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A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens
Oral Oncology (2005) 41, 1034–1043
http://intl.elsevierhealth.com/journals/oron/
A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens Julia Anne Woolgar *, Asterios Triantafyllou Oral Pathology, Liverpool University Dental Hospital, Pembroke Place, Liverpool L3 5PS, UK Received 6 May 2005; accepted 7 June 2005
KEYWORDS
Summary Standardised reporting of head and neck cancer resections according to guidelines issued by the UK Royal College of Pathologists was introduced as a routine procedure in 1998. The guidelines include definitions of ‘‘mucosal’’, ‘‘deep’’, ‘‘clear’’, ‘‘close’’ and ‘‘involved’’ surgical margins. This study of routine diagnostic material describes the frequency, type and morphological features of involved margins, and assesses the influence of tumour site and pathological T and N stage. 301 consecutive radical resection specimens for oral/oropharyngeal squamous cell carcinoma assessed according to the guidelines were appraised. 70 resections (23%) had involved margins. The frequency was related to primary tumour site, and pathological T and N stage. Mucosal involvement was evident in 11 resections, bone in 10, and deep soft tissue in 61–12 resections had multiple category involvement. Both anatomical factors and histological ‘‘markers’’ of tumour characteristics influence the status of surgical resection margins. c 2005 Elsevier Ltd. All rights reserved.
Oral cancer; Oropharyngeal cancer; Squamous cell carcinoma; Resection margins; Histopathology
Introduction
Assessment of the resection margins forms an important part of the pathological examination of surgical specimens in patients undergoing surgery with curative intent for most forms of malignant disease, including squamous cell carcinoma of the mouth and oropharynx (OSCC). Although the histo* Corresponding author. Tel.: +44 151 706 5245; fax: +44 151 706 5845. E-mail address: [email protected] (J.A. Woolgar).
pathologic status of the resection margins has long been used as a potential indicator of local recurrence and survival, there is still considerable uncertainty concerning many aspects of resection margins including their nomenclature and definition, and the influence of anatomical and histological factors.1 The UK Royal College of Pathologists issued guidelines and a minimum dataset for head and neck carcinomas in 19982 in an attempt to improve and standardise cancer services in line with the Calman–Hine Report.2,3 The Guidelines divided the surgical margins into ‘‘mucosal’’ and ‘‘deep’’
1368-8375/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2005.06.008
A histopathological appraisal of surgical margins in resection specimens and in each category, defined a histological distance from invasive carcinoma to surgical margins of more than 5 mm as clear, 1–5 as close and less than 1 mm as involved. Involved cases may, or may not, show histological cut-through.2 However, to date, there have been no studies of resection specimens reported according to those criteria. In particular, there is no information on the morphological features of ‘‘involved’’ margins. A retrospective review of the Oral Pathology Diagnostic Service at the Liverpool University Dental Hospital showed that 301 surgical resection specimens for OSCC have been reported since the introduction of the Guidelines. This material provided us with the opportunity to remedy the aforementioned deficiencies and the present investigation was undertaken. Our aims were (1) to determine the relative frequency of involved versus close and clear margins; (2) to assess the influence of tumour site and pathological T and N status, and pathological stage4 on the relative frequency of the three categories; (3) in the cases of involved margins, to determine the relative frequency of involved mucosal and deep margins; and (4) to seek possible histological explanations for the involved status.
