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Detailed topography of cervical lymph-node metastases from oral squamous cell carcinoma
Int. J. Oral Maxillofac. Surg. 1997; 26:3-9 Printed in Denmark. All rights reserved
Copyright 9 Munksgaard 1997 [ntemationa]Jouma] of
Oral& MaxillofacialSurgery ISSN 0901-5027
Leading article
Detailed topography of cervical lymph-node metastases from
Julia A. Woolgar University of Liverpool School of Dentistry, Liverpool, UK
0ral squam0us cell carcinoma J. A. Woolgar. Detailed topography of cervical lymph-node metastases from oral squamous cell carcinoma. Int. J. Oral Maxillofac. Surg. 1997, 26: 3-9. 9 Munksgaard, 1997
Abstract. The histologic presence and detailed topography of cervical lymphnode metastatic tumours was investigated in a series of neck dissections from 154 previously untreated patients with oral mucosal squamous cell carcinoma. Metastasis was evident in 73 patients (47%), including 13 (8%) with bilateral spread and 14 (9%) with only micrometastases. Multiple positive nodes were recovered from 58 (67%) of the 86 positive sides of neck dissection, and fusion of nodes was seen in 22 dissections (26%). Both direct extracapsular and embolic spread accounted for advanced disease. An orderly progressive ("overflow") involvement of anatomic levels was seen in 85% of positive dissections. "Skipping" of anatomic levels II and/or III was seen in 10%, and "peppering" of nodes at multiple levels without any macroscopic focus in 5%. Hence, "fasttracks" may account for the distribution of metastatic carcinoma in ! 5% of positive necks. Adjuvant radiotherapy was dependent on the pathologic stage. The range of postoperative follow-up was 1-6 years. Death from recurrent regional disease occurred only in patients who had exhibited macroscopic or microscopic extracapsular spread. Survival was similar (75%) for patients with either macroscopic or microscopic metastases confined to lymph nodes or no evidence of metastasis. Hence, with surgery and adjuvant radiotherapy, metastases confined to lymph nodes do not appear to affect the short-term prognosis.
The distribution of cervical lymph-node metastases from squamous cell carcinoma (SCC) of the oral cavity and oropharynx has proved sufficiently consistent 5'9'13,18 to permit the design and successful application of the standard radical neck dissection7 and selective neck dissections2-r Nevertheless, the mechanisms involved and the precise routes of spread within the cervical lymphatic system are open to discussion. T h e embolic character of the initial intranodal metastatic deposit is well accepted 21,26. At least three mechanisms are possible in advanced disease: embolic spread from node to node leading to multiple discrete positive nodes,
or permeation of internodal lymphatics, or direct extracapsular spread (ECS) resulting in fused (matted) nodes 26. The relative contribution of each mechanism in oral/oropharyngeal SCC is uncertain. Some sites within the oral cavity may also drain directly to distant lymph nodes via long-range pathways or fast-tracks 14, but data on the involvement of such routes are not readily available. Hence, the detailed topography of cervical lymph-node metastases from oral and oropharyngeal SCC was investigated with four main aims: 1) to assess the mechanisms of spread in advanced disease
Key words: oral squamous cell carcinoma; lymph-node metastasis. Accepted for publication 15 September 1996
2) to assess the evidence for and frequency of fast-track involvement 3) to assess the prognostic importance of the various manifestations of lymph-node metastasis 4) to assess the accuracy of the preoperative detection of metastatic disease.
Material and methods Surgical cases
A series of 154 consecutive patients undergoing surgery as the primary treatment for intraoral/oropharyngeal SCC at the Mersey Regional Centre for Maxillofacial Surgery, Walton Hospital, Liverpool, UK, between
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October 1989 and October 1994, formed the material for the study. None of the patients had received preoperative radiotherapy, chemotherapy, or previous surgery, other than routine dentoalveolar procedures and recent diagnostic biopsy. The series comprised 99 males (64%) and 55 females (36%o). The males had a mean age of 58 years (SD 11.8, range 30-80 years), significantly lower than the mean age of 62 years (SD 13.2, range 11-81 years) of the females (two-sample t-test, t=2.091, df=152, P=0.035). The clinical stage of the primary tumour was determined according to the recommendations of the AJCC 1, except for one modification, namely, tumours of the oral tongue and floor of mouth (FOM) were divided into three categories: lateral border of tongue, ventral (under surface) of tongue/FOM, and FOM. Lateral border of tongue was the site of the primary tumour in 37 patients (24%), ventral tongue/FOM in 30 (19%0), FOM in 27 (I 8%), retromolar trigone in nine (6%), lower alveolar ridge in 16 (10%), buccalmucosa in 14 (9%o), and oropharynx in the remaining 21 patients (14%). Thirty-three (21%) of the primary tumours were stage T1, 50 tumours (32%) were T2, 13 tumours (8%) were T3, and the remaining 58 tumours (38%) were stage T4. The preoperative metastatic status of the cervical lymph nodes was determined by palpation under general anaesthesia during clinical staging/endoscopic evaluation, supplemented in 22 patients by computerized tomography (CT), and in 119 patients by CT and magnetic resonance imaging (MRI). The neck was recorded as clinically positive if any of the investigations suggested that metastatic disease was present. All other necks were recorded as clinically negative. Both sides of the neck were clinically positive in 11 patients (7%), and one side of the neck was clinically positive in 47 patients (31%). Both sides of the neck were clinically negative in the remaining 96 patients (62%). A total of 103 patients (67%) underwent resection of the primary tumour with simultaneous unilateral neck dissection; in the remaining 51 patients (33%), the neck dissection was bilateral. Thus, a total of 205 sides of neck were available for histologic assessment. Twenty-three (11%) were radical neck dissections7, and 182 (89%) were modified (conservative) procedures z15. Seventy-four of the modified neck dissections encompassed levels I - V 15 and the remaining 108 modified dissections encompassed levels I - IV is. Postoperative radical radiotherapy was employed on the basis of pathologic staging under the following criteria: 1) involved or close (within 5 ram) resection margins at the primary site 2) two or more positive cervical lymph nodes 3) ECS from one or more positive lymph nodes. Seventy-four (48%) of the 154 patients were found to have one or more of these features. The radiotherapy (external beam, 60-65 Gy
fractionated over 6 weeks) was started, whenever possible, 6 weeks after surgery. Patients were reviewed at regular intervals. At the time of analysis, all patients had at least a 1-year follow-up. Status at last contact was recorded as one of the following: 1) alive and well 2) alive and currently disease-free after treatment for further intraoral SCC (recurrent or metacbronous) 3) dead of SCC (The site of initial failure was recorded as local (intraoral/oropharyngeal), regional (lymphatic metastases), or systemic (haematogenous metastases).) 4) Dead of other cause, with no signs of locoregional or systemic SCC. Pathologic assessment
In order to minimize tissue distortion, the surgical specimens were sutured to polystyrene sheets before fixation in 10% buffered formalin and transport to the Oral Pathology Diagnostic Laboratory at Liverpool University Dental Hospital, where all the gross dissections and histologic assessments were made by the author. The specimens were examined in the laboratory after 24-48 h of fixation. Lymph nodes larger than 0.3 cm in diameter were identified by palpation and visual inspection, and dissected out from each of the five main anatomic levelslS: level I, submandibular and submental nodes; levels II, III, and IV, upper, middle, and lower cervical; and level V, contents of the posterior triangle. In nodes with obvious metastatic involvement, any spread into perinodal fibroadipose tissue or adjacent anatomic structures (macroscopic ECS), or fusion (matting) of adjacent nodes was recorded, and blocks of tissue showing the maximum extent of spread were processed routinely for paraffin embedding. Nodes without macroscopic involvement were processed with the pericapsular fibroadipose tissue attached. Lymph nodes larger than 0.5 cm were bisected in the long axis, or sliced, depending on their size and shape, and smaller nodes were processed whole. Initial histologic assessment of each node was made on a single section stained with haematoxylin and eosin (HE). Step-serial sections (100/zm apart) were prepared from those nodes >2.4 cm that appeared tumourfree on initial assessment. All nodes were recorded as negative or positive for metastatic SCC. Metastatic deposits measuring no more than 0.3 cm after step-serial sectioning were designated "micrometastases". Extracapsular spread evident only on histologic assessment was recorded as "microscopic ECS". Any permeation (continuous columns of tumour) or embolization (detached groups of tumour cells) of the perinodal lymphatics was recorded. The pathologic findings in each patient were charted on a topographic diagram showing the anatomic location and size of the positive node(s), the size andintranodal position of the metastatic deposit(s),
and the presence and extent of ECS. An example of a patient with four positive nodes in the left side of the neck is shown in Fig. 1. Advanced disease was defined as multiple positive lymph nodes, and a single positive node was described as early metastatic disease. Involvement of fast tracks was defined as "skipping" of anatomic levels (other than level I), or histologic involvement of multiple levels in the absence of any macroscopic metastatic focus. For assessment of the prognostic importance of the various manifestations of lymph-node metastasis, patients were assigned to one of the following five categories on the basis of the presence and extent of ECS and the size of the intranodal metastatic deposit: 1) at least one positive node showing macroscopic ECS involving perinodal anatomic structures 2) at least one positive node showing macroscopic ECS confined to the perinodal fibroadipose tissue 3) at least one positive node showing microscopic ECS 4) no ECS, at least one node containing a metastatic deposit >0.3 cm 5) no ECS, only micrometastases. Statistical methods
The results were analysed with a commercial software package (Arcus PRO-II, lain E. Buchan, 1993) and an IBM microcomputer. Parametric data from two independent groups were compared with Student's twosample (unpaired) t-test. Frequency tables of categorical data were analysed with the chisquare test, with Yates' correction when the expected cell frequency was less than five. Statistical significance was claimed for a twosided P value of less than 0.05. Results Nodal yield
T h e m e a n n u m b e r o f n o d e s recovered f r o m each o f the three types o f surgical neck dissection specimens was as follows: radical, 45 n o d e s (SD 15.4, range 30-96); modified, levels I - V, 36 nodes (SD 9.9, r a n g e 18-63); a n d modified, levels I - IV, 21 n o d e s (SD 7.5, range 8 42). In total, 5932 n o d e s were e x a m i n e d histologically, a n d 347 (5.8%) were positive for m e t a s t a t i c SCC.
