Original Research

Nerve Growth Factor Signals as Possible Pathogenic Biomarkers for Perineural Invasion in Adenoid Cystic Carcinoma

Otolaryngology– Head and Neck Surgery 1–7 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599815584762 http://otojournal.org

Kenya Kobayashi, MD1,2, Mizuo Ando, MD, PhD1, Yuki Saito, MD1, Kenji Kondo, MD, PhD1, Go Omura, MD1, Aya Shinozaki-Ushiku, MD, PhD3, Masashi Fukayama, MD, PhD3, Takahiro Asakage, MD, PhD1, and Tatsuya Yamasoba, MD, PhD1

No sponsorships or competing interests have been disclosed for this article.

Abstract Objective. The molecular mechanisms underlying perineural invasion (PNI)—a characteristic pathological feature of adenoid cystic carcinoma (ACC)—remain largely unclear. Recently, nerve growth factor (NGF) has been implicated in perineural invasion in certain malignancies. Overexpression of Myb related to the MYB-NFIB fusion gene in ACC has also been correlated with perineural invasion and survival. However, this concept is controversial. The aim of this study was to examine the expression of NGF together with its receptors, tropomyosin receptor kinase A (TrkA) and p75NRT, and Myb in ACC and assess their relationship with perineural invasion and survival. Study Design. Case series with chart review. Setting. The University of Tokyo Hospital. Subjects and Methods. We retrospectively analyzed 37 patients with ACC surgically treated from 1991 to 2011. We examined expression levels of NGF, TrkA, p75NRT, and Myb in the ACC specimens and their correlations with PNI and prognosis. Results. NGF, TrkA, p75NRT, and Myb overexpression rates were 65%, 65%, 30%, and 62%, respectively. Pearson product-moment correlation coefficient revealed a strong correlation between NGF/TrkA immunostaining and PNI (NGF: r = 0.68, P \ .0001; TrkA: r = 0.53, P = .0007). Moreover, NGF overexpression was significantly associated with worse 8-year local control rate (27% vs 80%, P = .005). However, p75NRT and Myb expression was related to neither perineural invasion nor survival. Conclusion. Our findings demonstrated that NGF and TrkA overexpression, but not Myb and p75NRT overexpression, may contribute to PNI and thus cause local recurrence in patients with ACC. Keywords adenoid cystic carcinoma, NGF, TrkA, perineural invasion, Myb

Received November 23, 2014; revised March 31, 2015; accepted April 9, 2015.

P

erineural invasion (PNI) is a characteristic pathological feature of adenoid cystic carcinoma (ACC), causing locoregional recurrence and severely impairing quality of life.1 PNI is an independent factor in local spread2-4; however, the molecular mechanisms underlying PNI remain largely unclear. Neurotrophins (NTs) are a family of proteins that contribute to nerve growth, maintenance, and guidance.5 They are secreted by muscular, glandular, fibroblastic, and Schwann cells, and they target receptors on nerve cells. In many tumors, such as prostate or pancreatic cancer, the nerve growth factor (NGF) family of NTs and their receptors have been demonstrated to influence the process of PNI.6-8 NGF, brain-derived neurotrophic factor (BDNF), and NT-3-5 are members of the NT family. Trk receptors, a family of tyrosine kinase receptors, are selective for NTs, with tropomyosin receptor kinase A (TrkA) preferring NGF, TrkB preferring BDNF and NT-4/5, and TrkC preferring NT-3. In contrast, p75NRT is a low-affinity receptor that binds to all NTs.9 Overexpression of NGF and TrkA is especially responsible for PNI in some types of cancer.5,6,10 However, few reports have described the causal relationship between NTs and PNI in head and neck ACC.

