL outcomes using SNOT-22 and olfactory function using the Smell Identification Test (SIT40) at 6 months after surgery in patients who had NSF as part of pituitary surgery. In their study, SNOT-22 scores significantly improved although subjective smell discrimination scores did not change. They emphasized that preservation of the olfactory strip can provide a low morbidity approach without adversely affecting olfaction and maintaining reconstruction options. Upadhyay et al. [8] compared the postoperative olfactory outcomes using UPSIT between patients who had NSF (n = 7) and those who had bilateral rescue flaps (n = 35) at 6 weeks, 3 months, and 6 months after surgery. As a result, in the group of bilateral rescue flaps, olfactory function significantly improved at 6 months. In the group of NSFs, in contrast, the function temporarily deteriorated at 6 weeks, but recovered to the baseline level at 3 months. Altogether, pituitary surgery via EETSA with or without NSF may not be associated with a negative impact on olfactory function, rather it has a potential to improve the function. The olfactory epithelium is located close to the NSF or superior turbinate. Surgical management in these regions can affect the air flow to the olfactory epithelium. When the damage to the olfactory epithelium is carefully eliminated, improvements in the air flow to the olfactory epithelium due to surgical procedures in EETSA may have positive impacts on olfactory function. Among all the populations, in the present study, three patients (12%) showed olfactory deterioration. This rate corresponds well with the recent literature review of 604 patients from 19 studies [23] reporting that the rate of olfaction dysfunction after pituitary surgery (either moderate or severe or anosmia) was 14.4% in endoscopic group with a nasoseptal or rescue flap. Two of the three deteriorated patients were with the recurrent NFA, which indicates that revision surgery might be attributed to postoperative olfactory dysfunction. We should explain to patients in advance the potential risk of olfactory dysfunction after pituitary surgery via EETSA, especially for patients with recurrent tumors.
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There are several limitations to this study. First, this was a retrospective study with only a small number of cases. Metaanalysis may serve as a valuable tool for evaluating rare and unintended effects of a treatment like the current study, however, we consider that the meta-analysis to validate effects of surgical procedures on olfaction may not be effective at this moment, because study population, smell testing, definition of olfactory dysfunction, and data acquisition were heterogeneous among previous studies [23]. Second, we performed olfactometry tests only twice, before and 6 months after surgery, for each patient. This is why we could not determine how the function changed with time. In the previous reports [8,11,22], however, the olfactory function usually showed a temporal decline 1 month after surgery due to postoperative nasal crusting and discharge [11,22], then recovered, and thereafter reached a steady state by 6 weeks to 3 months after surgery [11]. Therefore, our results can be regarded as not transient but steady-state outcomes. Further follow-up and further research are needed to validate the results. 5. Conclusions In the present study, olfactory function in 26 patients who underwent pituitary surgery via EETSA was assessed by recognition threshold values with T&T olfactometer. Unexpectedly, postoperative mean recognition threshold values in T&T olfactometer were significantly improved 6 months after operation compared to those before operation. Olfactory improvement was observed in 50% of patients and 38% exhibited the maintenance of olfactory function. The use of NSF for the seller reconstruction showed no negative impact on postoperative olfactory function. Conflict of interest The authors have no funding, financial relationships, or conflicts of interest to disclose Acknowledgment We would like to thank Editage (www.editage.jp) for English language editing. References [1] Rotenberg B, Tam S, Ryu WH, Duggal N. Microscopic versus endoscopic pituitary surgery: a systematic review. Laryngoscope 2010;120:1292–7. [2] Strychowsky J, Nayan S, Reddy K, Farrokhyar F, Sommer D. Purely endoscopic transsphenoidal surgery versus traditional microsurgery for resection of pituitary adenomas: systematic review. J Otolaryngol Head Neck Surg 2011;40:175–85. [3] Hadad G, Bassagasteguy L, Carrau RL, Mataza JC, Kassam A, Snyderman CH, et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope 2006;116:1882–6. [4] Rivera-Serrano CM, Snyderman CH, Gardner P, Prevedello D, Wheless S, Kassam AB, et al. Nasoseptal "rescue" flap: a novel modification of the nasoseptal flap technique for pituitary surgery. Laryngoscope 2011;121:990–3.
