Compartmental tongue surgery: Long term oncologic results in the treatment of tongue cancer

Oral Oncology 47 (2011) 174–179

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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Compartmental tongue surgery: Long term oncologic results in the treatment of tongue cancer Luca Calabrese a,⇑, Roberto Bruschini a, Gioacchino Giugliano a, Angelo Ostuni a, Fausto Maffini b, Maria Angela Massaro a, Luigi Santoro c, Valeria Navach a, Lorenzo Preda d, Daniela Alterio e, Mohssen Ansarin a, Fausto Chiesa a a

Division of Head and Neck Surgery, European Institute of Oncology, Milan, Italy Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy d Division of Radiology, European Institute of Oncology, Milan, Italy e Division of Radiotherapy, European Institute of Oncology, Milan, Italy b c

a r t i c l e

i n f o

Article history: Received 28 July 2010 Received in revised form 17 December 2010 Accepted 21 December 2010 Available online 22 January 2011 Keywords: Tongue cancer Compartmental surgery Oncological results

s u m m a r y Compartmental tongue surgery (CTS) is a surgical technique that removes the compartments (anatomofunctional units) containing the primary tumor, eliminating the disease and potential muscular, vascular, glandular and lymphatic pathways of spread and recurrence. Compartment boundaries are defined as each hemi-tongue bounded by the lingual septum, the stylohyoid ligament and muscle, and the mylohyoid muscle. In this non-randomized retrospective study we evaluated the oncologic efficacy of CTS in patients with squamous cell carcinoma (SCCA) of the tongue treated from 1995 to 2008. We evaluated 193 patients with primary, previously untreated cT2-4a, cN0, cN+, M0 SCCA with no contraindication to anesthesia and able to give informed consent. Fifty patients treated between October 1995 and July 1999 received standard surgery (resection margin >1 cm); 143 patients treated between July 1999 and January 2008 received CTS. Study endpoints were: 5-year local disease-free, locoregional disease-free and overall survival. After 5 years, local disease control was achieved in 88.4% of CTS patients (16.8% improvement on standard surgery); locoregional disease control in 83.5% (24.4% improvement) and overall survival was 70.7% (27.3% improvement). The markedly improved outcomes in CTS patients, compared to those treated by standard surgery, suggest CTS as an important new approach in the surgical management of tongue cancer. Ó 2010 Elsevier Ltd. All rights reserved.

Introduction Surgery remains the primary therapeutic approach to early stage tongue cancer, and is often part of a multi-modal approach to advanced disease. Overall survival for advanced tongue cancer is about 50% and has not changed substantially over the last three decades.1,2 Surgery with curative intent aims to remove the primary tumor with a wide margin of normal tissue – a 1–2 cm circumferential macroscopic margin is usually considered sufficient.3 However the rational bases for such a margin are unclear,4 actual margins vary,5 and portion of tongue musculature to be removed in accordance with the ‘wide margin’ approach is not always well-defined pre-operatively. Wide resection is the common surgical approach to solid tumors in various parts of the body. However for musculoskeletal ⇑ Corresponding author. Address: European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy. Tel.: +39 02 57489490; fax: +39 02 94379216. E-mail address: [email protected] (L. Calabrese). 1368-8375/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2010.12.006

or parenchymal sarcomas, application of the notions of anatomical compartments has revolutionized the concept of radicality.6–10 Since cancer progresses following the path of least resistance, it is possible to define an anatomical compartment that confines the tumor, and whose boundaries (layers of fascia) form a barrier to tumor spread. Complete removal of such a compartment is therefore the goal of compartmental surgery and has resulted in significant improvements in local disease control compared to wide resection.6–10 In one of the key experiences on 471 patients, Azzarelli7 found that local disease control was 76% in sarcoma patients treated with compartmental surgery, compared to 53% in those receiving wide excision (P < 0.001) although other ‘traditional’ variables also significantly influenced outcome. The tongue is a symmetrical organ whose extreme boundaries are the periosteum (lateral, inferior, and anterior) and the midline lingual septum. It is composed of intrinsic and extrinsic muscles that function in a highly coordinated manner to perform the fundamental functions of speech and swallowing. Anatomically, the tongue consists of paired symmetrical compartments, without

