Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection

ORAL ONCOLOGY

Oral Oncology 35 (1999) 257±265

Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection J.A. Woolgar a,*, S. Rogers b, C.R. West c, R.D. Errington d, J.S. Brown b, E.D. Vaughan b a Oral Diseases Unit, The University of Liverpool School of Dentistry, Liverpool L3 5PS, UK Regional Centre for Maxillofacial Surgery, University Hospital, Aintree, Liverpool L9 7AL, UK c Department of Public Health, The University of Liverpool, Liverpool L69 3BX, UK d Clatterbridge Centre for Oncology, Wirral L63 4JY, UK

b

Received 23 October 1998; accepted 30 October 1998

Abstract The outcome of 200 patients with squamous cell carcinoma of the oral/oropharyngeal mucosa managed by primary radical surgery and simultaneous neck dissection and followed for 2.2±8.5 years is reported and related to the pathological features. Ninetynine patients (50%) had cervical lymph node metastases including 16 (8%) with bilateral metastases. Actuarial (life tables) survival analysis showed the overall 2-year survival probability was 72%, falling to 64% at 5 years. The 5-year survival probability was 81% for patients without metastasis, 64% for patients with intranodal metastases and 21% for patients with metastases showing extracapsular spread. A total of 60 patients (30%) died of/with their cancer: 36 (18%) of local recurrence; 4 (2%) of a metachronous primary tumour; 14 (7%) of regional disease, and 6 (3%) with systemic metastases. A further 15 patients (8%) had relapsed but were clinically disease-free after additional surgery. In all, 7% of the series developed metachronous primary tumours. In addition to nodal metastasis, survival was related to the site and stage of the primary tumour, the histological grade and pattern of invasion, status of the resection margins and pathological TNM stage. For patients with lymph node metastasis, extracapsular spread was an important indicator of tumour behaviour and we recommend its use as a criterion for pathological N staging. # 1999 Elsevier Science Ltd. All rights reserved. Keywords: Oral cancer; Squamous cell carcinoma; Metastasis; Survival; Recurrence; Outcome

1. Introduction Although oral squamous cell carcinoma (SCC) accounts for over 1100 deaths each year in England and Wales [1], it is still an uncommon disease. Historically, patients have been referred to various specialities, nonsurgical and surgical, o€ering a variety of treatment regimes and this wide dispersal of patients and the lack of de®ned treatment protocols explain the paucity of reliable data on patient management and survival [2, 3]. It is hoped that the rationalisation of cancer services [4] will allow more e€ective audit of cancer treatments and outcome and, hence, facilitate the development of standard management protocols. Since the late 1980s, the Regional Centre for Maxillofacial Surgery at the University Hospital, Aintree, * Corresponding author. Tel.: +44-151-706-5245; Fax: +44-151706-5240.

Liverpool, UK (which receives referrals from the geographic area of the former Mersey Regional Health Authority), has adopted a standard policy for the management of oral cancer. The majority of patients are treated by primary radical surgery including functionpreserving neck dissection and the resulting defects are reconstructed primarily with free tissue transfer; all the resection specimens are assessed by a single pathologist using a standard protocol [5] and patients are selected for post-operative radiotherapy on the basis of detailed pathological staging. We presented our preliminary results (based on a minimum 1-year post-operative follow-up) in 1995 [6]. The present study is based on a larger series of patients (including the original cohort) with a longer post-operative review period (between 2.2 and 8.5 years). In addition, we present a detailed analysis of the patterns of locoregional relapse including the occurrence of metachronous (second) primary tumours.

1368-8375/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S1368 -8 375(98)00113 -4

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J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