1 Department of Otolaryngology, Head and Neck Surgery, The University of Tokyo Hospital, Tokyo, Japan 2 Department of Head and Neck Oncology, National Cancer Center Hospital, Tokyo, Japan 3 Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan

This article was presented at the 2014 AAO-HNSF Annual Meeting & OTO EXPO; September 21-24, 2014; Orlando, Florida. Corresponding Author: Kenya Kobayashi, MD, Department of Otolaryngology, Head and Neck Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Email: [email protected]

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In contrast, the MYB proto-oncogene was recently shown to be overexpressed in head and neck ACC, partly owing to the MYB-NFIB fusion product.11 As a unique change not seen in any other tumors, MYB-NFIB fusion may become a useful diagnostic biomarker for ACC.12 However, its impact on clinicopathological factors, including PNI, remains unknown.13 In this study, we aimed to detect pathogenic biomarkers for PNI in head and neck ACC. We examined the expression levels of NGF, its receptors (TrkA and p75NRT), and Myb in surgical specimens and investigated their relationship with PNI and prognosis.

Materials and Methods Patients We treated 47 patients with ACC at the University of Tokyo Hospital from 1991 to 2011 and analyzed 37 wellpreserved, formalin-fixed, paraffin-embedded (FFPE) surgical specimens. The patient characteristics are shown in Table 1. We adopted the 2010 version of the TNM classification by the International Union against Cancer and the American Joint Committee on Cancer for clinical staging. Carcinomas of the lacrimal gland and temporal bone were classified using the 2009 version of the TNM classification and the 2000 version of the Pittsburgh staging system.14 All patients were previously untreated and underwent surgical treatment. Neck dissection was performed in 11 patients: 5 for node-positive neck and 6 for node-negative neck for microvascular anastomosis in free flap reconstruction. Postoperative radiotherapy was performed in 12 patients with inadequate surgical margins. The pathological subtype (ie, tubular, cribriform, or solid) was determined according to the World Health Organization classification. Although many of these tumors could be observed as composite pathological patterns, the most dominant component was defined as its pathological subtype: 7 tubular, 18 cribriform, and 12 solid. The Institutional Review Board of the University of Tokyo Hospital approved this study.

PNI The extent of PNI was blindly reviewed by a pathologist (A.S.-U.). An average number of PNI per 3 low-power fields (LPFs) was counted. An average of .3 PNI per 3 LPFs was defined as 21, 1 to 3 as 11, and none as 0. PNI 21 and 11 were categorized as PNI positive and 0 as PNI negative (Figure 1).

Table 1. Patient Characteristics. Characteristic Sex, male/female, No. Age, median (range), y Follow-up period (range), mo Primary tumor site, No. Salivary gland Nasal cavity/paranasal sinus Oral cavity Pharynx/larynx Lacrimal gland Other T stage, T1/T2/T3/T4, No. N stage, N0/N1/N2, No. Histopathological type, tubular/cribriform/solid, No. Perineural invasion, positive/negative, No. Neck dissection, yes/no, No. Postoperative radiotherapy, yes/no, No.

Value 16/21 56 (26-77) 97 (8-274) 14 7 5 4 4 3 3/10/12/12 32/1/4 7/18/12 25/12 11/26 12/25

100, 1:500 dilution; Biosensis, Thebarton, Australia), rabbit anti-p75NRT polyclonal antibody (ab8875, 1:250 dilution; Abcam, Cambridge, Massachusetts), and rabbit anti–v-Myb 1 c-Myb monoclonal antibody (ab45150, 1:500 dilution; Abcam). Isotype-only negative controls were used to assess the background staining. The following control antibodies were used: rabbit IgG isotype control polyclonal antibody (GTX35035, 1:2500 dilution; GeneTex, Irvine, California) for NGF and p75NRT, rabbit serum (140-06571, 1:2500 dilution; Wako, Osaka, Japan) for TrkA, and rabbit IgG isotype control monoclonal antibody (ab125938, 1:100 dilution; Abcam) for Myb. Histofine Simple Stain MAX-PO (Nichirei, Tokyo, Japan) was used as a secondary antibody, according to the manufacturer’s instructions. Visualization was performed using 3,3#-diaminobenzidine (Nichirei), and the sections were counterstained with hematoxylin. Scoring NGF, TrkA, and p75NRT immunohistochemistry, the percentage of positive cells .50% was classified as 31, 25% to 50% as 21, 1% to 25% as 11, and 0% as 0, as previously reported.15 We categorized 31/21 as high staining (overexpressed) and 11/0 as low staining. Myb immunostaining was considered high staining (overexpressed) if .5% of tumor cells displayed strong nuclear immunoreactivity.16 All specimens were blindly reviewed by a pathologist (A.S.-U.).