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distinction between the body and the base of the tongue. The lingual septum is the medial margin separating adjacent compartments in each hemi-tongue. The periosteum along the lingual surface of the mandible constitutes the lateral and anterior margins. The stylohyoid muscle and ligament form the posterior boundary. The mylohyoid muscle forms the floor of the compartment along its entire length. The compartments contain the tongue musculature (intrinsic and extrinsic) together with stromal, glandular (sublingual) and neuro-vascular structures (lingual nerve, artery and vein, terminal portion of hypoglossal nerve). We recently reported on technical aspects of compartmental tongue surgery (CTS).11 In essence it involves: (a) an anatomical approach to the disease involving removal of the primary lesion and all of its potential pathways of progression – muscular, lymphatic and vascular; and (b) identification of the territory at risk for metastatic representation: the muscular (mylohyoid), neurovascular (lingual nerve and vein) and glandular (sublingual and submandibular) tissues within the compartment, that form a bridge between the primary tumor and the cervical lymphatic chain. In this retrospective study we assessed the long-term oncologic efficacy of compartmental tongue surgery in comparison to standard surgery in 193 patients treated from October 1995 to January 2008 at the European Institute of Oncology (IEO) in Milan. Patients treated from 1995 to 1999 received standard surgery; patients treated after 1999 received CTS.

Table 1 Preoperative characteristics, pathological findings and postoperative treatments of patients undergoing standard and compartmental tongue surgery (CTS).

Materials and methods Patient selection We considered consecutive patients treated for stages II–IV (AJCC 7th edition12) squamous cell carcinoma (SCCA) of the oral tongue or base of the tongue who underwent major ablative surgery followed by reconstruction. Data on the cases was archived in the prospective database of the Division of Head and Neck Surgery, European Institute of Oncology. Eligible patients were >18 years of age, of any sex, able to give written informed consent (standard surgery or CTS), who had previously untreated cT3-4a, cN0, cN+, M0 SCCA of the tongue or the tongue base, or patients with cT2, cN0, cN+, M0 SCCA and clinical or radiologic suspicion of infiltration of the deeper muscle planes suggesting higher pathological than clinical stage. We excluded patients with stage ycT1, cT2 (without clinical or radiological evidence of infiltration of the extrinsic musculature), cN0, cM0 disease amenable to trans-oral surgery, and patients with co-morbidities compromising the safety of surgery. Pre-operative evaluation Patients who presented for initial evaluation were interviewed, given a physical examination together with a lifestyle questionnaire and assessed by fiber-optic-video pharyngolaryngoscopy (FOVPL). Lesions were biopsied with a conchotome or punch to avoid distortion of lesion architecture and also avoid subsequent underestimation of tumor size and possibly stage. Staging was completed with CT or MRI with contrast, and PET if considered necessary. MRI is the preferred imaging modality as it allows identification of individual muscle involvement and provides estimates of lesion thicknesses that strongly correlate with histologic tumor thicknesses (although MRI estimates are usually greater than histologic findings).13 However, not all patients received MRI, as a considerable proportion come from other parts of Italy and had variable preoperative work-up (often CT rather than MRI). Imaging studies performed outside the Institute were reviewed with radiol-

Characteristic

Conventional (N = 50)

CTS (N = 143)

P value

Median age (interquartile range) <40 years 40–49 years 50–59 years P60 years Sex Men Women Alcohol consumption No Yes Former Smoking No Yes Former No. of comorbiditiesa 1 2 3 Neck involvement Bilateral Ipsilateral Tumor site Base of the tongue Tongue Reconstruction flap None Chinese ALT Pectoralis major Platysma Others Tumor grade G1 G2 G3 Metastatic nodes (N) 0 1 2 3 4 >4 Surgical margin (microscopic) Negative Positive Close (down to 1 mm) T status T2 T3 T4a N status N0 N1 N2 (a,b,c) N3 Stage II III IVa IVb Postoperative treatment None RT RT + chemotherapy Follow-up duration, years Median (range)

