intermediate-grade parotid carcinoma: Outcome of watch and wait policy

Oral Oncology 68 (2017) 1–4

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Close surgical margin after conservative parotidectomy in early stage low-/intermediate-grade parotid carcinoma: Outcome of watch and wait policy Dominik Stodulski a,⇑, Bogusław Mikaszewski a, Hanna Majewska b, Piotr Wis´niewski c, Czesław Stankiewicz a a

´ sk, Poland Department of Otolaryngology, Medical University of Gdan ´ sk, Poland Department of Pathomorphology, Medical University of Gdan c ´ sk, Poland Department of Endocrinology and Internal Medicine, Medical University of Gdan b

a r t i c l e

i n f o

Article history: Received 14 February 2017 Received in revised form 28 February 2017 Accepted 4 March 2017

a b s t r a c t Aim: The aim of the study was to assess the watch&wait strategy for management of patients with close surgical margin after conservative parotidectomy due to early low/intermediate grade parotid carcinoma. Patients and methods: Out of 78 patients operated on due to primary parotid gland cancer we selected 32 patients with a history of parotidectomy, and preservation of 7th nerve, with negative (1 mm), but close (5 mm) surgical margin and who did not receive supplementary radiotherapy due to other indications. Margins ranged from 1 to 3 mm (in 27 cases it was 1 mm, in 3 cases – 2 mm and in 2 cases – 3 mm), average 1.2 mm. The patients underwent further clinical-histological analysis. Results: 3 of 32 (9.38%) patients experienced a local recurrence 36, 53 and 56 months post-surgery. The 5-year disease-free survival (DFS) was 90.6%. Recurrences were treated surgically, followed by radiotherapy, which resulted in an overall survival of 107, 104 and 104 months. One patient died 72 months after surgery due to non-oncological causes. The 10-year disease-free survival (DFS) was 96.3%. The 3 patients with recurrence of cancer had histological diagnosis of epithelial-myoepithelial carcinoma LG, with a margin of 2, 1 and 3 mm, respectively. There were no other distinctive features. Conclusion: The watch&wait strategy with intensive follow-up seems justified in cases of close margin after excision of I/LG T1/T2 parotid tumors. EMC should be considered as a neoplasm associated with higher risk of recurrence. Ó 2017 Elsevier Ltd. All rights reserved.

Introduction Patients with early-stage primary parotid carcinoma have a good chance of recovery and normal function of 7th nerve when treated solely by surgery. Is such cases the surgeon must decide whether to perform radical procedure or to preserve facial nerve [1]. Excision of the nerve, regardless of various reconstruction techniques, is associated with a severe aesthetic and functional defect. On the other hand, positive surgical margin is an independent negative factor [2,3]. In the case of a positive margin it is necessary to carry out a radical procedure (frequently with excision of 7th nerve) and/or radiotherapy. In the case of a close margin after excision of early T1/T2 low-/intermediate-grade carcinomas and no other indications for supplementary treatment, the management ⇑ Corresponding author at: Department of Otolaryngology, Medical University of Gdan´sk, ul. Smoluchowskiego 17, 80-214 Gdan´sk, Poland. E-mail address: [email protected] (D. Stodulski). http://dx.doi.org/10.1016/j.oraloncology.2017.03.001 1368-8375/Ó 2017 Elsevier Ltd. All rights reserved.

is not so obvious and a decision has to be made between adjuvant radiotherapy and the wait&watch strategy [4]. In order to assess the legitimacy of the wait&watch strategy the authors evaluated their own material.

Material and methods The study was conducted according to the Declaration of Helsinki on biomedical research involving human subjects. Of 78 patients operated on in the Department of Otolaryngology, due to primary parotid gland cancer (PPC) from 2001 to 2011, 32 patients were selected with a history of parotidectomy with preservation of 7th nerve and negative (1), but close (5) surgical margin, who did not receive supplementary radiotherapy due to other indications (including T3/T4 status or/and high grade or/ and neural/perineural invasion or/and lymphatic/vascular invasion or/and intra/periparotid or/and cervical lymph node metastases).