Immunohistochemistry Tissue sections (4 mm thick) prepared from FFPE tissue samples were deparaffinized by passage through xylene and 3% hydrogen peroxide. Sections were then autoclaved for 20 minutes in target retrieval solution (Dako Japan, Kyoto, Japan) for antigen retrieval. The following were used as primary antibodies: rabbit anti-NGF polyclonal antibody (H20, 1:500 dilution; Santa Cruz Biotechnology, Santa Cruz, California), rabbit anti-TrkA polyclonal antibody (R-152-

Statistical Analysis Potential correlations between the immunohistochemistry (IHC) expression level (the percentage of immunostaining positivity) and the extent of PNI (number of PNI per LPF) were evaluated using the Pearson product-moment correlation coefficient. The association between other clinicopathological variables and IHC expression status was evaluated using the x2 test. Local control rate (LCR) and disease-specific

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Figure 1. Perineural invasion (PNI). Four PNI per low-power field (A, PNI 21). One PNI per low-power field (B, PNI 11). Original magnification, 1003. Bar, 400 mm.

Table 2. Expression of NGF, TrkA, p75NRT, and Myb in Adenoid Cystic Carcinoma. No. of Patients

NGF TrkA p75NRT Myb

IHC: High Staining

IHC: Low Staining

Positive Rate, %

24 24 11 23

13 13 26 14

65 65 30 62

Abbreviations: IHC, immunohistochemistry; NGF, nerve growth factor; TrkA, tropomyosin receptor kinase A.

survival (DSS) were calculated using the Kaplan-Meier method, and differences were evaluated using the log-rank test. P \ .05 was considered significant. All analyses were performed with Statmate version 2.0 (GraphPad Software, La Jolla, California).

Results Extent of PNI Among the 37 patients, 25 (68%) were PNI positive (8 with PNI 21 and 17 with PNI 11) and 12 were PNI negative. The median number of PNI per 3 LPFs was 2 (range, 9-0). There was no correlation between PNI and tumor site, histological subtype, or other clinicopathological variables.

Expression Status of NGF, TrkA, p75NRT, and Myb Immunohistochemical study of 37 ACC specimens revealed that NGF, TrkA, p75NRT, and Myb overexpression was 24 (65%), 24 (65%), 11 (30%), and 23 (62%), respectively (Table 2). Representative immunostaining results are shown in Figure 2. Among the 24 patients with NGF overexpression, 21 (88%) had TrkA overexpression, while only 3 (30%) had TrkA overexpression among the 13 patients without NGF overexpression. TrkA expression was thus significantly associated with NGF overexpression (P = .00037), whereas p75NRT, a low-affinity receptor of NGF, was not. Myb overexpression was not related to any other expression status.

Figure 2. Immunohistochemistry. Positive immunostainings and isotype negative controls of NGF, TrkA, p75NRT, and Myb are shown in A-1/A-2, B-1/B-2, C-1/C-2, and D-1/D-2, respectively. Original magnification, 2003. Bar, 100 mm.