Occurrence of cervical lymph node metastasis
N o d a l metastasis was diagnosed histologically in 73 (47%) o f the 154 patients. T h i r t e e n patients (8%) h a d bilateral metastases. Hence, 86 sides o f neck dissection c o n t a i n e d positive nodes. T h e occurrence o f metastasis was related to the site a n d stage o f the p r i m a r y
Metastasis from oral SCC
Fig. 1. Topographic diagram showing anatomic level and size of positive nodes, and volume and distribution of metastatic SCC (arrows indicate presence of ECS).
tumour. Metastasis was present in 23 (62%) of the 37 tumours of the lateral tongue, in 18 (60%) of the 30 tumours of the ventral tongue/FOM, in 11 (40%) of the 27 tumours of the FOM, in six (67%) of the nine turnouts of the retromolar trigone, in none (0%) of the 16 tttmours of the lower alveolar ridge, in three (21%) of the 14 tumours of the buccal mucosa, and in 12 (57%) of the 21 oropharyngeal tumours (chi-square test, Z2=27.468, df=6, P=0.0001). Metastasis was present in seven (21%) of the 33 T1 turnouts, in 28 (56%) of the 50 T2 tumours, in eight (62%) of the 13 T3 tumours, and in 30 (52%) of the 58 T4 tumours (chisquare test, Z2=12.029, df=3, P 0.0073). Metastasis occurred in 53 (54%) of the 99 males and in 20 (36%) of the 55 females (chi-square test, Z2=7.308, df= 1, P=0.0069). There was no significant difference in the occurrence of metastasis in relation to age (two-sample ttest, t=0.744~ df= 152, P=0.54). General topography of cervical metastases
In 12 of the 13 patients with bilateral metastases, the primary turnout was sited on the tongue or F O M and crossed the midline. The remaining patient h a d synchronous bilateral oropharyngeal tumours. One patient had only micrometastases in both sides of the neck, and in a further five of the 13 patients, micrometastases accounted
for the contralateral neck disease. Thirty-four (57%) of the 60 patients with unilateral metastasis showed involvement of a single anatomic level (level I in 15 cases, level II in 18 cases, and level IV in a single case), and 16 (27%) showed involvement of two levels. As shown in Table 1, the frequency of involvement of nodes at level I was related to the site of the primary tumour (chi-square test, Z2= 26.431, df=5, P<0.0001). Levels II, III, and IV were involved in all five dissections showing involvement of nodes at level V. In 53 (73%) of the 73 patients with metastasis and in 64 (74%) of the 86 positive sides of neck dissection, metastasis was associated with discrete nodes, and in the remaining 20 patients (22 dissections), some of the positive nodes were partially fused (matted). Macroscopic ECS was detected in eight (15%) of the 53 patients with discrete positive nodes, and microscopic ECS was present in a further 13 patients (25%). Hence, in total, 41 patients (56% of the 73 patients with metastasis and 27% of the series) had ECS (macroscopic, 28; microscopic, 13). Micrometastases only accounted for the metastatic disease in 14 of the 32 patients without ECS (that is, 19% of the 73 patients with metastasis and 9% of the series). Permeation of the perinodal lym-
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phatics was evident in eight patients (two of whom had fused nodes), and embolization was evident in a further seven patients (four of whom had fused nodes). The 86 positive sides of neck dissection yielded 206 discrete positive nodes and 37 masses of fused nodes. Each mass appeared to be made up of 2-25 nodes (mean 3.8, SD 3.93, median 3), and the apparent total number of fused positive nodes was 141. Hence, the 86 dissections yielded, in total, 347 positive nodes. The number of positive nodes per patient ranged from 1 to 29 (mean 4.8 nodes, SD 5.83, median 2). Of the 347 positive nodes, 71 (20%) were located at level I, 164 (47%) at level II, 55 (16%) at level III, 46 (13%) at level IV, and 1 l (3%) at level V. Of the 206 discrete positive nodes., 18 (9%) showed macroscopic ECS, 33 (16%) showed microscopic ECS, and 84 (41%) were micrometastases. Frequency of early and advanced metastatic disease
Twenty-one patients (29%) had a single positive node. There was no significant difference in the frequency of early metastatic disease in relation to the site and stage of the primary turnout (chisquare test, Zz=2.230, df=5, P=0.82; and Z2=1.211, df=3, P=0.75, respectively). The group of 52 patients with multiple positive nodes included the 13 patients with bilateral metastases, seven of whom had only early disease in one side of the neck. Topography of early metastatic disease
Twenty-eight (33~ of the 86 positive sides of neck dissection contained a single positive node. This was located at level I in 14 cases, at level II in 12 cases, at level III in one case, and at level IV in the remaining case. Microscopic ECS was evident in four cases, and of the remaining 24 cases without ECS, 13 were micrometastases. Topography of advanced metastatic disease
Fifty-eight (67%) of the 86 positive sides of neck dissection contained more than one positive node. In 22 of the 58 sides, at least one mass of fused nodes was present, and, in addition, in 16 of the 22 dissections, at least one positive discrete node. The
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Woolgar in four of the 20 dissections, at two levels in nine, at three levels in five, and at four levels in the remaining two cases. At the numerically highest level of involvement, tumour was confined to the lymph .node(s) in six of the 20 dissections, and present as only micrometastases in a further four cases. In the other 16 neck dissections with advanced disease, tumour appeared to be confined to the lymph nodes. In these cases, the number of positive nodes per dissection ranged fi-om 2 to 6 (mean 2.8, SD 1.24, median 2). The positive nodes were located at a single anatomic level in nine of the 16 dissections, at two levels in six, and at three levels in the remaining case. Metastatic disease was present as only micrometastases in six of the 16 dissections, and micrometastases accounted for the highest level of involvement in a further three dissections.