55 (47–66) 7 (14.0%) 11 (22.0%) 13 (26.0%) 19 (38.0%)

53 25 32 38 48

0.40

33 (66.0%) 17 (34.0%)

109 (76.2%) 34 (23.8%)

18 (36.7%) 29 (58.0%) 3 (6.0%)

59 (41.3%) 81 (56.6%) 3 (2.1%)

19 (38.0%) 15 (30.0%) 16 (32.0%)

40 (28.0%) 55 (38.5%) 48 (33.6%)

28 (56.0%) 17 (34.0%) 5 (10.0%)

84 (58.7%) 33 (23.1%) 26 (18.2%)

25 (50.0%) 25 (50.0%)

89 (62.2%) 54 (37.8%)

12 (24.0%) 38 (76.0%)

31 (21.7%) 112 (78.3%)

5 (10.0%) 10 (20.0%) 6 (12.0%) 21 (42.0%) 7 (14.0%) 1 (2.0%)

5 (3.5%) 38 (26.6%) 62 (43.4%) 27 (18.9%) 6 (4.2%) 5 (3.5%)

7 (14.0%) 26 (52.0%) 17 (34.0%)

9 (6.6%) 56 (39.2%) 78 (54.5%)

16 (32.0%) 14 (28.0%) 5 (10.0%) 7 (14.0%) 3 (6.0%) 5 (10.0%)

47 (32.9%) 35 (24.5%) 20 (14.0%) 19 (13.3%) 8 (5.6%) 14 (9.8%)

43 (86.0%) 1 (2.0%) 6 (12.0%)

130 (90.9%) 2 (1.4%) 11 (7.7%)

25 (50.0%) 4 (8.0%) 21 (42.0%)

46 (32.2%) 12 (8.4%) 85 (59.4%)

16 (32.0%) 11 (22.0%) 23 (46.0%) 0 (-)

46 (32.2%) 31 (21.7%) 65 (45.4%) 1 (0.7%)

9 (18.0%) 8 (16.0%) 33 (66.0%) 0 (-)

24 (16.8%) 12 (8.4%) 106 (74.1%) 1 (0.7%)

21 (42.0%) 24 (48.0%) 5 (10.0%)

46 (32.2%) 53 (37.0%) 44 (30.8%)

2.4 (0–9.8)

2.6 (0.1–9.1)

(45–63) (17.5%) (22.4%) (26.6%) (33.6%)

0.92

0.16

0.35

0.37

0.19

0.13

0.73

0.0003

0.03

0.98

0.62

0.07

0.87

0.42

0.015

a

From among the following: cardiovascular disease, lung disease, gastrointestinal disease, renal disease, metabolic disease, central nervous system disease, viral diseases.

ogists as part of surgical planning and repeat scans were obtained if considered necessary.

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In accord with the policy in force at our institute before 2005, patients with disease infiltrating a surgical margin, inadequate surgical margins, residual disease, advanced tumors (pT4 and some pT3) or metastatic disease in removed lymph nodes, received postoperative RT. After 2005, patients with positive margins and extracapsular spread in lymph nodes were considered high risk12–16 and were given chemotherapy in addition to standard postoperative RT.