2. Materials and methods 2.1. Surgical cases A series of 200 consecutive patients undergoing surgery as the primary treatment for an intra-oral/ oropharyngeal SCC at the Regional Centre for Maxillofacial Surgery, University Hospital, Aintree, Liverpool, UK, between October 1989 and December 1995, formed the material for the study. None of the patients had received pre-operative radiotherapy, chemotherapy or previous oral surgery, other than routine dento-alveolar procedures and a recent diagnostic biopsy. The series comprised 130 males (65%) and 70 females (35%). The males had a mean age of 58 years (SD=11.74, range 30±88 years), signi®cantly lower than the mean age of 64 years (SD=11.39, range 33±87 years) of the females (w2=11.03, 1 df, P=0.0009). The clinical stage of the primary tumour was determined according to the recommendations of the UICC [7], except for one modi®cation, namely tumours of the oral tongue and ¯oor of mouth (FOM) were divided into three categories: lateral border of tongue, ventral tongue/FOM and FOM. The assessment of the patients included examination under general anaesthesia, supplemented by diagnostic imaging (computerised tomography and/or magnetic resonance imaging). The neck was recorded as clinically positive (N+) if any of the investigations suggested that nodal metastasis was present. The lateral border of tongue was the site of the primary tumour in 51 patients (26%), ventral tongue/ FOM in 33 (17%), FOM in 30 (15%), retromolar area in 20 (10%), lower alveolus/gum in 14 (7%), upper alveolus/gum in 2 (1%), buccal mucosa in 18 (9%) and oropharynx in the remaining 32 patients (16%). Tumour site was related to sex such that the male:female ratios were 5.7:1 and 3.3:1 for tumours of the retromolar area and FOM, respectively, whereas the ratio was 0.6:1 for tumours of the lower alveolus/gum and the buccal mucosa (w2=18.88, 8 df, P=0.016). Thirty (15%) of the primary tumours were Stage T1; 81 tumours (41%) were T2; 16 tumours (8%) were T3, and the remaining 73 tumours (37%) were T4. Clinical T stage was related to site with a high frequency of T4 tumours sited on the lower alveolus/gum, retromolar area and ventral tongue/FOM (w2=93.86, 24 df, P<0.0001). There was no signi®cant relationship between T stage and sex (w2=1.33, 3 df, P=0.72). Seventy-seven patients (39%) were N+. All patients were M0. The clinical TNM stage was Stage I in 26 patients (13%), Stage II in 58 (29%), Stage III in 41 (21%), Stage IVA in 69 (35%) and Stage IVB in 6 (3%). A total of 139 patients (70%) underwent resection of the primary tumour with simultaneous unilateral (ipsilateral) neck dissection. In the remaining 61 patients (31%), the neck dissection was bilateral. Thus, a total of

261 sides of neck were available for histological assessment. Twenty-four (9%) were radical neck dissections and 237 were modi®ed procedures; 107 encompassed lymph nodes at Levels I±V [5, 8] and 146 encompassed nodes at Levels I±III/IV [5, 8]. Post-operative radiotherapy was employed when pathological staging showed involved/close (within 5 mm) resection margins at the primary site or multiple positive cervical lymph nodes or extracapsular (extranodal) spread (ECS). Of the 200 patients, 110 (55%) were found to have one or more of these features. Radiotherapy (external beam, 50±60 Gy in 25±30 fractions over 5±6 weeks) was started, whenever possible, within 6 weeks of surgery. Patients were reviewed at regular intervals. At the time of analysis, all patients had at least 2.2-years follow-up. Status at last contact was recorded as one of the following: 1. dead of other cause, clinically free of SCC; 2. dead of/with SCC; 3. alive but having received further surgery for SCC; or 4. alive and clinically free of SCC. For Categories 2 and 3, the site of initial relapse was recorded. The disease-free interval and survival were measured to the nearest month. 2.2. Pathological methods The surgical team orientated and labelled the operation specimens and pinned them onto polystyrene blocks before immersion in 10% bu€ered formalin. The ®xed specimens were examined and dissected by a single pathologist (the principal author) according to a standard protocol [5, 9, 10]. The primary tumour was sliced to show maximum size and relation to resection margins. Lymph nodes larger than 0.3 cm were identi®ed by visual inspection and palpation, harvested and assigned to one of the ®ve anatomical levels. The tissue was processed routinely. Histological assessment of haematoxylin and eosin-stained sections of the primary tumour included measurement of the tumour diameter and depth of invasion [5], the histological malignancy grade (HMG) score [10, 11]; the pattern of invasion at the advancing front [5] and nerve and vascular invasion [5, 11]. Each lymph node was recorded as negative or positive for metastatic SCC. Metastatic deposits were measured and the presence and extent of ECS were recorded [5, 9]. Intranodal metastatic deposits measuring less than 3 mm in pro®le were designated micrometastases [9]. 2.3. Statistical methods Survival probability was calculated using the actuarial (life table) method with comparisons by the Wilcoxon test [12]. Pearson's chi-square test (with Yates'