Correlation between PNI, Expression Status, and Other Clinicopathological Characteristics The associations between IHC and PNI were plotted in Figure 3. In NGF and TrkA, Pearson product-moment

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Figure 3. Associations between immunostaining positivity and PNI in NGF (A), TrkA (B), p75NRT (C), and Myb (D). There are strong correlations between these 2 parameters in NGF and TrkA. LPF, low-power field; PNI, perineural invasion.

correlation coefficient showed a strong correlation between these 2 parameters (NGF: r = 0.68, P \ .0001; TrkA: r = 0.53, P = .0007). However, there was no correlation in p75NRT and Myb (p75NRT: r = 0.036, P = .83; Myb: r = 0.12, P = .50). The other clinicopathological characteristics of this cohort are represented in Table 3. Overexpression of NGF was significantly associated with advanced T classification (P = .03). Of note, overexpression of Myb was significantly associated with the tubular/cribriform pathological type (P = .03).

LCR and DSS by Expression Status Overexpression of NGF was significantly associated with 8year LCR (27% vs 80%, P = .005). Other factors did not reach statistical significance in LCR and DSS (Figure 4).

Discussion Here, we report our immunohistochemical study of possible biomarkers for PNI in ACC. We found that 65% of patients had NGF overexpression and that the overexpression of TrkA receptor was significantly correlated with NGF expression. Moreover, there were strong correlations between NGF/TrkA expression and PNI. These results suggest the contribution of the NGF/TrkA system to PNI. The NGF/TrkA pathway has been implicated in influencing PNI in some types of cancer, including ACC, although this is controversial.10,17 The hypothetical molecular mechanism of PNI is summarized in Figure 5.18,19 Neural affinity might be stimulated by NGF binding to the TrkA in the perineurium, and neural destruction

also occurs via proteolytic matrix metalloproteinase 2 induced by NGF/TrkA signals. The NGF autocrine loop may exist in the tumor microenvironment. NGF- and TrkA-positive cells were observed not only around the PNI but also over the entire tumors. Moreover, advanced T classification of tumors had a significantly higher rate of NGF overexpression, with a similar tendency for TrkA. Given that, NGF/TrkA signals are suspected to contribute to PNI and tumor proliferation. Overexpression of NGF/TrkA might otherwise occur along with tumor growth. Zhu et al20 reported that NGF signals stimulate cell growth in a pancreatic cancer cell line. In the absence of established cell lines in ACC, we performed NGF administration in the primary culture of patient-derived ACC cells. However, we could not obtain reliable results because the cell proliferation rate was low. We now plan to develop patient-derived xenograft models in mice. Solid tumor subtype is reported to be associated with a high rate of PNI.21 This argument has been supported by some studies22,23 but contradicted by others.24 In general, there is no consensus that PNI correlates with site, pathological subtype, or other clinicopathological variables.1 In line with this, we found no correlations between expression of NGF or TrkA and anatomical site or pathological subtype in our cohort. We observed a low positive rate of p75NRT immunostaining, and there was no correlation between overexpression of p75NRT and PNI. Although TrkA activates downstream phosphatidylinositol 3-kinase (PI3K), Ras, and

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Table 3. Association between NGF, TrkA, p75NRT, and Myb Overexpression and Clinical Characteristics. No. of Patients

No. of Patients

No. of Patients

No. of Patients

NGF(1) NGF(–) P Value TrkA(1) TrkA(–) P Value p75NRT(1) p75NRT(–) P Value Myb(1) Myb(–) P Value Sex Male Female Age, y \70 .70 Primary site Major gland Minor gland Other T classification T1/2 T3/4 N classification N0 N1-3 Histopathological type Tubular/cribriform Solid

13 11

3 10

.14

11 13

5 8

.93

5 6

11 15

.85

8 15

8 6

.32

18 6

11 2

.79

17 7

12 1

.27

7 4

22 4

.33

18 5

11 3

.70

9 7 8

5 2 6

.60

10 6 8

4 3 6

.74

4 3 4

10 6 10

.88

8 7 8

6 2 6

.54

5 19

8 5

.03

6 18

7 6

.16

6 5

7 19

.22

8 15

5 9

.77

22 2

10 3

.45

22 2

10 3

.45

10 1

22 4

.99

20 3

12 2

.70

15 9

10 3

.59

16 8

9 4

.83

9 2

16 10

.45

19 4

6 8

.03

Abbreviations: NGF, nerve growth factor; TrkA, tropomyosin receptor kinase A.