number of positive nodes (fused and discrete) per dissection ranged from 2 to 29 (mean 9.1, SD 7.32, median 7). Metastatic disease was limited to nodes at anatomic level I in one of the 22 cases, to nodes at level II in four cases, and to nodes at levels I and II in a further two cases. In the remaining 15 cases, a "cone" of metastatic disease was present, with the base (the greatest volume of tumour) at level II, and the apex extending to involve nodes at level III (five cases), level IV (five cases), and level V (five cases). The numerically highest level of involvement was represented by only discrete positive nodes in five cases, and by only micrometastases in five cases. In the latter 10 dissections, negative lymph nodes were recovered from the area between the fused nodes and :the discrete positive nodes. The metastatic carcinoma had spread from the fused nodes to involve other anatomic structures in 10 of the 22 necks (internal jugular vein, 10 cases (with full-thickness involvement in six); skeletal muscle, six cases; skin of neck, two cases). In the remaining 12 dissections containing fused nodes, the metastatic tumour appeared to be confined to the .perinodal fibroadipose tissue. In the remaining 36 sides of neck dissection showing advanced disease, the metastatic tumour was associated with multiple discrete positive nodes. In 20 of the 36 dissections, ECS to perinodal fibroadipose tissue was diagnosed from at least one~ positive node (macroscopic ECS, eight dissections; microscopic ECS, 12 dissections). Direct contact between the positive nodes was not evident and adjacent/intervening nodes were histologically negative. In the 20 dissections with ECS, the number of positive nodes per dissection ranged from 2 to 9 (mean 3.7, SD 2.23, median 3). The positive nodes were located at a single anatomic level
Evidence for fast-track involvement
Skipping of anatomic levels (other than level I) was seen in seven sides of neck dissection from patients with tumours of the lateral tongue (six cases) or ventral tongue/FOM (one case). In three dissections, a positive node was detected at levels IlI or IV without evidence of involvement of levels I and II. In the remaining four dissections, positi ve nodes were recovered from levels II and IV with no evidence of disease in nodes at level III. Six dissections from four patients (lateral tongue, two cases; ventral tongue/FOM, one case; FOM, one case) showed involvement of nodes at multiple levels without any macroscopic focus ("peppering"). Microscopic ECS, perinodal embolization, or permeation was evident in three dissections. The microscopic deposits were confined to the nodes and measured <0.3 cm in the
Table 1. Prevalence of nodal metastasis by anatomic level in 86 positive sides of neck dissection in 73 patients~
Anatomic level T site
I
Lateral tongue n=23 8 (35%) Ventral tongue/FOM n=18 15 (83%) FOM n = l l 12 (109%) Oropharynx n=12 3 (25%) Retromolar trigone n=6 3 (50%) Buccal mucosa n=3 3 (100%) All T sites n=86 44 (51%)
II
III
IV
V
20 (87%) 16 (89%) 9 (82%) 12 (100%) 5 (83%) 0 62 (72%)
14 (61%) 7 (39%) 3 (27%) 3 (25%) 1 (17%) 0 28 (33%)
9 (39%) 5 (28%) 2 (18%) 2 (17%) 0 0 18 (21%)
1 (4%) 2 (11%) 0 2 (17%) 0 0 5 (6%)
a Involvement of multiple levels accounts for percentages > 100. FOM: floor of mouth.
remaining three dissections (micrometastases). Prognostic importance of the various manifestations of lymph-node metastasis
The number of patients allocated to each of the five topographic categories and their status at last contact are shown in Table 2. All patients in categories 1, 2, and 3; eight (44%) of the 18 patients in category 4; eight (57%) of the 14 patients in category 5; and 17 (21%) of the 81 patients without metastasis fulfilled the criteria for postoperative radiotherapy. There were significant differences in both the number of patients alive at last contact and the number dead of SCC in relation to the topographic category (chi-square test, X2=26.390, df=4, P<0.0001; and za=12.821, df=4, P = 0.012, respectively). However, there were no significant differences in patients with metastasis confined to the lymph nodes (categories 4 and 5) and patients without metastasis (chi-square test, Z2=0, d f = l , P = I ; and Z2=1.421, df = 1, P=0.23, respectively). Accuracy of the preoperative detection of metastatic disease
Metastasis was detected histologically in 48 (70%) of the 69 clinically positive sides of neck, and in 38 (28%) of the 136 clinically negative sides of neck. Hence, the overall accuracy of the preoperative assessment was 71% (sensitivity, 56%; specificity, 82%). In total, 80 positive nodes were recovered from the 38 false-negative sides of neck dissection. The number of positive nodes per dissection ranged from 1 to 9 (mean 2.1 nodes, SD 1.79), but 19 dissections contained a single positive node. The positive node(s) were confined to a single anatomic level in 26 dissections, but four different levels were involved in one case. Twenty-eight (35%) of the 80 positive nodes were located at level I, 38 (48%) at level II, seven (9%) at level III, and the remaining seven nodes were located around the tendon of the omohyoid muscle (level IV). Macroscopic ECS to perinodal fibroadipose tissue was present in two of the false-negative dissections, and microscopic ECS was present in a further nine dissections. Hence, 11 (29%) of the 38 false-negative necks (8% of the 136 clinically negative necks) showed ECS.
Metastasis f r o m oral S C C
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Table 2. Status of patient at last contact in relation to topographic category of cervical metastases
Topographic pattern category 1
Dead, intraoral disease
Dead, regional metastases
Dead, systemic metastases
Dead, other cause
Further treatment, alive, disease-free
Alive, well
1 (n=lO) 2 (n=18) 3 (n=13) 4 (n=18) 5 (n=14) No metastasis (n=81) Total series (n=154)
2 (20%) 5 (28%) 3 (23%) l (6%) 4 (29%) 7 (9%) 22 (18%)
5 (50%) 3 (17%) 2 (15%o) 1(6%)" 0 (0%) 0 (0%) 11 (7%)
0 (0%) 2 (11%) 1 (8%) 0 (0~ 0 (0%0) 2 (2%) 5 (3%)
3 (30%) 4 (22%0) 4 (31%) 2 (11%o) 0 (0%) 11 (14%) 24 (16%)
0 (0%) 0 (0%0) 2 (15%) 0 (0%) 1 (7%) 9 (I 1%) 12 (8%)
0 (0%) 4 (22%) 1 (8%) 14 (78%) 9 (64%) 52 (64%) 80 (52%)
1These five categories are explained in text (Material and methods), aContralateral (nonoperated) neck.
Fifteen (39%) of the 38 clinically false-negative sides of neck contained only micrometastases, and in 11 necks (29%), the metastatic deposit(s) measured 0.3-0.5 cm. In a further case, the positive node had occupied a depression within the lingual aspect of the mandible. There were no pathologic features to account for the false-negative clinical assessments in the remaining 11 cases (29%).
Discussion
The present study sought to investigate the detailed topography of metastatic oral SCC within the cervical lymphatic system and assess certain clinical implications. The results provide an insight into the patterns of spread of metastatic SCC within the neck, and show the prognostic value of detailed pathologic staging. However, before discussion of the main findings, certain limitations of the study should be mentioned. Firstly, a large percentage of the series underwent a modified neck dissection encompassing levels I - IV; hence, in these cases, level V nodes were not available for histologic assessment. However, several studies have shown that nodes within the posterior triangle are rarely, or never, involved in oral SCC in the absence of extensive metastatic disease at levels I I - I V 41819. Preoperative investigations are likely to detect such extensive disease28, and in these circumstances, radical neck dissection would be performed. In the present study, patients with a 1.5 cm positive but mobile node at levels II/III were also treated by modified neck dissection encompassing levels I - V Only patients with clinically minimal disease and those with clinically negative necks were treated by a modified dissection encompassing levels I - IV Hence, inaccuracies due to failure to examine level V nodes are un-
likely. The modified I - IV neck dissections provided also material from a large number of clinically negative necks, and the subsequent important histologic findings would appear to counterbalance any criticism of their inclusion in the present study. The second limitation of the present study relates to the pathologic methods. The most important shortcoming is that clearing techniques 8 were not used; hence, the lymphatic tree could not be visualized en bloc. However, a strict protocol was followed to ensure that specimens were fixed with minimal distortion 27, and all the laboratory dissections and histologic assessments were made by a single pathologist. The detection of microscopic ECS and embolization/permeation of the perinodal lymphatics were facilitated by processing nodes with the perinodal fibroadipose tissue attached. Immunostaining was not used to detect micrometastases since it has been reported 23 that this has no significant advantage over assessment of HE-stained sections by an experienced pathologist. Nevertheless, in common with previous studies, it must be accepted that some falsenegative pathologic assessments and other inaccuracies are inevitable. The frequency of nodal metastasis in relation to the T site and T stage of the primary tumour is in keeping with previous reports is'2~ A likely explanation for the higher frequency of metastasis in males in the present study is tumour site males had a higher frequency of tumours of the tongue and FOM, and females had a higher frequency of tumours of the alveolar ridge. The observed distribution of cervical metastases in relation to the site of the primary tumour (Table 1) is in agreement with previous reports 5,9,13,18. Since the precise site of origin of tumours involving both the ventral tongue and F O M is difficult to determine, even on labora-