J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

correction for 22 tables) and the two-sample t-test were used in analysis of other clinical and histological data. The analyses were performed using the SPSS-PC package on a microcomputer. Statistical signi®cance is claimed for a two-sided P value of less than 0.05. 3. Results 3.1. Histological features of the primary tumour and the cervical lymph nodes Tumour diameter ranged from 4±100 mm (median=30 mm, mean=33 mm, SD=16.66) and the depth of invasion ranged from 1±65 mm (median=11 mm, mean=13.2 mm, SD=10.39). The pathological T stage was pT1 in 41 cases (21%), pT2 in 68 (34%), pT3 in 19 (10%) and pT4 in the remaining 72 cases (36%). The margins of the resection specimen appeared clear in 107 cases (54%), close in 84 cases (42%) and involved in the remaining 9 cases (5%). An average of 46 lymph nodes were examined in the radical neck dissections, 38 nodes in the modi®ed Levels I±V dissections and 25 nodes in the modi®ed Levels I± III/IV dissections. Nodal metastasis was diagnosed histologically in 99 patients (50%) with 16 (8%) having bilateral metastases. The number of positive nodes per patient ranged from 1 to 39 (median=2, mean=4.7, SD=6.41). Thirty-one patients had a single positive node and 44 patients had between 2 and 5 positive nodes. In 48 patients, the positive nodes were con®ned to a single anatomical level. The numerical highest level of involvement was Level I in 21 patients, Level II in 43, Level III in 17, Level IV in 12, and Level V in 6. In 44 patients, the metastatic tumour was con®ned within the lymph node(s) and, in 16 of these, the largest deposit was a micrometastasis. In 55 patients, ECS was detected, either macroscopically during the laboratory dissection of the surgical specimen (38 patients) or only on histological assessment (17 patients). Tumour was

259

con®ned to perinodal ®brous/adipose tissue in 40 patients but involvement of the internal jugular vein, the sternocleidomastoid muscle or other perinodal structures was evident in 15 cases. The largest metastatic deposit measured 30 mm or less in 87 patients, 31±60 mm in 7 patients and more than 60 mm in 5 patients. The pathological N stage was pN1 in 31 patients, pN2 in 63 patients (pN2a, 1; pN2b, 48; pN2c, 14) and pN3 in the remaining 5 patients. The pTNM stage was I in 32 patients (16%), II in 32 (16%), III in 28 (14%) and IV in 108 patients (54%). The occurrence of metastasis was related to the sex of the patient, the site and stage of the primary tumour, and several histological features. Table 1 summaries the statistical analyses of the groups with and without metastases. Metastasis occurred in 74 (57%) of the 130 males and in 25 (36%) of the 70 females. Metastasis was diagnosed in 59±64% of tumours of the tongue, retromolar area and oropharynx compared to 22% of buccal tumours and less than 7% of alveolar/gingival tumours. Metastasis occurred in 9 (22%) of the 41 pT1 tumours, in 37 (54%) of the 68 pT2 tumours, in 10 (53%) of the 19 pT3 tumours and in 43 (60%) of the 72 pT4 tumours. 3.2. Clinical outcome The post-operative period ranged from 2.2±8.5 years (median 4.5 years). At last contact, 42 patients (21%) had died clinically free of SCC, 60 patients (30%) had died of/with SCC, 15 patients (8%) were alive but had undergone further surgery and 83 patients (42%) were alive and clinically free of SCC. Outcome was signi®cantly related to several clinical features (age, T site, T stage, N stage, but not sex) and multiple histological features (tumour diameter and depth of invasion, HMG score, pattern of invasion, nerve and vascular invasion, status of resection margins, presence and extent of nodal metastasis, pT stage, pN stage and pstage). Table 2 details some of the more important ®ndings.

Table 1 Clinical and histological features related to the presence of lymph node metastasis Feature Sex Tumour site Clinical T stage Clinical N stage Tumour diameter Depth of invasion Histological malignancy grade Pattern of invasion Nerve invasion Vascular invasion Pathological T stage