Figure 5. Hypothetical perineural invasion mechanism. NGF autocrine signals arise. Neural affinity occurs via NGF binding to the TrkA receptor. NGF/TrkA signals also induce matrix metalloproteinase 2, which has a key role in tissue destruction.

Figure 4. Prognosis by expression of NGF (A), TrkA (B), p75NRT (C), and Myb (D). NGF overexpression was significantly associated with poor 8-year LCR. Other biomarkers were not significantly related to prognosis. DSS, disease-specific survival; LCR, local control rate.

phospholipase Cg pathways that act as survival, proliferation, and invasion signals, p75NRT activates the nuclear factor–kB and C-Jun N-terminal kinase (JNK) pathways that mediate apoptosis.5 In breast cancer, for example, it has been shown that NGF signals activate TrkA and downregulate p75NRT,25,26 resulting in a decrease in the proliferation rate. In ACC, NGF might bind mainly to TrkA and exert its proliferative and invasive effect, whereas p75NRT may have limited biological relevance. In our analysis, patients with NGF overexpression had significantly lower LCR. The LCR was also worse in

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patients with TrkA overexpression. Although the data regarding the influence of PNI on survival are contradictory, 27 tumors with upregulated NGF and TrkA were suspected to be of the highly invasive phenotype via PNI and may cause decreased local control. Expression of NGF and TrkA has been demonstrated as a marker of tumor aggressiveness and prognosis in pancreatic cancer.28 We would be able to predict the degree of invasiveness and plan surgical margins better if we knew the status of NGF or TrkA preoperatively. MYB proto-oncogene is a member of the MYB (myeloblastosis) family of transcription factors and plays a role in tumorigenesis of leukemia.29 The t(6;9) translocation and resulting MYB-NFIB fusion gene have recently been reported as unique changes in ACC,11 leading to overexpression of MYB-NFIB fusion protein and activation of critical MYB targets. We revealed that 62% of our patients had Myb overexpression, although there was no association between Myb expression status and PNI. MYB-NFIB fusion may not be the only mechanism to explain overexpression of Myb in ACC. Further investigations are warranted to clarify the contribution of Myb to the molecular mechanisms of PNI. In conclusion, the overexpression rate of both NGF and TrkA was 65%. There were strong correlations between NGF/TrkA immunostaining and PNI, supporting the contribution of the NGF/TrkA system to PNI. These findings also suggest that further understanding of the pathway may provide a new therapeutic target in the treatment of ACC. Acknowledgments We acknowledge Masafumi Yoshida, MD, Chisato Fujimoto, MD, PhD, Kaori Kanaya, MD, and Takashi Sakamoto, MD, PhD, for their substantial contributions to the conception and design of the paper, technical supports of IHC, and critical manuscript revisions.

Author Contributions Kenya Kobayashi, wrote article, study design, collected data; Mizuo Ando, study design, revised article, data interpretation; Yuki Saito, study design, data interpretation, revised article; Kenji Kondo, revised article, study design, data interpretation; Go Omura, collected data, revised article; Aya Shinozaki-Ushiku, revised article, pathological analysis, data interpretation; Masashi Fukayama, revised article, pathological analysis, data interpretation; Takahiro Asakage, revised article, data interpretation; Tatsuya Yamasoba, revised article, data interpretation.

Disclosures Competing interests: None. Sponsorships: None. Funding source: No role in study.

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Nerve Growth Factor Signals as Possible Pathogenic Biomarkers for Perineural Invasion in Adenoid Cystic Carcinoma.

The molecular mechanisms underlying perineural invasion (PNI)-a characteristic pathological feature of adenoid cystic carcinoma (ACC)-remain largely u...
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