was considered as a competing event.17 Overall survival was calculated from date of surgery to date of death or latest followup. Survival experience was represented by the Kaplan–Meier approach18 with differences between groups evaluated by the log-rank test. The analysis focused on the influence of type of surgery (standard vs. CTS) on the main endpoints of disease-free and overall survival. Since patients were not randomized to type of surgery, multivariate proportional hazard Cox modeling was necessary to take account of differences in patient, tumor and surgery variables between the two groups.19 Covariates candidate for inclusion in the multivariate models were selected from: surgery (standard vs. CTS), T status (T2 vs. T3–T4), N status (N0 vs. N+), neck involvement (bilateral vs. ipsilateral), tumor grade (G1 + G2 vs. G3), postoperative treatment (none vs. RT vs. RT + chemotherapy), alcohol consumption (no vs. yes) and BMI (<25 vs. P25 kg/ m2). Predictors for inclusion in the multivariable models were chosen stepwise, if the Wald-test P value was 60.20. The results from the Cox models were presented as hazard ratios (HR) with 95% confidence intervals (CI) along with the Wald test P value. The Gray test,20 which takes competing risks into account, was also used to support the Cox model results. The groups defined by type of surgery were also characterized by descriptive statistics (medians with range for continuous variables; proportions for categorical variables) with the significance of differences assessed by Wilcoxon’s rank-sum test for continuous variables and Pearson’s chisquare for categorical variables. The analyses were performed with SAS statistical software (SAS Institute, Cary, NC). All tests were two-sided.

Follow-up

Results

Clinical examination with FOVPL were performed every 3 months in the first 2 years, every 6 months from years three to five and annually thereafter. USG, CT, MRI, or PET-CT images were obtained if considered necessary.

As the study was non-randomized it is unsurprising that patients in the two surgical groups differed considerably. Specifically the two series differed in terms of sex (P = 0.036), and type of reconstruction (P = 0.0003) (Table 1). Tumor grade was worse in the CTS group (P = 0.03), and RT plus chemotherapy more often applied (P = 0.015); CTS patients also tended to have more advanced disease stage (P = 0.07) (Table 1). Table 3 tabulates events, and shows that deaths, local recurrences and regional recurrences were less common in the CTS group, while the proportion who developed metastases in the

Surgical techniques All operations were performed under general anesthesia. Prophylactic tracheotomy (surgical or percutaneous), separate from the neck dissection field, was performed in all cases. Lateral neck dissection was performed depending on the primary lesion and clinical/radiological status of the neck, and was always en block with the primary. Glossectomy employed either standard surgery (margins >1 cm) or CTS.11 Post-operative pathologic staging The removed surgical specimen was oriented and mounted on a sponge block to prevent tissue retraction prior to fixation (10% formalin). Specimen were examined to determine histological isotype, grade, presence or absence of vascular invasion, and presence or absence of lymph node metastases. Postsurgical treatments

Statistical analysis Disease-free survival, local disease-free survival and locoregional disease-free survival were calculated from date of surgery to the date of event or latest follow-up. In these analyses death

Table 2 Univariate (Kaplan–Meier) and multivariate (Cox proportional hazards model) analyses of factors related to 5-year local recurrence. Characteristic

Overall surgery Standard CTSs Neck involvement Bilateral Ipsilateral Grade G1 G2 G3 T status T2 T3–T4a N status N0 N+ Postoperative therapy None RT RT + chemotherapy a b

N

Recurrence

Coxb

Kaplan–Meier a

N (%)

Estimate

P value

193 50 143

24 (12.4) 12 (24.0) 12 (8.4)

84.2% 71.6% 88.4%

HR (95% CI)

P value

0.003

1 0.31 (0.13–0.72)

0.006

114 79

11 (9.7) 13 (16.5)

86.8% 80.7%

0.10

16 82 95

2 (12.5) 14 (17.1) 8 (8.4)

89.4% 82.4% 85.6%

0.12

71 122

6 (8.4) 18 (14.7)

90.2% 79.3%

0.13

1 5.44 (1.89–15.69)

0.002

62 131

4 (6.4) 20 (15.3)

93.3% 78.6%

0.04

1 3.95 (1.29–12.09)

0.02

67 77 49

10 (14.9) 11 (14.3) 3 (6.1)

82.2% 80.9% 93.9%

0.36

1 0.48 (0.20–1.19) 0.26 (0.07–1.02)

1 3.37 (1.40–8.12)

0.007

0.044 (G1 + G2) 1 0.40 (0.16–0.98)

Log-rank test. Cox model with stepwise selection at P = 0.20 for entry. The table only shows variables entered in the final model.