tory assessment of the resection specimen, an additional site category, ventral tongue/FOM, was used in the present study. The latter tumours frequently spread to level I nodes, whereas tumours of the lateral border of tongue frequently spread directly to level I] nodes (Table 1). The definition of advanced metastatic disease used in the present study was that suggested by WmLIS26. it takes no account of the volume of metastatic carcinoma nor of ECS, which are more accurate measures of the actual pathologic stage. Nevertheless, the chosen criterion allowed an assessment of the possible mechanisms of spread within the cervical lymphatic system. The features reported in the present study (number of involved anatomic levels, number of positive nodes, fusion of nodes, and ECS) were an attempt to describe the topographic charts which were used to depict the volume and distribution of metastatic SCC ( F i g . 1). The charts showed that the topographic features were interrelated with an obvious positive association. In 85% of positive neck dissections, the metastatic disease was focused on one or more nodes at a single anatomic level with progressive ("overflow") involvement of neighbouring nodes, and a gradual reduction in the volume of metastatic disease and the extent and occurrence of ECS. Observation of the position of intranodal metastatic deposits, the degree of nodal replacement, and the extent of ECS in cases with fused nodes suggested that both direct spread between immediate neighbouring nodes and embolic spread to nearby nodes are important. Histologically, it was difficult to distinguish between permeation and embolization, but macroscopic permeation of the perinodal lymphatics was evident in a single case. Topographic features suggestive of fast-track involvement, seen in the re-
8
WooIgar
maining 15% of positive dissections, were almost exclusive to tongue tumours. "Skipping" of anatomic levels and "peppering" were not seen in association with primary tumours at any other site, apart from the single case of a t u m o u r of the anterior midline F O M . However, these findings should be interpreted with caution since the number of primary tumours at some sites was small. It is possible that extensive disease throughout the neck had obscured the true pattern of spread in some of the necks showing the "overflow" pattern. Nevertheless, this seems unlikely since, in the latter cases, the topographic maps showed that the disease was greatest in the upper part of the neck. The definition of "micrometastases" which was used in the present study was suggested by VAN DEN BRErd~L et al. 23. It is unlikely that such tiny deposits can be detected preoperatively by routine C T scans and MR122,28. We have, however, not assessed the value of sonography 16. In the present study, small tum o u r deposits or the' involvement of small nodes accounted for 68% of the false-negative clinical assessments. The metastatic status of some patients with micrometastases was assessed correctly. However, histologically, reactive hyperplasia of lymphoid tissue, rather than the metastatic deposit per se, accounted for the clinical nodal enlargement. In the present study, ECS, a feature of known prognostic importance 6'2~ was used as the main criterion for evaluating the prognostic value of the various manifestations of the cervical metastases. The results (Table 2) show that, with adjuvant radiotherapy based on the pathologic stage, survival is similar for patients with metastases confined to the lymph nodes and patients without histologic evidence of meta, stasis. The p o o r prognosis of patients with metastasis reported in .our previous study 29 appears to be due entirely to the p o o r survival of patients with ECS. However, the postoperative review period is short for cases accessioned late in the present study. Hence, although further regional failures are unlikely 1~ it is possible that the longterm survival of patients with intranodal metastases may be reduced by an increased frequency of late-presenting systemic metastases 11'25. Nevertheless, the results of the present study suggest that the presence of nodal metastasis with a favourable topographic location
does not affect the short-term prognosis. Acknowledgments. I thank Mr E. D. Vaughan and Mr J. S. Brown, Consultant Oral and Maxillofacial Surgeons, Walton Hospital, for their contribution to the study. References 1. AMERICANJOINT COMMITTEEON CANCER.
Head and neck sites. In: BEARHS OH, HENSEN DE, HUTTER RVP, MYERS ED, eds: Manual for staging of cancer. 3rd ed. Philadelphia: JP Lippincott, 1988: 27-38. 2. BIER J, SCHLUMS D, METELMANN H, HOWALDTH-P, PITZ H. A comparison of ra~iical and conservative neck dissection. Int J Oral Maxillofac Surg 1993: 22: 1027. 3. BYERSRM. Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg 1985: 150: 414-21. 4. BYERS RM, WOLF PF, BALLANTYNEAJ. Rationale for elective modified neck dissection. Head Neck Surg 1988: 10: 1607. 5. CANDELAFC, KOTItARIK, SHAHJR Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck Surg 1990>, 12: 197-203. 6. CARTERRL, BLISSJM, Soo KC, O'BRIEN CJ. '~' Radical neck dissections from squamous carcinomas: pathological findings and their clinical implications with particular reference to transcapsular spread. Int J Rad Oncol Bid Phys 1987: 13: 825-32. 7. CRILE GW Excision of cancer of the head and neck with special reference to the plan of dissection based upon one hundred and thirty-two operations. JAMA 1906: 47: 1780-6. 8. DE LA PAVA S, PICKREN JW. On lymph node clearing as applied to head and neck tumours. In: RUTTIMANA, ed.: Progress in lymphology. Proceedings of the International Symposium on Lymphology, Switzerland, 1966. Stuttgart: Georg Thieme, 1967: 290-2. 9. FEIND CR. The head and neck. In: HAAGENSEN CD, FEIND CR, HERTER FP, SLANETZ CA, WEINBERG JA, eds.: The
lymphatics in cancer. Philadelphia: WB Saunders, 1972: 59-227. 10. FOOTERL, OLSENKD, DAVISU. Base of tongue carcinoma: patterns of failure and predictors of recurrence after surgery alone. Head Neck Surg 1993: 15: 30~7. 11. KOTWALLC, SAKOK, RAZACKMS, RAO U, BAKAMJIANV, SHEDD DR Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987: 154: 439-42. 12. LANGDONJD, HARVEYPW, RAPIDISAD, PATELME JOHNSONNW, HOVPSR. Oral cancer: the behaviour and response to treatment of 194 cases. J Max-Fac Surg 1977: 5: 221-37.
13. L1NDBERG R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972: 29: 1446-9.
14. McK~LvIE E Metastatic routes in the neck. Can J Otolaryngol 1974: 3: 473-9. 15. O'BRIEN CJ, URIST MM, MADDOXWA. Modified radical neck dissection. Terminology, technique and indications. Am J Surg 1987: 153: 310-6. 16. RAINIER T, OFNER G, MARCKHGOTT E. Ultrasound diagnosis of regional lymph node metastasis of the neck in patients with head-neck neoplasms: sonomorphologic criteria and diagnostic accuracy. Laryngorhinootologie 1993: 72: 73-7. 17. ROBBINSKT, MEDINAJE, WOLFEGT, LEVINEPA, SESSIONSRB, PRUETCW. Standardizing neck dissection terminology. Arch Otolaryngol Head Neck Surg 1991: 117: 601-5. 18. SHAHJR CANDELAFC, PODDARAK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer 1990: 66: 109-13. 19. SKOLNIK EM, YEE KF, FRIEDMAN M, GOLDENT. The posterior triangle in radical neck surgery. Arch Otolaryngol 1976: 102: 1M.
20. SNOW GB, ANNYAS AA, VAN SLOOTEN EA, BARTELINKH, HART AAM. Prognostic factors of neck node metastasis. Clin Otolaryngol 1982,: 7:185 92. 21. TOYd~RC. Some observations on the deposition of metastatic carcinoma within cervical lymph nodes. Cancer 1963: 16: 364-74. 22. VAN DEN BREKEL MWM, STEL HV, CASTELnNS JA, CROLL GJ, SNOW GB. Lymph node staging in patients with clinically negative neck examinations by ultrasound and ultrasound-guided aspiration cytology. Am J Surg 1991: 162: 362-6. 23. VAN DEN BREKEL MWM, STEL HV, VAN DER VALK P~ VAN DER WAAL I, MEYER
CJLM, SNOWGB. Micrometastases from squamous cell carcinoma in neck dissection specimens. Eur Arch Otorhinolaryngo1 1992: 249: 349-53. 24. VIKRAM B, STRONGEW, SHAH JR SPIRO R. Failure in the neck followihg multimodality treatment for advanced head and neck cancer. Head Neck Surg 1984: 6: 724-9. 25, VIKRAMB, STRONGEW, SHAH JP, Svlao N. Failure at distant sites following multimodality treatment for advanced head and neck cancer. Head Neck Surg 1984: 6: 730-3. 26. WILLIS RA. Direct spread of tumours. Metastasis via the lymphatics. In: The spread of tumours in the human body. 3rd ed. London: Butterworth, 1973: 132. 27. WOOLGARJA. Lymph node metastasis in oral cancer. PhD thesis. University of Liverpool, 1994. 28. WOOLGARJA, BEIRNEJC, VAUGHANEl),
Metastasis from oral SCC LEWIS-JONES HG, SCOTT J, BROWN JS. Correlation of histopathologic findings with clinical and radiologic assessments of cervical lymph-node metastases in oral cancer. Int J Oral Maxillofac Surg 1995: 24: 30-7.
29. WOOLGAR JA, SCOTT J, VAUaHAN ED, BROWN JS, WEST CR, ROaERS S. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl 1995: 77: 325-31.