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[5] Kim BY, Shin JH, Kang SG, Kim SW, Hong YK, Jeun SS, et al. Bilateral modified nasoseptal "rescue" flaps in the endoscopic endonasal transsphenoidal approach. Laryngoscope 2013;123:2605–9. [6] Harvey RJ, Winder M, Davidson A, Steel T, Nalavenkata S, Mrad N, et al. The olfactory strip and its preservation in endoscopic pituitary surgery maintains smell and sinonasal function. J Neurol Surg B Skull Base 2015;76:464–70. [7] Rioja E, Bernal-Sprekelsen M, Enriquez K, Ensenat J, Valero R, de Notaris M, et al. Long-term outcomes of endoscopic endonasal approach for skull base surgery: a prospective study. Eur Arch Otorhinolaryngol 2016;273:1809–17. [8] Upadhyay S, Buohliqah L, Dolci RLL, Otto BA, Prevedello DM, Carrau RL. Periodic olfactory assessment in patients undergoing skull base surgery with preservation of the olfactory strip. Laryngoscope 2017;127:1970–5. [9] Puccinelli CL, Yin LX, O’Brien EK, Van Gompel JJ, Choby GW, Van Abel KM, et al. Long-term olfaction outcomes in transnasal endoscopic skull-base surgery: a prospective cohort study comparing electrocautery and cold knife upper septal limb incision techniques. Int Forum Allergy Rhinol 2019;9:493–500. http://dx.doi.org/10.1002/alr.22291. [10] Zimmer LA, Shah O, Theodosopoulos PV. Short-term quality-of-Life changes after endoscopic pituitary surgery rated with SNOT-22. J Neurol Surg B Skull Base 2014;75:288–92. [11] Jalessi M, Jahanbakhshi A, Amini E, Kamrava SK, Farhadi M. Impact of nasoseptal flap elevation on sinonasal quality of life in endoscopic endonasal approach to pituitary adenomas. Eur Arch Otorhinolaryngol 2016;273:1199–205. [12] Bedrosian JC, McCoul ED, Raithatha R, Akselrod OA, Anand VK, Schwartz TH. A prospective study of postoperative symptoms in sinonasal quality-of-life following endoscopic skull-base surgery: dissociations based on specific symptoms. Int Forum Allergy Rhinol 2013;3:664–9. [13] Hanson M, Patel PM, Betz C, Olson S, Panizza B, Wallwork B. Sinonasal outcomes following endoscopic anterior skull base surgery with nasoseptal flap reconstruction: a prospective study. J Laryngol Otol 2015;129(Suppl. (3)):S41–6.
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Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach Fumihiko Kuwata a, Masahiro Kikuchi a,*, Masaaki Ishikawa b, Masahiro Tanji c, Tatsunori Sakamoto d, Masaru Yamashita e, Mami Matsunaga a, Koichi Omori a, Takayuki Nakagawa a a
Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan b Department of Otolaryngology-Head and Neck Surgery, Hyogo Prefectual Amagasaki General Medical Center, 2-17-77, Higashi-naniwa-cho, Amagasaki, 660-8550, Japan c Department of Neurosurgery, Kyoto University Hospital, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan d Department of Otolaryngology-Head and Neck Surgery, Kitano Hospital, 2-4-20, Ogimachi, Kita-ku, Osaka, 530-8480, Japan e Department of Otolaryngology-Head and Neck Surgery, Shizuoka General Hospital, 4-27-1, Kita Ando, Aoi-ku, Shizuoka, 420-8527, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 March 2019 Accepted 1 July 2019 Available online xxx
Objectives: To evaluate long-term olfactory outcomes in patients who underwent pituitary surgery through the endoscopic endonasal transsphenoidal approach (EETSA) by T&T olfactometer. Methods: We retrospectively reviewed 26 patients who underwent pituitary surgery via EETSA. Olfactory function was assessed by T&T olfactometer before and 6 months after surgery. The mean of recognition thresholds for five different odorants was used. The change in the mean recognition threshold values was evaluated in the entire cohort and the subgroup analysis was performed according to the age, sex, past history of pituitary surgery (primary surgery or revision surgery), histopathology (non-functioning adenoma (NFA) or functioning adenoma (FA)), reconstruction procedure (rescue flap or nasoseptal flap), and superior turbinate management (preserved or resected). Results: Of the 26 patients (12 men and 14 women, median age 53 years), 21 patients were newly diagnosed with pituitary gland tumor (16 NFAs, 5 FAs) and the remaining 5 were diagnosed with recurrent pituitary gland tumor (4 NFAs and 1 FA). In the whole cohort, the mean recognition threshold values of T&T olfactometer significantly improved after surgery (P = 0.01). Thirteen out of 26 patients (50%) showed olfactory improvement, whereas only 3 (12%) showed deterioration. In the subgroup analysis, olfactory function outcomes were not significantly different between the subgroups with respect to the age, sex, past history of pituitary surgery, histopathology, reconstruction procedure, or superior turbinate management. The olfactory function tended to worsen in the revision surgery group compared to that in the primary surgery group, but not significantly (P = 0.06). Conclusions: The olfactory function was improved or maintained after pituitary surgery via EETSA in 88% of patients, indicating the benefits of low invasiveness of our surgical treatment. On the other hand, three patients (12%) demonstrated deterioration of olfactory function, suggesting that the risk of postoperative olfactory dysfunction should be informed to patients. © 2019 Elsevier B.V. All rights reserved.
Keywords: Endoscopic endonasal transsphenoidal approach Pituitary adenoma Olfactory function T&T olfactometer
* Corresponding author. E-mail address: [email protected] (M. Kikuchi). https://doi.org/10.1016/j.anl.2019.07.002 0385-8146/© 2019 Elsevier B.V. All rights reserved.
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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1. Introduction The traditional surgical approach for pituitary adenoma has been the microscopic endonasal transsphenoidal approach. However, the endoscopic endonasal transsphenoidal approach (EETSA) has become popular in recent years. Compared to the microscopic approach, its outcomes are similar, the complications are fewer, the hospital stay and operating time are shorter, and patient discomfort is reduced [1,2]. As part of EETSA surgery, however, pedicled nasoseptal flap (NSF) [3] and/or its modified nasoseptal “rescue” flap [4,5] are often used for the reconstruction of skull base defects. In addition, resection of the inferior third part of the superior turbinates are sometimes performed to easily access the sphenoid sinus. The olfactory epithelium is located on the cribriform plate, the medial portion of the superior/middle turbinate, and the superior portion of the nasal septum. Considering the location of the olfactory mucosa, the elevation of NSF and/or the resection of superior turbinate may cause an unintended loss or damage of olfactory epithelium. There are few reports [6–9] to evaluate long-term outcomes of olfactory function after pituitary surgery via EETSA, although some authors have reported its short-term outcomes or outcomes evaluated by subjective questionnaire investigation [10–16]. This study aimed to evaluate long-term olfactory outcomes in patients who underwent pituitary surgery via EETSA by using T&T olfactometer. 2. Materials and methods 2.1. Study population From January 2015 to March 2017, 50 patients with pituitary tumors were treated by EETSA at Kyoto University hospital. Twenty-six of them met the eligibility criteria and were enrolled in the study. The inclusion criteria were as follows: patients with newly diagnosed or recurrent pituitary tumor who underwent pituitary surgery via EETSA. The olfactory function was assessed before and 6 months after surgery using T&T olfactometer. The exclusion criteria were as follows: patients with a past history of radiotherapy for pituitary tumor and/or any pituitary surgery within the last 12 months. The study followed the principles of the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of the Graduate School of Medicine, Kyoto University (R1896). 2.2. Endoscopic endonasal approach We routinely use three-handed endonasal trans-sphenoidal approach via binostrils. First, the middle turbinate was lateralized for access to the superior turbinate and sphenoid sinus ostium. Second, the bilateral nasoseptal mucosa was incised horizontally (posterior to anterior) from the sphenoid ostium towards the anterior end of the middle turbinate, and bilateral modified nasoseptal ‘rescue’ flaps were elevated to expose the sphenoid crest [4,5]. Third, the bony structure of the anterior wall of sphenoid sinus between bilateral sphenoid ostia and perpendicular plate of the ethmoid were removed. When a