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Materials and methods The 301 resection specimens were consecutive cases from patients with histologically-confirmed OSCC. None of the patients had known multiple primary OSCCs nor had received previous radiotherapy, chemotherapy or surgery other than biopsy, and all cases underwent radical surgical resection of the primary tumour (with curative intent) together with selective or comprehensive neck dissection. Of the 301 specimens, 175 (58%) included bone (67 mandibular rim resections; 73 mandibular segmental block resections; 24 partial maxillectomies; 11 complex specimens including both mandibular and maxillary bone). All the operations were carried out by one of three consultant teams at the Regional Centre for Oral and Maxillofacial Surgery, Aintree Hospitals NHS Trust, Liverpool, where well-established standard management protocols are in place.5,6 The series comprised 190 males (63%) and 111 females (37%) with a mean age of 60 years (SD 11.50, range 30–88 years). The site of the primary tumour, and the pathological T and N status, and pathological stage4 are shown in Table 1. The fixation, orientation and
Table 1 Histological status of margins of resected primary tumour in relation to site, and pathological (p) TN classification and staging in 301 resection specimens of OSCCs Site
Floor of mouth
Total
81
Margin status
Total
pT
pN
T1
T2
T3
T4
N0
N1
N2b
N2c
Clear Close Involved
22 44 15
8 11
9 16 2
5 3
5 12 10
14 19 5
4 7 4
4 14 3
4 3
2 1 1
1 9 3
30 15 4
3 6
6 4 3
1 3 1
3 4 9
6 5 2
2 4
4
8 20 6
7 16 2
1 3 2
2 2
1 2 4
1 2 1
1
1 1 3
Oral tongue
76
Clear Close Involved
40 28 8
15 9 1
22 9 3
Retromolar
26
Clear Close Involved
7 9 10
1
3 5
Clear Close Involved
8 21 6
Clear Close Involved
2 4 5
Mandibular alveolus
Maxillary alveolus
35
11
pStage
1 1 1 2 1
1
24
Clear Close Involved
10 6 8
3
4 4 3
1 1
2 1 5
7 3 6
2 2
1 1 2
Oropharynx
48
Clear Close Involved
14 16a 18
3 3 2
7 4 1
1 4 4
3 5 11
9 4 7
2
3 9 5
One tumour was classified as N3.
3
II
III
IV
7 5
5 6 1
2 8 2
8 25 12
15 9 1
14 2 2
3 2
8 15 5
1
3 2 1
2
Buccal
a
I
1
8 20 6
1 1 1
1
1
2 3
3 6 9
1 3 4
2
4 2 2
1 2
3 2 6
3
3 2 2
2 1 3
6 13 12
1
1036 laboratory dissection of the specimens were carried out according to the Guidelines and details are reported elsewhere.5 During histological assessment of the routinely prepared sections, the status of the resection margins (clear, close, involved or involved with cut-through of tumour epithelium) was noted together with a descriptive account of the tumour invasive front and its distance from the margins. In involved cases, the site of involvement—mucosal or deep or both—was noted. Mucosal margins were considered involved when the primary tumour was cut-through or less than 1 mm from the margin; dysplasia or carcinoma-in situ did not qualify. ‘‘Deep’’ included the submucosa and skeletal muscle, bone, etc, both around and underneath the tumour. In cases with involved deep margins without histological cut-through, features of the invasive front—the patterns of invasion as defined in the Guidelines;2 the presence of single streaks or satellite nodules of tumour; lymphovascular emboli/permeation; and perineural/intraneural invasion—were noted. In addition, in cases that included mandibular and/or maxillary bone, the status of the bone and periosteal margins in demineralised tissue sections was recorded.
Results The status of the resection margin in relation to the site of the primary, and the pathological T and N status, and pathological stage, is given in Table 1. In this table, no distinction is made between mucosal and deep and bone resection margins, and the ‘‘worst’’ category (involved > close > clear)—whether mucosal or deep or bone or a combination—is recorded. Overall, 70 resections (23%) had involved margins, 38 (13%) with histological cut-through; 128 (43%) were close and 103 (34%) were clear. The percentage of involved margins was higher in maxillary alveolar (45%), retromolar (38%) and oropharyngeal tumours (38%); intermediate in tumours of the buccal mucosa (33%); and lower in tumours of the floor of mouth (19%), mandibular alveolus (17%) and oral tongue (11%). Involved margins were present in only four (7%) of the 58 pT1 tumours and in 10 (10%) of the 96 pT2 tumours, compared with eight (35%) of the 23 pT3 and 48 (39%) of the 124 pT4 tumours. Involved margins were present in 27 (16%) of the 165 patients with a pN0 neck compared to 14 (30%) of the 46 patients with a pN1 neck and 29 (32%) of the 90 patients with a pN2/3 neck. Involved margins were present