Test statistic Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square

7.36 24.99 15.90 50.23 19.82 46.40 89.83 52.31 33.40 70.87 16.19

Degrees of freedom

P

1 8 3 1 1 1 1 1 1 1 3

0.0066 0.0016 0.0012 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0010

260

J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

Table 2 Outcome in relation to clinical and histological features Feature

No. of cases

Dead, SCC-free

Dead of/with SCC

Alive, further surgery

Alive, clinically free of SCC

200

65 years

59 years

58 years

58 years

0.0035

30 81 16 73

4 14 6 18

3 24 4 29

7 6 0 2

16 37 6 24

0.0017

Nodal metastasis Absent Present Intranodal MicroECS MacroECS

101 99 44 17 38

19 23 7 5 11

14 46 15 9 22

10 5 2 2 1

58 25 20 1 4

<0.0001

Pathological TNM stage pstage I pstage II pstage III pstage IV

32 32 28 108

3 4 8 27

3 3 4 50

5 4 2 4

21 21 14 27

<0.0001

Surgical resection margins Clear Close Involved

107 84 9

23 18 1

17 36 7

6 8 1

61 22 0

<0.0001

Mean age T stage T1 T2 T3 T4

P

0.033

ECS, extracapsular (extranodal) spread. Table 3 Statistical analysis of clinical and histological features in patients dead of/with squamous cell carcinoma (SCC) compared to patients alive or dead free of SCC Feature Sex Age Tumour site Clinical T stage Clinical N stage Tumour diameter Depth of invasion Histological malignancy grade Pattern of invasion Nerve invasion Vascular invasion Pathological T stage Surgical margins Lymph node metastasis Pathological N stage Pathological TN stage

Test statistic Chi-square t value Chi-square Chi-square Chi-square t value t value Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square Chi-square

Table 3 shows the statistical analyses comparing the group of 60 patients dying of/with SCC with the group of 140 patients who were either alive or had died clinically free of SCC. Between 38 and 41% of patients with retromolar, oropharyngeal and lateral tongue tumours had died of/with their cancer compared with 10±17% of patients with FOM and buccal tumours. The mean tumour diameter of patients dying of/with SCC was 42 mm (SD=16.7, range 8±100 mm) compared to 29 mm (SD=15.1, range 4±80 mm) and the mean depth of

0.00 0.56 12.51 9.19 22.32 5.37 6.44 89.83 11.89 19.43 29.83 15.92 21.82 25.31 8.39 29.91

Degrees of freedom

P

1 198 6 3 1 198 198 1 1 1 1 3 1 1 2 3

1.00 0.57 0.052 0.027 <0.0001 <0.0001 <0.0001 <0.0001 0.0005 <0.0001 <0.0001 0.0012 <0.0001 <0.0001 0.0039 <0.0001

invasion was 20 mm (SD=11.7, range 2±65 mm) compared to 10 mm (SD=8.4, range 1±40). Of the 60 patients dying of/with SCC, 43 (72%) had close/ involved resection margins and 46 (76%) had lymph node metastasis. Of the 46 patients with metastasis who died of/with SCC, there was a signi®cant di€erence in pN stage (w2=8.39, 2 df, P=0.0039), the presence and extent of ECS (w2=4.31, 4 df, P=0.038), the size of the largest metastatic deposit (t=2.12, 97 df, P=0.036) and the numerical highest anatomical level of metastasis

J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

(w2=4.08, 4 df, P=0.043), but no signi®cant dI€erence in the number of positive nodes (t=1.47, 97 df, P=0.15), the number of positive levels (t=1.63, 97 df, P=0.11) and the laterality of the positive nodes (w2=0.62, 1 df, P=0.43). 3.3. Survival probability Actuarial survival analysis showed the overall 2-year survival probability was 72%, falling to 64% at 5 years.

261

The impact of metastasis and ECS is shown in Fig. 1. The 5-year survival probability was 81% in patients without histological lymph node metastasis, 64% for patients with intranodal metastases and 21% for patients with metastasis and ECS. There were signi®cant di€erences between each of the three survival probability curves (Wilcoxon statistic=8.88 and 12.52, 1 df, P=0.0029 and 0.0004). The survival probability classi®ed by pathological stage in shown in Fig. 2. The 5-year survival probability was 85, 90, 82 and 42% for

Fig. 1. Actuarial survival probability classi®ed by the histological metastatic status of the cervical lymph nodes. The upper curve shows patients without metastasis, the middle curve shows patients with metastases con®ned to the lymph node(s) and the lower curve shows patients with metastases and extracapsular spread.

Fig. 2. Actuarial survival probability classi®ed by pathological stage.