0.11 0.054

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CTS group was more than double that in the standard group. Tables 2 and 3 present the results of univariate (Kaplan–Meier) and multivariate (Cox) analyses of the influences of risk factors on outcomes. CTS was associated with significantly decreased risk of local (HR: 0.31; 95%-CI: 0.13–0.72, P = 0.006, Wald test) and locoregional recurrence at 5 years (HR: 0.36; 95%-CI: 0.17–0.80, P = 0.011, Wald test), whereas there was no difference in distant relapse risk at 5 years (HR: 1.90; 95%-CI: 0.55–6.51, P = 0.31, Wald test). For all these outcomes, the Gray test provided similar results (data not shown). Overall survival was also better in the CTS group,

with risk of dying (any cause) within 5 years about one third of that in the standard surgery group (HR: 0.41; 95%-CI: 0.24–0.70, P = 0.0012, Wald test). Survival analyses were performed with censoring at 5 years since most events occurred within the first 5 years (local 24 of 26; regional 15 of 15; metastases 24 of 25; deaths 63 of 68). Discussion Cancer of the tongue is aggressive, as evidenced by its locally invasive behavior and propensity to metastasize to cervical lymph

Table 3 Univariate (Kaplan–Meier) and multivariate (Cox proportional hazards model) analyses of factors related to 5-year locoregional recurrence, metastasis, any recurrence and overall survival. Characteristic

Events (%)

Estimate (%) Locoregional recurrence Standard CTS Metastasis Standard CTS Any recurrence Standard CTS Overall survival Standard CTS a b c d e f

38 (19.7) 17 (34.0) 21 (14.7) 22 (11.4) 3 (6.0) 19 (13.3) 60 (31.1) 20 (40.0) 40 (28.0) 61 (31.4) 27 (54.0) 34 (23.8)

Coxb

Kaplan–Meier

75.9 59.1 82.0 86.5 93.0 84.4 64.3 54.0 68.1 62.6 43.4 70.7

a

P value

HR (95% CI)

P value

0.002

1 0.36 (0.17–0.80)

0.011c

0.22

1 1.90 (0.55–6.51)

0.31d

0.06

1 0.57 (0.32–0.99)

0.047e

0.0004

1 0.41 (0.24–0.70)

0.0012f

Log-rank test. Cox models with stepwise selection at P = 0.20. Final model included alcohol consumption, type of surgery (standard vs. CTS), T status, N status, neck involvement (0.05 < P 6 0.20) and BMI (0.05 < P 6 0.20). Final model included CTS, T status (0.05 < P 6 0.20), N status (0.05 < P 6 0.20) and neck involvement. Final model included type of surgery (standard vs. CTS), T status, N status, neck involvement, and tumor grade. Final model included type of surgery (standard vs. CTS), neck involvement, T status, N status, tumor grade and postoperative therapy.

Figure 1 Tongue cancer: tumor progression. (A) Cadaver specimen showing the orientation of the tongue musculature. (B) Gross specimen of a tongue tumor: progression along the orientation of the muscle fibers. (C) Surgical specimen: progression along the genioglossus muscle. (D) Pre-operative MRI images of the patient in C.