wide sphenoidotomy was needed for a large tumor, partial resection of the superior turbinate and posterior ethmoidectomy through the superior meatus was additionally performed. For preservation of the olfactory epithelium, the upper two-thirds of the superior turbinate was preserved as much as possible. Finally, after the removal of the intersphenoidal septum and anterior wall of the sellar, the pituitary tumors were extirpated. After tumor removal, the sellar reconstruction is performed according to the degree of intraoperative cerebrospinal fluid (CSF) leak and the size of the sellar defect. Intraoperative CSF leaks were categorized based on Esposito/Kelly classification [17]: Grade 0, no leak observed; Grade 1, small “weeping” CSF leak confirmed by Valsalva maneuver without a visible diaphragmatic defect; Grade 2, moderate leak with definite diaphragmatic defect; or Grade 3, large diaphragmatic and/or dural defect. In general, NSF is used in cases with intraoperative CSF leaks in Grades 2 and 3 by Esposito/Kelly classification [17]. Two days after surgery, patients began to rinse their nose with a saline solution and continued the irrigation for at least 3 months. No specific medication was performed. 2.3. Olfactory function assessment To assess the olfactory function, the Toyota and Takagi (T&T) olfactometer (Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan) was used. The test identifies olfactory detection and each corresponding recognition threshold. Five different odorants were used, and a 10-fold dilution was carried out for each odorant. Four odorants were evaluated at 8 levels ( 2 to 5) and the remaining one odorant was evaluated at 7 levels ( 2 to 4): 0 is the normal olfactory threshold concentration, 5 (or 4) is the highest, and 2 is the lowest. The olfactory function is divided into 5 grades according to the mean values of the five obtained recognition threshold values: mean value 2 1 is normal, 1.2– 2.4 is mild hyposmia, 2.6–4.0 is moderate hyposmia, 4.2–5.4 is severe hyposmia, and >5.6 is anosmia. The test was carried out with low-concentration odorants to high-concentration odorants sequentially (from 2 to 4 or 5). When a patient detected the odor, this concentration was defined as the detection threshold. When a patient identified what kind of odor it was, the concentration was the recognition threshold. Both nostrils were tested simultaneously. Tests were performed twice, before and 6 months after surgery. When the mean threshold value increases/decreases by 1 or more after surgery, the change of olfactory function was defined as deteriorated/improved, respectively. The other cases were defined as stable. 2.4. Evaluation of olfactory function outcomes after surgery The change in the mean recognition threshold values was evaluated in the entire cohort. The subgroup analysis was also performed according to the following factors: age, sex, previous history of pituitary surgery (primary surgery or revision surgery), histopathology (non-functioning adenoma; NFA or functioning adenoma; FA), reconstruction procedure (rescue flap or NSF), and superior turbinate management (preserved or resected).
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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ANL-2634; No. of Pages 6 F. Kuwata et al. / Auris Nasus Larynx xxx (2019) xxx–xxx Table 1 Patient characteristics (n = 26).
3.2. Surgical approach
Characteristic a
Age Sexb
Past history of pituitary surgeryb Histopathologyb
3
Male Female None Revision NFA GHoma ACTHoma
53.7 12.1 12 (46) 14 (54) 21 (81) 5 (19) 20 (77) 5 (19) 1 (4)
NFA: non-functioning pituitary adenoma. GHoma: growth hormone-secreting pituitary adenoma. ACTHoma: ACTH-secreting pituitary adenoma. a data are presented as mean standard deviation. b data are presented as number (percentage).