262

J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

Stages I, II, III and IV, respectively. The Wilcoxon test showed the survival curves for Stages I, II and III were similar while the curve for Stage IV was signi®cantly di€erent (Wilcoxon statistic=40.65, 3 df, P<0.0001). 3.4. Disease-free interval and survival The site of initial relapse was in the mouth or oropharynx in 40 (67%) of the 60 patients dying of/with SCC (20% of the series). Regional relapse accounted for 14 deaths and 6 patients died with systemic metastases in the absence of locoregional disease. Details of the type and timing of the relapse are presented in Table 4. The site and timing of the relapse in the 15 patients who were alive after further surgery are shown in Table 5. In total, 38 patients (19%) developed a recurrence adjacent to or under the reconstruction and 15 (7%) developed a second (metachronous) primary tumour. Of the 38 recurrences, 29 (76%) were diagnosed within 12 months and 16 (42%) were diagnosed within 6 months. In the group of 42 patients who had died clinically free of SCC, survival ranged from <1 month to 88 months (median=10 months). Nine deaths occurred within 1 month of surgery (due to respiratory or cardiovascular failure or stroke) and 4 more occurred during radiotherapy (from bronchopneumonia). Later deaths were due to the following: carcinoma of the bronchus

(5 cases); carcinoma of the oesophagus, nasopharynx, colon and pancreas (1 case each); stroke (3 cases); myocardial infarction (2 cases); chronic heart/lung failure (2 cases); infective endocarditis (1 case); drug/acute alcohol abuse (4 cases); and respiratory arrest during the insertion of a percutaneous endoscopic gastrostomy (2 cases). In the remaining cases, the general practitioner sent noti®cation of the date of death but no further details are available. 4. Discussion The present study con®rms yet again that local recurrence is the major cause of death in oral cancer patients treated by radical surgery [2, 3, 6, 13]. The performance of a node clearing procedure, even the neck is clinically negative, has radically altered the incidence of neck failure from recurrent disease (7% in this series). All 12 patients dying of recurrent disease in the operated positive neck had pN2 or pN3 disease with ECS. In the present series, only 1 of the 34 patients with metastasis con®ned to the lymph node succumbed to a regional relapse and this was due to a late-presenting retropharyngeal metastasis. Furthermore, our policy of performing bilateral neck dissections when the primary tumour involves or crosses the midline means that only

Table 4 The timing and site of initial relapse in the 60 patients dying of/with squamous cell carcinoma (SCC) Site of initial relapse

No. of cases

Disease-free interval (months)

Survival (months)

Median

Range

Median

Range

Local Recurrence under reconstruction Metachronous SCC

36 4

8 17

1±55 10±46

14 29

3±58 20±56

Regional Operated positive neck Operated negative neck Retropharyngeal nodes

12 1 1

5 16 18

1±11

7 19

2±15

6

18

13±36

20

15±41

Systemic Systemic metastases

22

Table 5 The timing and site of initial relapse in the 15 patients alive after further surgery Site of initial relapse

No. of cases

Disease-free interval (months) Median

Range 10±11 17±44 11±64

Local Recurrence under reconstruction Small SCC at edge of reconstruction Metachronous SCC

2 6 5

11 17 30

Regional Operated negative neck Contralateral neck

1 1

48 7

SCC, squamous cell carcinoma.

J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

a tiny percentage of patients (0.5% of the series) relapse in the contralateral neck. No deaths occurred due to disease in the contralateral neck and this contrasts sharply with previous reports [13, 14]. In the present study, two patients (1% of the series and 2% pN0 cases) developed disease at Level IV in the operated negative neck in the absence of an intra-oral recurrence. Both patients had tongue tumours and probably had skip lesions involving Level IV (jugulo-omohyoid) nodes which were inadvertently not included in the original neck dissection. Our incidence of relapse in the negative operated neck is low compared to other studies [13, 15, 16], but our ®ndings emphasise the importance of including Level IV in neck dissections for all tumours involving the tongue even when the neck is clinically negative [10, 17]. In the present study, local relapse was divided into three categories: (1) a true recurrence developing from residual microscopic foci of tumour cells left in the operative site which subsequently undermine the reconstruction, (2) a new primary (metachronous) SCC developing from the oral mucosa adjacent to the reconstruction and (3) a new primary (metachronous) SCC at a di€erent site in the mouth or oropharynx well away from the site of the ®rst tumour. The type of relapse was determined by clinical examination and careful macroscopic and histological assessment of the biopsy and, when available, the second resection specimen. True recurrences develop much earlier than metachronous tumours (Tables 3 and 4). Their position under the reconstruction means that they are usually advanced at the time of detection and the prognosis, even after a second resection, is very poor. In contrast, new primary tumours develop from the surface mucosa and, hence, are usually obvious on clinical examination, even at an early stage, and, thus, they are more amenable to successful local excision. All six SCCs developing at the edge of the skin-¯ap, and all nine metachronous primary tumours at other oral sites were resected and assessed histologically. All the metachronous tumours adjacent to the reconstruction were super®cial and some showed only microinvasion or a small focus of invasion within a larger area of epithelial dysplasia. Several patients have since undergone repeated surgery or laser excision for multiple small tumours. The size and histological features of the nine metachronous primary tumours at sites away from the original tumour varied and this is re¯ected in the diverse clinical outcome (Tables 3 and 4). To date, second primary tumours have developed in 7% of the series and this is consistent with previous reports [18, 19]. It is likely that further tumours will develop particularly in those patients who continue to smoke and drink heavily [18, 19]. Six patients died with systemic metastases in the absence of locoregional disease. At the time of their original operation, all six patients had pathological