J.A. Woolgar, A. Triantafyllou in only two (4%) of the 45 p Stage Group I tumours compared with eight (15%) of the 53 p Stage Group II, six (21%) of the 28 p Stage Group III and 54 (31%) of the 175 p Stage Group IV tumours. Statistical tests showed there were significant differences in the number of involved cases in relation to pT stage (pT1/2 versus pT3/4, v2 = 37.1, p < 0.001, df = 1), pN status (pN0 versus pN1-3, v2 = 8.9, p < 0.01, df = 1), and p Stage Group (p Stage Group I/II versus p Stage Group III/IV, v2 = 14.9, p < 0.001, df = 1). Of the 70 cases designated ‘‘involved’’, only 11 (16%)—four oropharyngeal, two floor-of-mouth, two oral tongue, two retromolar and one maxillary alveolus—had an involved mucosal margin. Three of the oropharyngeal tumours, one of the retromolar tumours and the maxillary alveolar tumour also had an involved deep soft tissue margin, and one of floor-of-mouth cases had an involved bone margin (Table 2). In six of the eleven cases, the mucosal margin cut through superficially invasive tumour that was not obvious macroscopically. In these six cases, the histological edge of the primary tumour was ill-defined due to the presence of multiple foci of invasion against a background of carcinomain situ, dysplasia or epithelial atrophy (Fig. 1). In a further three cases, the mucosal margin was involved due to histological presence of a second (clinically undiagnosed) primary tumour (Fig. 2). Cut-through of the clinically and macroscopically obvious primary tumour accounted for the remaining two cases. Of the 301 resection specimens, 100 (33%) qualified for pT4 status on account of invasion through the cortical bone and into marrow spaces.4 Twelve were mandibular rim resections; 66 were mandibular segmental block resections; 11 were partial maxillectomies and the remaining 11 cases were the complex resections including both mandibular and maxillary bone. In ten of the 100 cases with pT4 bone status (14% of the 70 cases with involved margins), the bone margin was involved. The site of the primary tumour in these cases was mandibular alveolus (3); retromolar region (2); floor of mouth (2); oral tongue (1); buccal mucosa (1); oropharynx (1). Five of the ten cases also had an involved deep soft tissue margin and as mentioned above, one had an involved mucosal margin (Table 2). In four of the 10 cases with an involved bone margin, the resection specimen was a mandibular segmental block with tumour present within cancellous bone at either the posterior (3 cases) or anterior (1 case) resection margin (Fig. 3). In a further three mandibular segmental blocks, macroscopically undetected tumour had crept along the alveolar (‘‘occlusal’’) periosteal surface to reach the
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Figure 1 SCC of lateral/ventral aspect of tongue. The rectangular demarcated area shows spreading of invasive elements below atrophic surface epithelium and lateral to the tumour bulk (asterisk). Part of the area is magnified in the inset wherein tumour islands and cords are indicated by arrows (objective magnification · 4). (M, mucosal excision margin; D, deep excision margin; E, surface epithelium; t, tonsil; n, nerve; skm, skeletal muscle; sgl, salivary gland.)
3 5 5 70 All sites
3
1
1
1 1
Floor of mouth Oral tongue Retromolar Mandibular alveolus Maxillary alveolus Buccal Oropharynx
1
1037
6 1
1 1
12 5 6 3 4 7 13 1 1 2 1 1
1 2 1
15 8 10 6 5 8 18
Involvement of mucosal and deep soft tissue margins Involvement of mucosal margin only Total number of involved cases Anatomical site of primary tumour
Table 2
Histopathological type of involvement in relation to site of primary tumour
Involvement of bone margin only
Involvement of bone and mucosal margins
Involvement of bone and deep soft tissue margins
Involvement of deep soft tissue margin only
A histopathological appraisal of surgical margins in resection specimens
Figure 2 SCC of soft palate/oropharynx. The asterisk indicates part of the clinically obvious tumour. The thick arrow indicates a second, clinically undiagnosed tumour that involves a mucosal excision margin. The mucosa between the tumours is indicated by the thin arrow and was of normal appearances on step-serial sectioning. (ln, lymph node free from tumour.)