2.5. Statistical analysis The mean recognition threshold before and 6 months after surgery for each patient was compared by the Wilcoxon signedrank test. The Fisher’s exact test was used for the subgroup analysis. The level of statistical significance was set at P < 0.05. 3. Results 3.1. Study population Twenty-six patients (12 men, 14 women; median age 53 [range 28–76] years) met the eligibility criteria and were enrolled in the study. The patient characteristics are summarized in Table 1. Of the 26 patients surveyed, 21 patients (81%) were newly diagnosed with pituitary gland tumor (16 NFAs, 5 FAs (4 growth hormone-secreting adenomas and 1 ACTHsecreting adenoma) and the remaining 5 (19%) were diagnosed with recurrent pituitary gland tumor (4 NFAs and 1 FA (growth hormone-secreting adenoma)).
All the patients underwent pituitary adenoma resection using EETAS. Ipsilateral or bilateral resection of the inferior third part of the superior turbinate were performed in 13 cases (50%). There were 18 cases (69%) who had an intraoperative CSF leak; 6 Grade 1, 3 Grade 2, and 9 Grade 3 by Esposito/Kelly classification [17]. NSF was used for the reconstruction in 14 cases. No patients developed postoperative nasal bleeding or CSF leak. 3.3. Olfactory function-Entire cohort T&T olfactometer after surgery was performed 3.0–10.5 months (median, 7.3 months) after surgery. The results of the T&T olfactometer test showed that preoperative recognition threshold values ranged from 0.4 to 5.6 (median, 2.2; Fig. 1). Six patients were normal; 8 patients had mild, 8 had moderate, and 3 had severe hyposmia; and 1 patient had anosmia. In contrast, the postoperative test showed that recognition threshold values were significantly improved (range, 0.2–5.4; median, 1.2, P = 0.01; Fig. 1). Thirteen patients were normal; 8 patients had mild, 4 had moderate, and 1 had severe hyposmia; while no patients had anosmia. Among all patients, 13 (50%), 10 (38%), and 3 (12%) had improved, stable, and deteriorated olfactory functions, respectively (Fig. 1). In short, olfactory function was preserved in 88% of patients. There were three patients whose olfactory function had deteriorated. Their characteristics are summarized in Table 2. Of the three cases, two were revision surgery cases, in which NSF was used for reconstruction. The other was a case with FA (ACTH secreting) with the superior turbinate resection. Obstruction of the olfactory cleft after surgery were not observed in these three cases. 3.4. Olfactory function- subgroup analysis Subgroup analysis of olfactory function after surgery was performed with 6 factors; age, sex, previous history of pituitary
Fig. 1. Olfactory function outcomes after endoscopic transsphenoidal pituitary surgery (all patients, n = 26). Left panel shows the change of recognition threshold values by T&T olfactometer. The threshold values were significantly improved after surgery (P = 0.01). Among all patients, 50%, 38%, and 12% had improved, stable, and deteriorated olfactory functions, respectively (right panel).
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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Table 2 Characteristics of three patients whose olfactory function deteriorated after surgery. Case No.
1 2 3
Age
46 73 57
Sex
Female Male Female
Past history of pituitary surgery
Histopathology
Revision surgery Revision surgery Primary surgery
NFA NFA ACTHoma
Operative procedure
T&T recognition threshold value
Reconstructive procedure
Superior turbinate
Before surgery
6 months after surgery
NSF NSF rescue flap
Preserved Resected Resected
2.6 2.6 0.4
5.3 4 1
NFA: non-functioning pituitary adenoma. ACTHoma: ACTH-secreting pituitary adenoma. NSF: nasoseptal flap.
surgery, histopathology, reconstruction procedure, and superior turbinate management (Table 3). No significant effect on olfactory outcomes was found in all factors. The olfactory function tended to worsen in the revision surgery group compared to the primary surgery group, but the difference was not significant (P = 0.06).
4. Discussion The current study was conducted to evaluate long-term olfactory outcomes in patients who underwent pituitary surgery via EETSA. T&T olfactometer, which is the Japanese standard olfactory test, was used to assess olfactory function. Exceeding our expectations, the mean recognition threshold values of T&T olfactometer were significantly improved after EETSA (P = 0.01). Regarding olfactory function, 50% showed improvement and 38% exhibited the maintenance of olfactory function. In the subgroup analysis, the olfactory function outcomes were not significantly different between the subgroups with respect to age, sex, past history of pituitary surgery, histopathology, reconstruction procedure, and superior turbinate management. These results indicated the low invasiveness of our surgical management for the olfactory system.