Address:
Dr Julia A. Woolgar, FRCPath Oral Pathology Laboratory University of Liverpool Dental Hospital Pembroke Place Liverpool L3 5PS UK
9
Copyright 9 Munksgaard 1997 [ntemationa]Jouma] of
Oral& MaxillofacialSurgery ISSN 0901-5027
Leading article
Detailed topography of cervical lymph-node metastases from
Julia A. Woolgar University of Liverpool School of Dentistry, Liverpool, UK
0ral squam0us cell carcinoma J. A. Woolgar. Detailed topography of cervical lymph-node metastases from oral squamous cell carcinoma. Int. J. Oral Maxillofac. Surg. 1997, 26: 3-9. 9 Munksgaard, 1997
Abstract. The histologic presence and detailed topography of cervical lymphnode metastatic tumours was investigated in a series of neck dissections from 154 previously untreated patients with oral mucosal squamous cell carcinoma. Metastasis was evident in 73 patients (47%), including 13 (8%) with bilateral spread and 14 (9%) with only micrometastases. Multiple positive nodes were recovered from 58 (67%) of the 86 positive sides of neck dissection, and fusion of nodes was seen in 22 dissections (26%). Both direct extracapsular and embolic spread accounted for advanced disease. An orderly progressive ("overflow") involvement of anatomic levels was seen in 85% of positive dissections. "Skipping" of anatomic levels II and/or III was seen in 10%, and "peppering" of nodes at multiple levels without any macroscopic focus in 5%. Hence, "fasttracks" may account for the distribution of metastatic carcinoma in ! 5% of positive necks. Adjuvant radiotherapy was dependent on the pathologic stage. The range of postoperative follow-up was 1-6 years. Death from recurrent regional disease occurred only in patients who had exhibited macroscopic or microscopic extracapsular spread. Survival was similar (75%) for patients with either macroscopic or microscopic metastases confined to lymph nodes or no evidence of metastasis. Hence, with surgery and adjuvant radiotherapy, metastases confined to lymph nodes do not appear to affect the short-term prognosis.
The distribution of cervical lymph-node metastases from squamous cell carcinoma (SCC) of the oral cavity and oropharynx has proved sufficiently consistent 5'9'13,18 to permit the design and successful application of the standard radical neck dissection7 and selective neck dissections2-r Nevertheless, the mechanisms involved and the precise routes of spread within the cervical lymphatic system are open to discussion. T h e embolic character of the initial intranodal metastatic deposit is well accepted 21,26. At least three mechanisms are possible in advanced disease: embolic spread from node to node leading to multiple discrete positive nodes,
or permeation of internodal lymphatics, or direct extracapsular spread (ECS) resulting in fused (matted) nodes 26. The relative contribution of each mechanism in oral/oropharyngeal SCC is uncertain. Some sites within the oral cavity may also drain directly to distant lymph nodes via long-range pathways or fast-tracks 14, but data on the involvement of such routes are not readily available. Hence, the detailed topography of cervical lymph-node metastases from oral and oropharyngeal SCC was investigated with four main aims: 1) to assess the mechanisms of spread in advanced disease
Key words: oral squamous cell carcinoma; lymph-node metastasis. Accepted for publication 15 September 1996
2) to assess the evidence for and frequency of fast-track involvement 3) to assess the prognostic importance of the various manifestations of lymph-node metastasis 4) to assess the accuracy of the preoperative detection of metastatic disease.
Material and methods Surgical cases
A series of 154 consecutive patients undergoing surgery as the primary treatment for intraoral/oropharyngeal SCC at the Mersey Regional Centre for Maxillofacial Surgery, Walton Hospital, Liverpool, UK, between
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Woolgar
October 1989 and October 1994, formed the material for the study. None of the patients had received preoperative radiotherapy, chemotherapy, or previous surgery, other than routine dentoalveolar procedures and recent diagnostic biopsy. The series comprised 99 males (64%) and 55 females (36%o). The males had a mean age of 58 years (SD 11.8, range 30-80 years), significantly lower than the mean age of 62 years (SD 13.2, range 11-81 years) of the females (two-sample t-test, t=2.091, df=152, P=0.035). The clinical stage of the primary tumour was determined according to the recommendations of the AJCC 1, except for one modification, namely, tumours of the oral tongue and floor of mouth (FOM) were divided into three categories: lateral border of tongue, ventral (under surface) of tongue/FOM, and FOM. Lateral border of tongue was the site of the primary tumour in 37 patients (24%), ventral tongue/FOM in 30 (19%0), FOM in 27 (I 8%), retromolar trigone in nine (6%), lower alveolar ridge in 16 (10%), buccalmucosa in 14 (9%o), and oropharynx in the remaining 21 patients (14%). Thirty-three (21%) of the primary tumours were stage T1, 50 tumours (32%) were T2, 13 tumours (8%) were T3, and the remaining 58 tumours (38%) were stage T4. The preoperative metastatic status of the cervical lymph nodes was determined by palpation under general anaesthesia during clinical staging/endoscopic evaluation, supplemented in 22 patients by computerized tomography (CT), and in 119 patients by CT and magnetic resonance imaging (MRI). The neck was recorded as clinically positive if any of the investigations suggested that metastatic disease was present. All other necks were recorded as clinically negative. Both sides of the neck were clinically positive in 11 patients (7%), and one side of the neck was clinically positive in 47 patients (31%). Both sides of the neck were clinically negative in the remaining 96 patients (62%). A total of 103 patients (67%) underwent resection of the primary tumour with simultaneous unilateral neck dissection; in the remaining 51 patients (33%), the neck dissection was bilateral. Thus, a total of 205 sides of neck were available for histologic assessment. Twenty-three (11%) were radical neck dissections7, and 182 (89%) were modified (conservative) procedures z15. Seventy-four of the modified neck dissections encompassed levels I - V 15 and the remaining 108 modified dissections encompassed levels I - IV is. Postoperative radical radiotherapy was employed on the basis of pathologic staging under the following criteria: 1) involved or close (within 5 ram) resection margins at the primary site 2) two or more positive cervical lymph nodes 3) ECS from one or more positive lymph nodes. Seventy-four (48%) of the 154 patients were found to have one or more of these features. The radiotherapy (external beam, 60-65 Gy
fractionated over 6 weeks) was started, whenever possible, 6 weeks after surgery. Patients were reviewed at regular intervals. At the time of analysis, all patients had at least a 1-year follow-up. Status at last contact was recorded as one of the following: 1) alive and well 2) alive and currently disease-free after treatment for further intraoral SCC (recurrent or metacbronous) 3) dead of SCC (The site of initial failure was recorded as local (intraoral/oropharyngeal), regional (lymphatic metastases), or systemic (haematogenous metastases).) 4) Dead of other cause, with no signs of locoregional or systemic SCC. Pathologic assessment
In order to minimize tissue distortion, the surgical specimens were sutured to polystyrene sheets before fixation in 10% buffered formalin and transport to the Oral Pathology Diagnostic Laboratory at Liverpool University Dental Hospital, where all the gross dissections and histologic assessments were made by the author. The specimens were examined in the laboratory after 24-48 h of fixation. Lymph nodes larger than 0.3 cm in diameter were identified by palpation and visual inspection, and dissected out from each of the five main anatomic levelslS: level I, submandibular and submental nodes; levels II, III, and IV, upper, middle, and lower cervical; and level V, contents of the posterior triangle. In nodes with obvious metastatic involvement, any spread into perinodal fibroadipose tissue or adjacent anatomic structures (macroscopic ECS), or fusion (matting) of adjacent nodes was recorded, and blocks of tissue showing the maximum extent of spread were processed routinely for paraffin embedding. Nodes without macroscopic involvement were processed with the pericapsular fibroadipose tissue attached. Lymph nodes larger than 0.5 cm were bisected in the long axis, or sliced, depending on their size and shape, and smaller nodes were processed whole. Initial histologic assessment of each node was made on a single section stained with haematoxylin and eosin (HE). Step-serial sections (100/zm apart) were prepared from those nodes >2.4 cm that appeared tumourfree on initial assessment. All nodes were recorded as negative or positive for metastatic SCC. Metastatic deposits measuring no more than 0.3 cm after step-serial sectioning were designated "micrometastases". Extracapsular spread evident only on histologic assessment was recorded as "microscopic ECS". Any permeation (continuous columns of tumour) or embolization (detached groups of tumour cells) of the perinodal lymphatics was recorded. The pathologic findings in each patient were charted on a topographic diagram showing the anatomic location and size of the positive node(s), the size andintranodal position of the metastatic deposit(s),
and the presence and extent of ECS. An example of a patient with four positive nodes in the left side of the neck is shown in Fig. 1. Advanced disease was defined as multiple positive lymph nodes, and a single positive node was described as early metastatic disease. Involvement of fast tracks was defined as "skipping" of anatomic levels (other than level I), or histologic involvement of multiple levels in the absence of any macroscopic metastatic focus. For assessment of the prognostic importance of the various manifestations of lymph-node metastasis, patients were assigned to one of the following five categories on the basis of the presence and extent of ECS and the size of the intranodal metastatic deposit: 1) at least one positive node showing macroscopic ECS involving perinodal anatomic structures 2) at least one positive node showing macroscopic ECS confined to the perinodal fibroadipose tissue 3) at least one positive node showing microscopic ECS 4) no ECS, at least one node containing a metastatic deposit >0.3 cm 5) no ECS, only micrometastases. Statistical methods
The results were analysed with a commercial software package (Arcus PRO-II, lain E. Buchan, 1993) and an IBM microcomputer. Parametric data from two independent groups were compared with Student's twosample (unpaired) t-test. Frequency tables of categorical data were analysed with the chisquare test, with Yates' correction when the expected cell frequency was less than five. Statistical significance was claimed for a twosided P value of less than 0.05. Results Nodal yield
T h e m e a n n u m b e r o f n o d e s recovered f r o m each o f the three types o f surgical neck dissection specimens was as follows: radical, 45 n o d e s (SD 15.4, range 30-96); modified, levels I - V, 36 nodes (SD 9.9, r a n g e 18-63); a n d modified, levels I - IV, 21 n o d e s (SD 7.5, range 8 42). In total, 5932 n o d e s were e x a m i n e d histologically, a n d 347 (5.8%) were positive for m e t a s t a t i c SCC.