263

TNM Stage IV disease. Four were pN2b with ECS and the other two were pN0. All six patients complained of bone pain, on average about 18 months after surgery. Metastatic SCC was con®rmed by bone scan and biopsy or autopsy. Several patients dying of locoregional disease also developed clinical evidence of systemic metastases, mainly in the bones and lungs. However, since autopsies were not performed routinely, the incidence of systemic metastases is uncertain. A total of 15 factors were identi®ed in¯uencing the survival of patients in this series. The present series had a close margin rate of 42% which contrasts unfavourably with the 24% rate reported in our original paper [6]. A variety of factors have to be considered to explain this deterioration. Almost 50% of the present series had T3/4 disease and it is technically more dicult to obtain clear margins in advanced disease, particularly tongue. The previous 123 cases were reviewed applying more stringent pathological criteria for margin clearance. In addition, unfavourable patterns of invasion with noncohesive cells and satellite lesions at the invasive front, high HMG scores, nerve and vascular invasion are related to pT stage (data not shown) and contribute to the histological diagnosis of close/involved resection margins [5, 10] and consequently to the local relapse rate of 20%. In the present study, there was no signi®cant di€erence in outcome in relation to sex: 50% of males and 46% of females were alive, and an identical percentage of males and females (30%) had died of/with SCC. The latter ®nding is surprising given the sex di€erence in tumour site and incidence of metastasis (Table 1). However, further analysis of the histological ®ndings provides a possible explanation: ECS was evident in 18 (72%) of the 25 females with metastasis compared with only 37 (50%) of the 74 males (w2=3.66, 1 df, P=0.05). The high incidence of ECS in females may, in fact, re¯ect the sex di€erence in tumour site. In the present series, 85% of the retromolar tumours occurred in males. Although the frequency of metastasis is high in retromolar tumours (60%), the metastatic deposits tend to be con®ned to Level II (17). In contrast, most of the females with metastases had tongue or oropharyngeal tumours which tend to give rise to more widespread metastases with an increased frequency of ECS [10, 17] and, hence, a worse prognosis. Nevertheless, it should be pointed out that the number of females in the present series is quite small and the disappointing outcome of females may be a spurious result. In the present study, 42 patients (21%) died while clinically free of SCC. A substantial number of incidental deaths are inevitable given the age pro®le of oral cancer su€erers. However, a review of the timing and cause of death suggests that at least 15 (36%) of the 42 deaths were related in some way to the management protocol and, hence, indirectly due to the oral cancer.