Considering the location of the olfactory mucosa, the elevation of NSF and/or the resection of superior turbinate may cause an unintended loss or damage of olfactory epithelia during pituitary surgery via EETSA. However, the impact of those surgical procedures on olfactory function is still controversial. Some authors have shown that postoperative olfactory dysfunction is associated with NSF-based skull base reconstruction [14,18,19], whereas there are other contradicting reports [8,9,11]. These contradicting outcomes may be due to several confounding factors, including different pathologies, different surgical approaches, different surgical skills, and differences in postoperative care and in the method of evaluating olfactory function [11]. Kim et al. [20] reported that coagulation and cutting mode electrocautery caused olfactory epithelial loss up to 76.9% and 55.8%, respectively, whereas a cold knife resulted in only 20% epithelial loss; therefore, they recommended the use of a cold knife in making superior nasal septum incision to reduce tissue damage with better olfactory outcomes. Hong et al. [21] also recommended the use of a cold knife when elevating nasoseptal rescue flaps, which are considered less likely to cause olfactory disruption than NSFs, to retain olfactory function during surgery. On the other hand, the recent study showed that there are differences in no short-term (3-month) or long-term (12-month) olfactory outcomes between a cold knife and monopolar cautery [9]. We
Table 3 Subgroup analysis of olfactory function after surgery. Olfactory function after surgery
Characteristic
Age, n (%) Sex, n (%) Past history of pituitary surgery, n (%) Histopathology, n (%) Reconstruction procedure, n (%) Superior turbinate management, n (%)
60 <60 Male Female Primary Revision NFA FA Rescue flap Nasoseptal flap Preserved Resected
P value
Improved
Stable
Deteriorated
(n = 13)
(n = 10)
(n = 3)
7 (44) 6 (60) 4 (33) 9 (64) 12 (57) 1 (20) 9 (45) 4 (66) 9 (64) 4 (33) 7 (54) 6 (46)
7 3 7 3 8 2 9 1 4 6 5 5
2 1 1 2 1 2 2 1 1 2 1 2
(44) (30) (58) (22) (38) (40) (45) (17) (29) (50) (38) (38)
(12) (10) (9) (14) (5) (40) (10) (17) (7) (17) (8) (16)
0.71 0.15 0.06 0.45 0.28 0.81
NFA: non-functioning pituitary adenoma. FA: functioning pituitary adenoma.
Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002
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found that the cutting-mode monopolar electrocautery is useful for reducing bleeding during the elevation of NSF or rescue flap, and its use is also safe for olfactory function if only used with low-power output. In addition, the location of the incision lines for flaps may also be important for preservation of olfaction. Similar to our results, several authors have reported improvement of nasal symptoms or olfactory function after pituitary surgery via EETSA. Hart et al. [22] evaluated postoperative olfactory function using the University of Pennsylvania Smell Identification Test (UPSIT) at 3 months after surgery and showed that 7% of patients (3 of 45) experienced improvement of greater than 25% in UPSIT scores after surgery. Zimmer and Shah [10] evaluated postoperative short-term quality-of-life (QOL) outcomes using Sinonasal Outcome Test-22 (SNOT-22) at 1 and 3 months for patients who underwent resection of the inferior third of the superior turbinates as part of pituitary surgery, and they concluded that SNOT scores were comparable between preoperative and 1-month testing. However, the scores were significantly improved at 3 months. Harvey et al. [6] assessed postoperative long-term QOL outcomes using SNOT-22 and olfactory function using the Smell Identification Test (SIT40) at 6 months after surgery in patients who had NSF as part of pituitary surgery. In their study, SNOT-22 scores significantly improved although subjective smell discrimination scores did not change. They emphasized that preservation of the olfactory strip can provide a low morbidity approach without adversely affecting olfaction and maintaining reconstruction options. Upadhyay et al. [8] compared the postoperative olfactory outcomes using UPSIT between patients who had NSF (n = 7) and those who had bilateral rescue flaps (n = 35) at 6 weeks, 3 months, and 6 months after surgery. As a result, in the group of bilateral rescue flaps, olfactory function significantly improved