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Table 1 Clinical-pathological data and follow-up of patients with close surgical margin. No

Age

Sex

Symptoms of malignacy C/F/I

Symptoms (time/months)

Parotidectomy (ESGS)

Histology/ grade

pT

Margin (mm)

Tumor size

Encapsulation

Tumor structure

DFS (months)

OS (months)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

53 68 31 75 11 51 53 42 77 29 51 47 26 47 50 27 83 19 60 62 75 55 32 74 22 65 52 21 24 63 36 75

F F M M F M M F F M F F F M F F M F M F F M F M F F F F F M M F

/ / / / / / / / / / / / / / +/ / / / / / / / / / +/ / / / +/ / / / / / / / / / +/+/+ / / / /+ /+/+ /+/ / / / /+ +/+/+ /+/+ /+/ / / /+/ / /

12 360 48 6 4 36 360 3 24 24 60 18 4 6 1 6 12 100 70 6 12 12 1 4 36 12 12 96 6 12 10 10

SCP (I,II) SCP (I,II) TCP (I,II,III,IV) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) TCP (I,II,III,IV) SCP (I,II) PCP (II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II) PCP (II) SCP (I,II) SCP (I,II) SCP (I,II) TCP (I,II,III,IV) SCP (I,II) SCP (I,II) SCP (I,II) SCP (I,II)

AcCC LG AdCC IG AdCC IG MEC IG AcCC LG CXPA LG AC NOS LG MASC LG AC NOS LG MAC LG MASC LG EMC LG AcCC LG CXPA LG AdCC IG EMC LG EMC LG AcCC LG AcCC LG AcCC LG MASC LG AcCC LG MCa LG MEC LG AcCC LG AC NOS LG MEC LG MEC LG AcCC LG MEC lG AcCC LG MEC LG

T1 T1 T1 T2 T1 T2 T2 T2 T2 T2 T2 T1 T2 T2 T1 T2 T2 T1 T1 T2 T2 T2 T2 T2 T1 T2 T1 T1 T1 T1 T1 T2

1 1 1 1 1 2 1 1 1 2 1 3 1 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3 1

1.4  1.4 1.2  1.2 11 3.8  3.5 2  1.5 2.5  2.5 44 2.2  1.1 3  3.2 33 2.5  1.2 2.5  1.7 43 33 1.9  1.9 44 3  2.5 11 1.5  1 2.5  2.5 32 2.2  3 2.4  2 2.5  2.2 0.8  1.2 3.4  2.7 1.3  1 1.2  1.2 11 1.8  1.7 1.8  1.8 2.2  1.8

Yes Yes Yes Yes Yes Yes Yes Yes No Yes Partial Yes Yes (infiltrated) Yes Yes Partial Yes Yes No Yes (infiltrated) Yes Yes Yes Yes Partial Yes (infiltrated) Yes Yes Yes Yes (infiltrated) Yes (infiltrated) Yes

Solid Cystic-solid Solid Cystic Solid Solid Solid Cystic Cystic-solid Solid Solid Solid cystic-solid Solid Solid Solid cystic-solid Solid Solid cystic-solid cystic-solid Solid Solid Cystic-solid Solid Cystic-solid Solid Solid Solid Solid Solid Cystic-solid

186 168 150 76 131 139 131 134 72 DOC 120 109 36 LR 107 108 101 53 LR 56 LR 74 84 88 89 86 80 78 78 68 72 67 61 61 152 60

186 168 150 76 131 139 131 134 72 DOC 120 109 107 107 108 101 104 104 74 84 88 89 86 80 78 78 68 72 67 61 61 152 60

C, clinical; F, fine needle aspiration biopsy; I, imaging (US, MR); SCP, superficial conservative parotidectomy; TCP, total conservative parotidectomy; PCP, partial conservative parotidectomy; ESGS,- European Salivary Gland Society; AcCC, acinic cell carcinoma; CXPA, carcinoma ex pleomorphic adenoma, AC NOS, adenocarcinoma not other specified; AdCC, adenoid cystic carcinoma; MEC, mucoepidermoid carcinoma; EMC, epithelial-myoepithelial carcinoma; MC, myoepithelial carcinoma; MASC, Mammary analogue secretory carcinoma; MAC, mucinous adenocarcinoma; IG, intermediate grade; LG, low grade; DFS, disease-free survival; OS, overall survival; LR, local recurrence; DOC, died of other cause.