Occurrence of cervical lymph node metastasis
N o d a l metastasis was diagnosed histologically in 73 (47%) o f the 154 patients. T h i r t e e n patients (8%) h a d bilateral metastases. Hence, 86 sides o f neck dissection c o n t a i n e d positive nodes. T h e occurrence o f metastasis was related to the site a n d stage o f the p r i m a r y
Metastasis from oral SCC
Fig. 1. Topographic diagram showing anatomic level and size of positive nodes, and volume and distribution of metastatic SCC (arrows indicate presence of ECS).
tumour. Metastasis was present in 23 (62%) of the 37 tumours of the lateral tongue, in 18 (60%) of the 30 tumours of the ventral tongue/FOM, in 11 (40%) of the 27 tumours of the FOM, in six (67%) of the nine turnouts of the retromolar trigone, in none (0%) of the 16 tttmours of the lower alveolar ridge, in three (21%) of the 14 tumours of the buccal mucosa, and in 12 (57%) of the 21 oropharyngeal tumours (chi-square test, Z2=27.468, df=6, P=0.0001). Metastasis was present in seven (21%) of the 33 T1 turnouts, in 28 (56%) of the 50 T2 tumours, in eight (62%) of the 13 T3 tumours, and in 30 (52%) of the 58 T4 tumours (chisquare test, Z2=12.029, df=3, P 0.0073). Metastasis occurred in 53 (54%) of the 99 males and in 20 (36%) of the 55 females (chi-square test, Z2=7.308, df= 1, P=0.0069). There was no significant difference in the occurrence of metastasis in relation to age (two-sample ttest, t=0.744~ df= 152, P=0.54). General topography of cervical metastases
In 12 of the 13 patients with bilateral metastases, the primary turnout was sited on the tongue or F O M and crossed the midline. The remaining patient h a d synchronous bilateral oropharyngeal tumours. One patient had only micrometastases in both sides of the neck, and in a further five of the 13 patients, micrometastases accounted
for the contralateral neck disease. Thirty-four (57%) of the 60 patients with unilateral metastasis showed involvement of a single anatomic level (level I in 15 cases, level II in 18 cases, and level IV in a single case), and 16 (27%) showed involvement of two levels. As shown in Table 1, the frequency of involvement of nodes at level I was related to the site of the primary tumour (chi-square test, Z2= 26.431, df=5, P<0.0001). Levels II, III, and IV were involved in all five dissections showing involvement of nodes at level V. In 53 (73%) of the 73 patients with metastasis and in 64 (74%) of the 86 positive sides of neck dissection, metastasis was associated with discrete nodes, and in the remaining 20 patients (22 dissections), some of the positive nodes were partially fused (matted). Macroscopic ECS was detected in eight (15%) of the 53 patients with discrete positive nodes, and microscopic ECS was present in a further 13 patients (25%). Hence, in total, 41 patients (56% of the 73 patients with metastasis and 27% of the series) had ECS (macroscopic, 28; microscopic, 13). Micrometastases only accounted for the metastatic disease in 14 of the 32 patients without ECS (that is, 19% of the 73 patients with metastasis and 9% of the series). Permeation of the perinodal lym-
5
phatics was evident in eight patients (two of whom had fused nodes), and embolization was evident in a further seven patients (four of whom had fused nodes). The 86 positive sides of neck dissection yielded 206 discrete positive nodes and 37 masses of fused nodes. Each mass appeared to be made up of 2-25 nodes (mean 3.8, SD 3.93, median 3), and the apparent total number of fused positive nodes was 141. Hence, the 86 dissections yielded, in total, 347 positive nodes. The number of positive nodes per patient ranged from 1 to 29 (mean 4.8 nodes, SD 5.83, median 2). Of the 347 positive nodes, 71 (20%) were located at level I, 164 (47%) at level II, 55 (16%) at level III, 46 (13%) at level IV, and 1 l (3%) at level V. Of the 206 discrete positive nodes., 18 (9%) showed macroscopic ECS, 33 (16%) showed microscopic ECS, and 84 (41%) were micrometastases. Frequency of early and advanced metastatic disease
Twenty-one patients (29%) had a single positive node. There was no significant difference in the frequency of early metastatic disease in relation to the site and stage of the primary turnout (chisquare test, Zz=2.230, df=5, P=0.82; and Z2=1.211, df=3, P=0.75, respectively). The group of 52 patients with multiple positive nodes included the 13 patients with bilateral metastases, seven of whom had only early disease in one side of the neck. Topography of early metastatic disease
Twenty-eight (33~ of the 86 positive sides of neck dissection contained a single positive node. This was located at level I in 14 cases, at level II in 12 cases, at level III in one case, and at level IV in the remaining case. Microscopic ECS was evident in four cases, and of the remaining 24 cases without ECS, 13 were micrometastases. Topography of advanced metastatic disease
Fifty-eight (67%) of the 86 positive sides of neck dissection contained more than one positive node. In 22 of the 58 sides, at least one mass of fused nodes was present, and, in addition, in 16 of the 22 dissections, at least one positive discrete node. The
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Woolgar in four of the 20 dissections, at two levels in nine, at three levels in five, and at four levels in the remaining two cases. At the numerically highest level of involvement, tumour was confined to the lymph .node(s) in six of the 20 dissections, and present as only micrometastases in a further four cases. In the other 16 neck dissections with advanced disease, tumour appeared to be confined to the lymph nodes. In these cases, the number of positive nodes per dissection ranged fi-om 2 to 6 (mean 2.8, SD 1.24, median 2). The positive nodes were located at a single anatomic level in nine of the 16 dissections, at two levels in six, and at three levels in the remaining case. Metastatic disease was present as only micrometastases in six of the 16 dissections, and micrometastases accounted for the highest level of involvement in a further three dissections.