at 6 months. In the group of NSFs, in contrast, the function temporarily deteriorated at 6 weeks, but recovered to the baseline level at 3 months. Altogether, pituitary surgery via EETSA with or without NSF may not be associated with a negative impact on olfactory function, rather it has a potential to improve the function. The olfactory epithelium is located close to the NSF or superior turbinate. Surgical management in these regions can affect the air flow to the olfactory epithelium. When the damage to the olfactory epithelium is carefully eliminated, improvements in the air flow to the olfactory epithelium due to surgical procedures in EETSA may have positive impacts on olfactory function. Among all the populations, in the present study, three patients (12%) showed olfactory deterioration. This rate corresponds well with the recent literature review of 604 patients from 19 studies [23] reporting that the rate of olfaction dysfunction after pituitary surgery (either moderate or severe or anosmia) was 14.4% in endoscopic group with a nasoseptal or rescue flap. Two of the three deteriorated patients were with the recurrent NFA, which indicates that revision surgery might be attributed to postoperative olfactory dysfunction. We should explain to patients in advance the potential risk of olfactory dysfunction after pituitary surgery via EETSA, especially for patients with recurrent tumors.
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There are several limitations to this study. First, this was a retrospective study with only a small number of cases. Metaanalysis may serve as a valuable tool for evaluating rare and unintended effects of a treatment like the current study, however, we consider that the meta-analysis to validate effects of surgical procedures on olfaction may not be effective at this moment, because study population, smell testing, definition of olfactory dysfunction, and data acquisition were heterogeneous among previous studies [23]. Second, we performed olfactometry tests only twice, before and 6 months after surgery, for each patient. This is why we could not determine how the function changed with time. In the previous reports [8,11,22], however, the olfactory function usually showed a temporal decline 1 month after surgery due to postoperative nasal crusting and discharge [11,22], then recovered, and thereafter reached a steady state by 6 weeks to 3 months after surgery [11]. Therefore, our results can be regarded as not transient but steady-state outcomes. Further follow-up and further research are needed to validate the results. 5. Conclusions In the present study, olfactory function in 26 patients who underwent pituitary surgery via EETSA was assessed by recognition threshold values with T&T olfactometer. Unexpectedly, postoperative mean recognition threshold values in T&T olfactometer were significantly improved 6 months after operation compared to those before operation. Olfactory improvement was observed in 50% of patients and 38% exhibited the maintenance of olfactory function. The use of NSF for the seller reconstruction showed no negative impact on postoperative olfactory function. Conflict of interest The authors have no funding, financial relationships, or conflicts of interest to disclose Acknowledgment We would like to thank Editage (www.editage.jp) for English language editing. References [1] Rotenberg B, Tam S, Ryu WH, Duggal N. Microscopic versus endoscopic pituitary surgery: a systematic review. Laryngoscope 2010;120:1292–7. [2] Strychowsky J, Nayan S, Reddy K, Farrokhyar F, Sommer D. Purely endoscopic transsphenoidal surgery versus traditional microsurgery for resection of pituitary adenomas: systematic review. J Otolaryngol Head Neck Surg 2011;40:175–85. [3] Hadad G, Bassagasteguy L, Carrau RL, Mataza JC, Kassam A, Snyderman CH, et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope 2006;116:1882–6. [4] Rivera-Serrano CM, Snyderman CH, Gardner P, Prevedello D, Wheless S, Kassam AB, et al. Nasoseptal "rescue" flap: a novel modification of the nasoseptal flap technique for pituitary surgery. Laryngoscope 2011;121:990–3.
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Please cite this article in press as: Kuwata F, et al. Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach. Auris Nasus Larynx (2019), https://doi.org/10.1016/j.anl.2019.07.002