264

J.A. Woolgar et al./Oral Oncology 35 (1999) 257±265

The vast majority of the series were heavy smokers and many abused alcohol, and consequently were not ideal candidates for major surgery. The peri-operative death rate was 4.5%. Many of the later deaths were tobacco or alcohol related and, thus, shared a common aetiology with the oral cancer. All 5 patients dying of carcinoma of the bronchus underwent bronchoscopy and biopsy to exclude the possibility of a lung metastasis. In the present study, T stage, pT stage, diameter and depth of invasion (equivalent to the reconstructed tumour thickness [5, 11]) were used as indicators of tumour size and all showed a signi®cant relationship to metastasis, overall outcome and death of/with SCC (Tables 1 and 2). Previous reports [11, 20±23] have shown that thickness measurements of tumours from well-de®ned anatomical sites are useful predictors of metastasis. However, the critical thickness has varied, both in relation to tumour site [11, 20±22] and in di€erent studies of similar sites [11, 20, 22], and the resulting uncertainty has limited the clinical application of thickness measurements. The present study includes tumours from diverse sites within the mouth and oropharynx, and yet the mean depth of invasion in patients dying of/with SCC was twice that of survivors/patients dying free of SCC. Hence, our results show that depth of invasion is a robust indicator of clinical outcome and we suggest that this simple measure merits further clinical investigation. Our results show that the 5-year actuarial survival rate for patients with metastases con®ned to the lymph node(s) was less than that of patients without metastasis (Fig. 1). The di€erence was due to relapse in the mouth rather than the neck. An increased rate of local recurrence is not unexpected in patients with metastasis since tumour size, unfavourable pattern of invasion, high HMG score, nerve and vascular invasion are all related to metastasis (Table 1) and all lead to high-risk features on histological assessment of the resection margins [10]. As shown in Fig. 1, the most dramatic fall in the 5-year survival rate was seen in patients with metastasis and ECS. Only 5 (9%) of the 55 patients with ECS were alive and clinically free of SCC. Moreover, the outlook was equally poor for patients with macroscopic ECS and patients with early ECS that was only detectable on histological assessment. In our unit, patients with ECS have a dismal prognosis even with post-operative radiotherapy. Early studies [24, 25] suggested that the timing of post-operative radiotherapy is critical in preventing tumour recurrence. However, more recent reports [26, 27] have suggested that e€ective control is dose (rather than time) related. The ®ndings in the present study have stimulated a review of our current radiotherapeutic practice. The present study con®rms the prognostic value of pathological staging. However, we believe that the current recommendations [7] for pathological staging of the

neck are inadequate. At present, the pN categories correspond to the N categories and are based on the laterality and number of positive nodes and the size of the largest metastasis. Our study shows that most patients are staged pN2b on account of multiple ipsilateral positive nodes. Only 1 patient had a single metastasis measuring more than 3 cm and only 5 patients had deposits of more than 6 cm. In fact, the largest metastatic deposit measured 2 cm or less in 63 (64%) of the 99 patients in the present study. As a consequence, the size criteria recommended by the TNM system are not helpful in the majority of patients. As in previous reports [28, 29], our ®ndings clearly show that ECS is a powerful indicator of prognosis. We believe that ECS is a simple but potent indicator of tumour aggression. It is easy to diagnose histologically and it is seen in both small and large metastases. In our experience, ECS is a sensitive indicator of prognosis in an individual patient and we recommend that it should be adopted as the major criterion in pathological N staging. Nevertheless, the current staging criteria are highly e€ective in showing the dramatic di€erence in actuarial survival probability for the pathological Stage IV group, and the survival curves shown in Fig. 2 provide an excellent visual summary of our study ®ndings. Our study highlights the critical importance of early presentation. If survival is to be improved, then an e€ective education campaign must be devised and instigated. References [1] Hindle I, Nally F. Oral cancer: a comparative study between 1962 and 1967 and 1980 and 1984 in England and Wales. British Dental Journal 1991;170:15±20. [2] Langdon JD, Harvey PW, Rapidis AD, Patel MF, Johnson NW, Hopps R. Oral cancer: the behaviour and response to treatment of 194 cases. Journal of Maxillofacial Surgery 1977; 5:221±37. [3] Worral SF, Corrigan M. An audit of one surgeon's experience of oral squamous cell carcinoma using a computerised malignancy database. Annals of the Royal College of Surgeons of England 1995;77:332±6. [4] Calman K. A Policy Framework For Commissioning Cancer Services: The Calman-Hine Report. HMSO, London, 1995. [5] Helliwell TR, Woolgar JA. Minimum Dataset for Head and Neck Carcinoma Histopathology Reports. Bulletin of the Royal College of Pathologists, in press. [6] Woolgar JA, Scott J, Vaughan ED, Brown JS, West CR, Rogers S. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Annals of the Royal College of Surgeons of England 1995;77:325±31. [7] Sobin LH, Wittekind C. (Eds.) Head and neck tumours. In: UICC TNM Classi®cation of Malignant Tumours, 5th Edition. John Wiley & Sons, New York, 1997, p. 17±32. [8] Shah JP, Candela FC, Poddar AK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer 1990;66:109±113. [9] Woolgar JA. Detailed topography of cervical lymph-node metastases from oral squamous cell carcinoma. International Journal of Oral and Maxillofacial Surgery 1997;26:3±9.

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