number of positive nodes (fused and discrete) per dissection ranged from 2 to 29 (mean 9.1, SD 7.32, median 7). Metastatic disease was limited to nodes at anatomic level I in one of the 22 cases, to nodes at level II in four cases, and to nodes at levels I and II in a further two cases. In the remaining 15 cases, a "cone" of metastatic disease was present, with the base (the greatest volume of tumour) at level II, and the apex extending to involve nodes at level III (five cases), level IV (five cases), and level V (five cases). The numerically highest level of involvement was represented by only discrete positive nodes in five cases, and by only micrometastases in five cases. In the latter 10 dissections, negative lymph nodes were recovered from the area between the fused nodes and :the discrete positive nodes. The metastatic carcinoma had spread from the fused nodes to involve other anatomic structures in 10 of the 22 necks (internal jugular vein, 10 cases (with full-thickness involvement in six); skeletal muscle, six cases; skin of neck, two cases). In the remaining 12 dissections containing fused nodes, the metastatic tumour appeared to be confined to the .perinodal fibroadipose tissue. In the remaining 36 sides of neck dissection showing advanced disease, the metastatic tumour was associated with multiple discrete positive nodes. In 20 of the 36 dissections, ECS to perinodal fibroadipose tissue was diagnosed from at least one~ positive node (macroscopic ECS, eight dissections; microscopic ECS, 12 dissections). Direct contact between the positive nodes was not evident and adjacent/intervening nodes were histologically negative. In the 20 dissections with ECS, the number of positive nodes per dissection ranged from 2 to 9 (mean 3.7, SD 2.23, median 3). The positive nodes were located at a single anatomic level
Evidence for fast-track involvement
Skipping of anatomic levels (other than level I) was seen in seven sides of neck dissection from patients with tumours of the lateral tongue (six cases) or ventral tongue/FOM (one case). In three dissections, a positive node was detected at levels IlI or IV without evidence of involvement of levels I and II. In the remaining four dissections, positi ve nodes were recovered from levels II and IV with no evidence of disease in nodes at level III. Six dissections from four patients (lateral tongue, two cases; ventral tongue/FOM, one case; FOM, one case) showed involvement of nodes at multiple levels without any macroscopic focus ("peppering"). Microscopic ECS, perinodal embolization, or permeation was evident in three dissections. The microscopic deposits were confined to the nodes and measured <0.3 cm in the
Table 1. Prevalence of nodal metastasis by anatomic level in 86 positive sides of neck dissection in 73 patients~
Anatomic level T site
I
Lateral tongue n=23 8 (35%) Ventral tongue/FOM n=18 15 (83%) FOM n = l l 12 (109%) Oropharynx n=12 3 (25%) Retromolar trigone n=6 3 (50%) Buccal mucosa n=3 3 (100%) All T sites n=86 44 (51%)
II
III
IV
V
20 (87%) 16 (89%) 9 (82%) 12 (100%) 5 (83%) 0 62 (72%)
14 (61%) 7 (39%) 3 (27%) 3 (25%) 1 (17%) 0 28 (33%)
9 (39%) 5 (28%) 2 (18%) 2 (17%) 0 0 18 (21%)
1 (4%) 2 (11%) 0 2 (17%) 0 0 5 (6%)
a Involvement of multiple levels accounts for percentages > 100. FOM: floor of mouth.
remaining three dissections (micrometastases). Prognostic importance of the various manifestations of lymph-node metastasis
The number of patients allocated to each of the five topographic categories and their status at last contact are shown in Table 2. All patients in categories 1, 2, and 3; eight (44%) of the 18 patients in category 4; eight (57%) of the 14 patients in category 5; and 17 (21%) of the 81 patients without metastasis fulfilled the criteria for postoperative radiotherapy. There were significant differences in both the number of patients alive at last contact and the number dead of SCC in relation to the topographic category (chi-square test, X2=26.390, df=4, P<0.0001; and za=12.821, df=4, P = 0.012, respectively). However, there were no significant differences in patients with metastasis confined to the lymph nodes (categories 4 and 5) and patients without metastasis (chi-square test, Z2=0, d f = l , P = I ; and Z2=1.421, df = 1, P=0.23, respectively). Accuracy of the preoperative detection of metastatic disease
Metastasis was detected histologically in 48 (70%) of the 69 clinically positive sides of neck, and in 38 (28%) of the 136 clinically negative sides of neck. Hence, the overall accuracy of the preoperative assessment was 71% (sensitivity, 56%; specificity, 82%). In total, 80 positive nodes were recovered from the 38 false-negative sides of neck dissection. The number of positive nodes per dissection ranged from 1 to 9 (mean 2.1 nodes, SD 1.79), but 19 dissections contained a single positive node. The positive node(s) were confined to a single anatomic level in 26 dissections, but four different levels were involved in one case. Twenty-eight (35%) of the 80 positive nodes were located at level I, 38 (48%) at level II, seven (9%) at level III, and the remaining seven nodes were located around the tendon of the omohyoid muscle (level IV). Macroscopic ECS to perinodal fibroadipose tissue was present in two of the false-negative dissections, and microscopic ECS was present in a further nine dissections. Hence, 11 (29%) of the 38 false-negative necks (8% of the 136 clinically negative necks) showed ECS.
Metastasis f r o m oral S C C
7
Table 2. Status of patient at last contact in relation to topographic category of cervical metastases
Topographic pattern category 1
Dead, intraoral disease
Dead, regional metastases
Dead, systemic metastases
Dead, other cause
Further treatment, alive, disease-free
Alive, well
1 (n=lO) 2 (n=18) 3 (n=13) 4 (n=18) 5 (n=14) No metastasis (n=81) Total series (n=154)
2 (20%) 5 (28%) 3 (23%) l (6%) 4 (29%) 7 (9%) 22 (18%)
5 (50%) 3 (17%) 2 (15%o) 1(6%)" 0 (0%) 0 (0%) 11 (7%)
0 (0%) 2 (11%) 1 (8%) 0 (0~ 0 (0%0) 2 (2%) 5 (3%)
3 (30%) 4 (22%0) 4 (31%) 2 (11%o) 0 (0%) 11 (14%) 24 (16%)
0 (0%) 0 (0%0) 2 (15%) 0 (0%) 1 (7%) 9 (I 1%) 12 (8%)
0 (0%) 4 (22%) 1 (8%) 14 (78%) 9 (64%) 52 (64%) 80 (52%)
1These five categories are explained in text (Material and methods), aContralateral (nonoperated) neck.
Fifteen (39%) of the 38 clinically false-negative sides of neck contained only micrometastases, and in 11 necks (29%), the metastatic deposit(s) measured 0.3-0.5 cm. In a further case, the positive node had occupied a depression within the lingual aspect of the mandible. There were no pathologic features to account for the false-negative clinical assessments in the remaining 11 cases (29%).
Discussion
The present study sought to investigate the detailed topography of metastatic oral SCC within the cervical lymphatic system and assess certain clinical implications. The results provide an insight into the patterns of spread of metastatic SCC within the neck, and show the prognostic value of detailed pathologic staging. However, before discussion of the main findings, certain limitations of the study should be mentioned. Firstly, a large percentage of the series underwent a modified neck dissection encompassing levels I - IV; hence, in these cases, level V nodes were not available for histologic assessment. However, several studies have shown that nodes within the posterior triangle are rarely, or never, involved in oral SCC in the absence of extensive metastatic disease at levels I I - I V 41819. Preoperative investigations are likely to detect such extensive disease28, and in these circumstances, radical neck dissection would be performed. In the present study, patients with a 1.5 cm positive but mobile node at levels II/III were also treated by modified neck dissection encompassing levels I - V Only patients with clinically minimal disease and those with clinically negative necks were treated by a modified dissection encompassing levels I - IV Hence, inaccuracies due to failure to examine level V nodes are un-
likely. The modified I - IV neck dissections provided also material from a large number of clinically negative necks, and the subsequent important histologic findings would appear to counterbalance any criticism of their inclusion in the present study. The second limitation of the present study relates to the pathologic methods. The most important shortcoming is that clearing techniques 8 were not used; hence, the lymphatic tree could not be visualized en bloc. However, a strict protocol was followed to ensure that specimens were fixed with minimal distortion 27, and all the laboratory dissections and histologic assessments were made by a single pathologist. The detection of microscopic ECS and embolization/permeation of the perinodal lymphatics were facilitated by processing nodes with the perinodal fibroadipose tissue attached. Immunostaining was not used to detect micrometastases since it has been reported 23 that this has no significant advantage over assessment of HE-stained sections by an experienced pathologist. Nevertheless, in common with previous studies, it must be accepted that some falsenegative pathologic assessments and other inaccuracies are inevitable. The frequency of nodal metastasis in relation to the T site and T stage of the primary tumour is in keeping with previous reports is'2~ A likely explanation for the higher frequency of metastasis in males in the present study is tumour site males had a higher frequency of tumours of the tongue and FOM, and females had a higher frequency of tumours of the alveolar ridge. The observed distribution of cervical metastases in relation to the site of the primary tumour (Table 1) is in agreement with previous reports 5,9,13,18. Since the precise site of origin of tumours involving both the ventral tongue and F O M is difficult to determine, even on labora-