They all underwent further clinical-histological analysis. The study group comprised 20 women and 12 men. The patients’ age ranged from 11 to 83 years (mean 48.6 years). Twenty-four patients presented only one symptom – slow growth of the parotid gland tumor. In addition to the tumor growth five other patients complained of pain. The other 3 patients reported fast tumor growth, with 2 of those cases accompanied by tumor tenderness. The duration of symptoms ranged from 1 to 360 months (mean 43.2 months, median 12 months). In 20 out of 32 (62.5%) patients there were no clinical, cytological (FNAC) or radiological (US and MRI) signs indicating malignancy. In 27 cases, superficial parotidectomy was performed (levels I and II according to ESGS), in 3 cases total parotidectomy (levels I–IV), and in 2 cases partial removal of the superficial lobe (level II) [5]. Local stage assessment was based on the TNM staging system from year 2009 - T1N0 -14, T2N0-18 [6]. For all cases, histological revision was carried out according to the WHO classification of parotid gland carcinomas (2005) and with addition of some new histological types of salivary gland neoplasms described since then [7]. Margins ranged from 1 to 3 mm (in 27 cases it was 1 mm, in 3 cases – 2 mm and in 2 cases – 3 mm), average 1.2 mm. There were no patients with a margin > 3 < 5 mm. The most common histological diagnosis was acinic cell carcinoma (AcCC) – 10 cases. This was followed by 6 cases of mucoepidermoid carcinoma (MEC), mammary analogue secretory carcinoma (MASC), epithelial-myoepithelial carcinoma (EMC), adenoid cystic carcinoma (AdCC) and adenocarcinoma not otherwise specified (ACa NOS) and 2 cases of Carcinoma ex pleomorphic adenoma (CXPA). There was one case of myoepithelial carcinoma

(MC) and one case of mucinous adenocarcinoma (mAC). 6 tumors were intermediate grade (IG). All others were low grade (LG). There were 27 encapsulated tumors, including 5 with infiltration into the capsule. In 3 cases the tumor was partly encapsulated, in 2 it was non-encapsulated. In 21 cases the structure of the tumor was solid, in 9 –cystic-solid, in 2 – cystic. All patients were under close clinical monitoring for 60–186 months (mean value for the analyzed group: 101 months). For the first 2 years of follow-up, we carried out palpable examinations every three months. In the subsequent years (years 3, 4 and 5) we examined the patients every six months, then once a year. During the first two years MRI was performed every 6 months. In the subsequent years it was performed once a year or immediately in cases of suspected clinical recurrence. Table 1 presents clinical-pathological data and follow-up of the analyzed group of patients. Statistical methods Statistical analysis was carried out using STATA 13.0 statistical package software (StataCorp, TX, USA). Descriptive analysis was conducted. Kaplan-Meier survival curves were used to show disease-free survival and the risk of treatment failure. Results During follow-up, one patient died 72 months after surgery due to non-oncological causes. All other patients are alive and

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and 104 months. The 10-year overall survival (OS) was 96.3% (95%CI 76.5–99.5%). All 3 patients with recurrence of carcinoma had histological diagnosis of epithelial-myoepithelial carcinoma LG, with a margin of 2, 1 and 3 mm, respectively. There were no other distinctive features. Figs. 1–3 present DFS, probability of local recurrence and OS. Discussion

Fig. 1. Kaplan-Meier estimate for disease-free survival (DFS). Vertical lines indicate censoring.

Fig. 2. Kaplan-Meier failure estimate for local recurrence.

Fig. 3. Kaplan-Meier estimate for overall survival (OS).

continuing follow-up. In 3 of the 32 (9.38%, 95% CI 3–26%) patients, local recurrence was observed after 36, 53 and 56 months. The 5-year disease-free survival (DFS) amounted to 90.6% (95%CI 73.7–96.9%). Recurrences were treated by surgery, followed by radiotherapy, which resulted in an overall survival of 107, 104