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nodes. The current goal of surgery with curative intent is removal of the primary together with as much surrounding tissue as necessary to ensure that all macroscopic disease is eradicated; this is thought to provide the best chance that microscopic disease – potential source of recurrence – is also removed. According to this ‘more-is-better’ approach, it is widely accepted that >1 cm of apparently healthy tissue beyond the macroscopic margin of the disease should be removed.4,21 Better disease-free survival is in fact associated with wide clear resection margins and negative nodes; and obtaining wide muscle margins is also considered important because the most common cause of tumor-related death is lack of disease control at the primary site. However, 9–25% of patients with negative margins develop recurrence at the primary site.22–24 For T1 and T2 disease, without clinical or radiological evidence of neck metastases, disease control is 80–90% and 60–70%, respectively, while 5-year survival for patients with stage III or IV disease is in the range 18–55%.25,26 The surgical approach to tongue cancer is influenced heavily by the current TNM classification12: cancers are primarily categorized according to the two-dimensional surface diameter approach (T), and the body and base of the tongue are considered distinct locations, notwithstanding the absence of any anatomical difference between them. Tumor size and invasion of the extrinsic muscles are the most important variables for the pathologic staging of the disease, regardless of location. Microscopic disease presence in the extrinsic muscles is one of the criteria for classifying a tumor as pT4 rather than pT2.12 The limitations of this approach to staging have been extensively discussed in the literature and indicate that surface diameter on its own has insufficient prognostic utility.4,5,25–27 Other prognostic indicators not contemplated by the TNM classification that are important are histopathologic risk score,24,28 depth of infiltration,29–33 the presence or absence of perineural34,35 and lymphovascular36 infiltration (permeation or embolization present in almost 50% of cases5,37,38), tumor-induced modification of myofibroblasts37,39,40 and the spread to the areolar fibro-fatty connective tissue that links the tongue (oral and mobile) to the sublingual and submandibular glands, and the cervical lymphatic chain.4,5,25 Furthermore, while the radiological41 and histological24,37,42 features of disease progression are well recognized, there is a fundamental lack of understanding of the anatomy of tumor progression. Steinhart and Kleinsasser43 described patterns of initial infiltration in floor of the mouth and tongue cancer: infiltration of the sublingual gland, infiltration between the tongue intrinsic muscles and the genioglossus, and direct infiltration of the intrinsic musculature. What they did not assess was macroscopic progression along those structures and how these features impact surgical therapy. We developed CTS based on an anatomical study of macroscopic specimens from tongue cancer patients (Fig. 1). We found that in the tongue, and contrary to some reports,4 the tumor behaved in an identical manner to tumors in musculoskeletal compartments of the extremities: tumor cell migration occurred longitudinally from the primary extending along and between the intrinsic and extrinsic muscle fibers, as noted by others5,43 and progression was deflected by the anatomical boundaries of the compartment. In agreement with Shaheen,44 we also found that tumor progression occurred inferiorly (in depth) as well as posteriorly following the sharp bend from the base of the tongue to the floor of the mouth. In this district the course of nerves and vessels runs parallel to the muscle fibers and these structures are also facile pathways for tumor progression. Anatomical relationships therefore force tumor progression to take place longitudinally, de-emphasizing the circumferential approach to removing primary lesions.

From these considerations it is evident that CTS introduces a rationale to what constitutes an adequate margin: complete removal of the involved muscle(s) affords oncologic radicality as it removes the most likely path of disease spread and potential sites of residual disease foci. These ideas are illustrated by our findings of statistically significant improvements of 16.8% in local disease control, 24.4% in locoregional disease control, and 27.3% in overall survival at 5 years follow-up, compared to our historical series undergoing standard surgery. We note, however, that CTS patients received significantly more chemotherapy plus radiotherapy than the standard group and this may have contributed to our good control rates. It is also noteworthy that results for the standard surgery group are consistent with those of the literature25,26 and control rate differences between the two groups were maintained throughout the 5 years of follow-up (Fig. 2). To conclude, we propose that the change from circumferential to longitudinal compartmental resection amounts to a paradigm shift in the surgical approach to locally advanced SCCA of the tongue. Our clinical experience also indicates that compartmental surgery permits a rational and functionally conservative approach to demolition and we are seeking to demonstrate this in a prospective evaluation of quality of life and functional rehabilitation in patients with locally advanced disease. At this point we make a simple observation to indicate how this might be possible: muscles lose

Figure 2 Kaplan–Meier curves showing local disease-free and overall survival in the standard surgery and CTS groups.

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