tory assessment of the resection specimen, an additional site category, ventral tongue/FOM, was used in the present study. The latter tumours frequently spread to level I nodes, whereas tumours of the lateral border of tongue frequently spread directly to level I] nodes (Table 1). The definition of advanced metastatic disease used in the present study was that suggested by WmLIS26. it takes no account of the volume of metastatic carcinoma nor of ECS, which are more accurate measures of the actual pathologic stage. Nevertheless, the chosen criterion allowed an assessment of the possible mechanisms of spread within the cervical lymphatic system. The features reported in the present study (number of involved anatomic levels, number of positive nodes, fusion of nodes, and ECS) were an attempt to describe the topographic charts which were used to depict the volume and distribution of metastatic SCC ( F i g . 1). The charts showed that the topographic features were interrelated with an obvious positive association. In 85% of positive neck dissections, the metastatic disease was focused on one or more nodes at a single anatomic level with progressive ("overflow") involvement of neighbouring nodes, and a gradual reduction in the volume of metastatic disease and the extent and occurrence of ECS. Observation of the position of intranodal metastatic deposits, the degree of nodal replacement, and the extent of ECS in cases with fused nodes suggested that both direct spread between immediate neighbouring nodes and embolic spread to nearby nodes are important. Histologically, it was difficult to distinguish between permeation and embolization, but macroscopic permeation of the perinodal lymphatics was evident in a single case. Topographic features suggestive of fast-track involvement, seen in the re-
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WooIgar
maining 15% of positive dissections, were almost exclusive to tongue tumours. "Skipping" of anatomic levels and "peppering" were not seen in association with primary tumours at any other site, apart from the single case of a t u m o u r of the anterior midline F O M . However, these findings should be interpreted with caution since the number of primary tumours at some sites was small. It is possible that extensive disease throughout the neck had obscured the true pattern of spread in some of the necks showing the "overflow" pattern. Nevertheless, this seems unlikely since, in the latter cases, the topographic maps showed that the disease was greatest in the upper part of the neck. The definition of "micrometastases" which was used in the present study was suggested by VAN DEN BRErd~L et al. 23. It is unlikely that such tiny deposits can be detected preoperatively by routine C T scans and MR122,28. We have, however, not assessed the value of sonography 16. In the present study, small tum o u r deposits or the' involvement of small nodes accounted for 68% of the false-negative clinical assessments. The metastatic status of some patients with micrometastases was assessed correctly. However, histologically, reactive hyperplasia of lymphoid tissue, rather than the metastatic deposit per se, accounted for the clinical nodal enlargement. In the present study, ECS, a feature of known prognostic importance 6'2~ was used as the main criterion for evaluating the prognostic value of the various manifestations of the cervical metastases. The results (Table 2) show that, with adjuvant radiotherapy based on the pathologic stage, survival is similar for patients with metastases confined to the lymph nodes and patients without histologic evidence of meta, stasis. The p o o r prognosis of patients with metastasis reported in .our previous study 29 appears to be due entirely to the p o o r survival of patients with ECS. However, the postoperative review period is short for cases accessioned late in the present study. Hence, although further regional failures are unlikely 1~ it is possible that the longterm survival of patients with intranodal metastases may be reduced by an increased frequency of late-presenting systemic metastases 11'25. Nevertheless, the results of the present study suggest that the presence of nodal metastasis with a favourable topographic location
does not affect the short-term prognosis. Acknowledgments. I thank Mr E. D. Vaughan and Mr J. S. Brown, Consultant Oral and Maxillofacial Surgeons, Walton Hospital, for their contribution to the study. References 1. AMERICANJOINT COMMITTEEON CANCER.
Head and neck sites. In: BEARHS OH, HENSEN DE, HUTTER RVP, MYERS ED, eds: Manual for staging of cancer. 3rd ed. Philadelphia: JP Lippincott, 1988: 27-38. 2. BIER J, SCHLUMS D, METELMANN H, HOWALDTH-P, PITZ H. A comparison of ra~iical and conservative neck dissection. Int J Oral Maxillofac Surg 1993: 22: 1027. 3. BYERSRM. Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg 1985: 150: 414-21. 4. BYERS RM, WOLF PF, BALLANTYNEAJ. Rationale for elective modified neck dissection. Head Neck Surg 1988: 10: 1607. 5. CANDELAFC, KOTItARIK, SHAHJR Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck Surg 1990>, 12: 197-203. 6. CARTERRL, BLISSJM, Soo KC, O'BRIEN CJ. '~' Radical neck dissections from squamous carcinomas: pathological findings and their clinical implications with particular reference to transcapsular spread. Int J Rad Oncol Bid Phys 1987: 13: 825-32. 7. CRILE GW Excision of cancer of the head and neck with special reference to the plan of dissection based upon one hundred and thirty-two operations. JAMA 1906: 47: 1780-6. 8. DE LA PAVA S, PICKREN JW. On lymph node clearing as applied to head and neck tumours. In: RUTTIMANA, ed.: Progress in lymphology. Proceedings of the International Symposium on Lymphology, Switzerland, 1966. Stuttgart: Georg Thieme, 1967: 290-2. 9. FEIND CR. The head and neck. In: HAAGENSEN CD, FEIND CR, HERTER FP, SLANETZ CA, WEINBERG JA, eds.: The
lymphatics in cancer. Philadelphia: WB Saunders, 1972: 59-227. 10. FOOTERL, OLSENKD, DAVISU. Base of tongue carcinoma: patterns of failure and predictors of recurrence after surgery alone. Head Neck Surg 1993: 15: 30~7. 11. KOTWALLC, SAKOK, RAZACKMS, RAO U, BAKAMJIANV, SHEDD DR Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 1987: 154: 439-42. 12. LANGDONJD, HARVEYPW, RAPIDISAD, PATELME JOHNSONNW, HOVPSR. Oral cancer: the behaviour and response to treatment of 194 cases. J Max-Fac Surg 1977: 5: 221-37.
13. L1NDBERG R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972: 29: 1446-9.
14. McK~LvIE E Metastatic routes in the neck. Can J Otolaryngol 1974: 3: 473-9. 15. O'BRIEN CJ, URIST MM, MADDOXWA. Modified radical neck dissection. Terminology, technique and indications. Am J Surg 1987: 153: 310-6. 16. RAINIER T, OFNER G, MARCKHGOTT E. Ultrasound diagnosis of regional lymph node metastasis of the neck in patients with head-neck neoplasms: sonomorphologic criteria and diagnostic accuracy. Laryngorhinootologie 1993: 72: 73-7. 17. ROBBINSKT, MEDINAJE, WOLFEGT, LEVINEPA, SESSIONSRB, PRUETCW. Standardizing neck dissection terminology. Arch Otolaryngol Head Neck Surg 1991: 117: 601-5. 18. SHAHJR CANDELAFC, PODDARAK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer 1990: 66: 109-13. 19. SKOLNIK EM, YEE KF, FRIEDMAN M, GOLDENT. The posterior triangle in radical neck surgery. Arch Otolaryngol 1976: 102: 1M.
20. SNOW GB, ANNYAS AA, VAN SLOOTEN EA, BARTELINKH, HART AAM. Prognostic factors of neck node metastasis. Clin Otolaryngol 1982,: 7:185 92. 21. TOYd~RC. Some observations on the deposition of metastatic carcinoma within cervical lymph nodes. Cancer 1963: 16: 364-74. 22. VAN DEN BREKEL MWM, STEL HV, CASTELnNS JA, CROLL GJ, SNOW GB. Lymph node staging in patients with clinically negative neck examinations by ultrasound and ultrasound-guided aspiration cytology. Am J Surg 1991: 162: 362-6. 23. VAN DEN BREKEL MWM, STEL HV, VAN DER VALK P~ VAN DER WAAL I, MEYER
CJLM, SNOWGB. Micrometastases from squamous cell carcinoma in neck dissection specimens. Eur Arch Otorhinolaryngo1 1992: 249: 349-53. 24. VIKRAM B, STRONGEW, SHAH JR SPIRO R. Failure in the neck followihg multimodality treatment for advanced head and neck cancer. Head Neck Surg 1984: 6: 724-9. 25, VIKRAMB, STRONGEW, SHAH JP, Svlao N. Failure at distant sites following multimodality treatment for advanced head and neck cancer. Head Neck Surg 1984: 6: 730-3. 26. WILLIS RA. Direct spread of tumours. Metastasis via the lymphatics. In: The spread of tumours in the human body. 3rd ed. London: Butterworth, 1973: 132. 27. WOOLGARJA. Lymph node metastasis in oral cancer. PhD thesis. University of Liverpool, 1994. 28. WOOLGARJA, BEIRNEJC, VAUGHANEl),
Metastasis from oral SCC LEWIS-JONES HG, SCOTT J, BROWN JS. Correlation of histopathologic findings with clinical and radiologic assessments of cervical lymph-node metastases in oral cancer. Int J Oral Maxillofac Surg 1995: 24: 30-7.
29. WOOLGAR JA, SCOTT J, VAUaHAN ED, BROWN JS, WEST CR, ROaERS S. Survival, metastasis and recurrence of oral cancer in relation to pathological features. Ann R Coll Surg Engl 1995: 77: 325-31.
Address:
Dr Julia A. Woolgar, FRCPath Oral Pathology Laboratory University of Liverpool Dental Hospital Pembroke Place Liverpool L3 5PS UK
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