The definition of a close margin in cancers originating from major salivary glands is not explicit. In the case of mucosal and skin H&N cancer, negative (meaning the safest and associated with low local recurrence risk) is a margin of healthy tissues of at least 5 mm. A positive margin is defined as presence of invasive or in situ cancer cells within the ink-dyed incision line, or according to some authors, a margin smaller than 1 mm. Therefore, a close margin can be defined in two ways: as a capsule of healthy tissues around the tumor <5 mm but without microscopic cut-through of tumor or a margin 1 and <5 mm [4,8]. However, this definition does not pertain to all locations of the squamous cell carcinoma of the head and neck. Alicandri-Ciufelli et al. performed a systematic review of publications on a close margin in SCC H&N. Based on this review it was shown that the criteria of a close margin significantly differ depending on the tumor’s location. In the case of the vocal cord (cordectomy) it is 1 mm, oral cavity 4 mm, and larynx (laryngectomy) and oropharynx usually 5 mm [9]. In the presented study, the lower limit of a close margin was at least 1 mm. This is because lack of tumor cells in the incision line did not seem to be a sufficiently reliable criterion. The opportunity for the pathologist to examine patient’s specimens once more in order to confirm the quality of the margins and possibly reclassify them histologically is extremely important. In the work by Ransohoff et al., in which they assessed margins after H&N carcinoma resections retrospectively only, in as much as 20% of patients, the primary site margin could not be definitively determined based on pathology reports, operative reports and follow-up notes [10]. In most publications concerning the parotid gland carcinoma, close margin is presented, along with positive margin, as an unfavorable prognostic factor. Such an approach makes it impossible to show the true significance of a positive margin. A close margin, which is not fully safe, is a type of negative margin and can unfavorably ‘‘blur” the prognosis of the positive margin, which is a microscopic residual disease. This was well shown in the work by Pohar et al., in which positive and close margins (jointly) were not statistically significant as risk factors for local failure-free survival in a univariate and multivariate [11]. Vander Poorten et al. performed a positive vs negative or close margin analysis and positive margin turned out to be the major factor predicting recurrence [12]. In the material of 179 LG salivary gland carcinomas (including 131 parotid), close margin (<5 mm) was found in 35.8% of patients. However, it did not turn out to be a significant risk factor for recurrence [13]. Adjuvant radiotherapy plays a very important role in the treatment of parotid gland cancer. Widely acknowledged indications for its use include: high stage (T3/T4), high grade, positive margins, neural/perineural invasion, cervical lymph node metastases and lymphatic/vascular invasion [1]. In addition to the abovementioned recommendations, the National Comprehensive Cancer Network also recommends consideration of post-operative radiotherapy in the case of close margins, intermediate grade, histology of AdCC and tumor spillage [4]. Based on the study conducted by Armstrong et al. it was observed, that supplementary RT significantly improved therapeutic results in patients with stage III and IV and/or LNM, but was of no significance in cases of patients with stage I and II [14]. Similar results were presented by Terhaard et al., who showed that postoperative radiotherapy vs surgery alone in

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malignant salivary gland tumors improved the 10-year local control only in T3/T4, perineural, bone invasion and 5-year regional control for pN+. However, supplementary radiotherapy significantly affected the therapeutic results in all patients with positive and close margins, regardless of the T-stage (82 vs 44% and 95 vs 55%, respectively) [15]. Cho et al. showed that adjuvant radiotherapy after low-grade salivary gland cancer resection, significantly reduces recurrences in patients with pathological risk factors (perineural or lymphovascular invasion, extraparenychmal extension, positive margin), node metastases and advanced T-stage tumors. Surgical treatment alone allows for very good oncological results in patients with pT1T2 low grade tumors, even cases of a close margin [13]. Richter et al. presented the outcomes of adjuvant radiotherapy from 17 patients with close/positive (14 and 4 cases, respectively) as the only indication after intermediate/low grade T1-T3 parotid carcinoma excision. All patients treated with radiotherapy with good tolerance (acute toxicity was limited to grade 1, late toxicity was not observed) and showed no recurrence for 11–154 months, with a median follow-up of 32 months [16]. In our group of patients, local recurrence was observed after 36–56 months, which means that we must wait for the final results of the treatment discussed in the material by Richter et al. In the presented material we achieved good oncological outcomes without adjuvant radiotherapy (5-y DFS 90.6%), and after combined treatment of the local recurrence, the OS for the entire group was approximately 100%. Perhaps, in the case of I/LG parotid T1/T2 tumors the safe margin should be >1 mm. Interestingly enough, all patients diagnosed with local recurrence had histological diagnosis of the epithelial-myoepithelial carcinoma. Even though this relatively rare neoplasm is classified as a low-grade tumor, it is characterized by a high proportion of local recurrences of 23–80% [17]. Therefore, every EMC should be considered a neoplasm of high recurrence risk, and supplementary radiotherapy should be considered in the case of a close margin. The number of patients in this study was limited and it is necessary to carry out a multi-center continuation study in order to fully assess the prognostic value of the close margin in early I/L grade parotid gland carcinoma.

Conclusion The watch&wait strategy with intensive follow-up is justified in the case of a close margin after excision of I/LG T1/T2 parotid tumors. EMC should be considered as a neoplasm associated with higher risk of recurrence.

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