posterior bone resection margin. Three remaining involved bone specimens were mandibular rim resections with tumour involving cancellous bone at the resection base, and one was a partial maxillectomy. In 50 of the 70 involved resections (71%), there was involvement of only the deep soft tissue margin. The site of the primary tumour in the 50 cases is shown in Table 2. In three of the eight retromolar
1
2 6 11
1 1 2 3
61 All sites
39
1 2 1
12 6 8 5 3 8 17 Floor of mouth Oral tongue Retromolar Mandibular alveolus Maxillary alveolus Buccal Oropharynx
7 3 6 5 1 6 9
3 1 1
1
1
1
1 2
Lymphovascular invasion ‘‘Spidery showering’’ Invasion pattern 1, <1 mm Satellite nodule Single ‘‘streak’’ Invasion pattern 3, 4 Total number with involved soft tissue deep margin Anatomical site of primary tumour
Histopathological explanation of soft tissue deep involvement in relation to site of primary tumour
tumours with involved deep margin (Table 2), this was due to involvement of the submucosa or muscle of the buccal sulcus, while in the other five, the tumour extended to the opposite side of the mandible to involve the lingual sulcus, floor-ofmouth or tongue margin. In the involved mandibular alveolar tumours, the tumour involved the buccal sulcus in four cases and the lingual sulcus in one case. Tumour involved the submucosa/ muscle of the buccal sulcus in all five maxillary alveolar tumours. Hence, in total, 12 resections (17% of all involved cases) involved the submucosa/muscle of the buccal sulcus. In the eight involved buccal mucosal tumours, the site of involvement involved the buccinator deep to the centre of the tumour. Of the 17 oropharyngeal tumours with involved deep margin (Table 2), the site of the involvement was base of tongue (10), tonsillar bed (3), glossotonsillar fossa (2) and soft palate (3). In total, 61 of the 70 involved resections (87%) had involvement of the deep soft tissue margins and the histological cause of the involvement is shown in Table 3. As shown there, the most common histological cause of involvement was patterns of invasion 3 and 4 (Fig. 4), followed by a single streak of tumour extending ahead of the main invasive front (Fig. 5). Satellite nodules were seen in six cases (Fig. 6). Less common pathological causes included a well-defined tumour front (pattern 1) at a distance less than 1 mm; lymphovascular emboli/permeation (Fig. 7); extension along vascular bundles (Fig. 8); and peri-/intraneural invasion (Fig. 9). In a single case, the growth pattern was extraordinary, consisting of
Table 3
Figure 3 SCC of maxillary alveolar process. Tumour islands (arrows) involve the marrow spaces. Artifactitious shrinkage that should not be confused with lymphovascular invasion, affects the islands indicated by the horizontal arrow. Objective magnification ·4.
1
J.A. Woolgar, A. Triantafyllou
Neural invasion
1038
A histopathological appraisal of surgical margins in resection specimens
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Figure 4 SCC of lateral aspect of tongue, patterns 3(a) and 4(b). The arrows indicate invasive tumour. Note Involvement of deep excision margin (a) and malignant keratinocytes invading as individual units (b, lower right). Objective magnification ·20 (a), ·40 (b).
Figure 7 SCC of oropharynx. Vascular invasion. Objective magnification · 20.
Figure 5 SCC of base of tongue. The arrows outline a tumour streak that extends below the clinically obvious tumour bulk (asterisk) and through the musculature, to involve deep excision margin.
Figure 8 SCC of floor of mouth. The rectangular demarcated area shows spreading of invasive elements lateral to the tumour bulk (asterisk). Part of the area is magnified in the inset wherein tumour islands and cords are indicated by arrows (objective magnification · 4).
Figure 6 SCC of floor of mouth. The arrows outline part of satellite tumour nodules below the clinically obvious tumour (asterisk), which are involving the deep excision margin.
Figure 9 SCC of soft palate/oropharynx. Involvement of deep excision margin through invasion of nerve fascicles (thick arrow) and skeletal muscle (thin arrow). The asterisk indicates the tumour bulk.
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J.A. Woolgar, A. Triantafyllou
Figure 10 SCC of oropharynx. Ulcerated granulation tissue (ugr) replaces mucosal surface; there is no evidence of tumour bulk in this or any of the multiple blocks processed from the resection. Invasive tumour elements that are demarcated or indicated by arrows, involve the deep excision margin. Part of the square and rectangular areas is magnified in (b) and (c) respectively. Irregular tumour islets (vertical arrow) surrounded by lymphoid inflammatory infiltrates invade fat and muscle (b; objective magnification · 4). Variably acantholytic tumour aggregates invade a nerve fascicle (c; objective magnification · 2). (f, fat; h, haemorrhage).
diffuse islands and spidery cords without the usual tumour bulk (Fig. 10).
Discussion To our knowledge, this is the first histopathological appraisal of involved margins in routine OSCC resection specimens reported according to the Royal College of Pathologists Guidelines.2 Surgical margins are frequently mentioned by authors reporting the outcome of OSCC, but rarely defined in detail. For example, often no distinction is made between mucosal and deep margins (as used in the present investigation), and the lack of universally accepted standardised terms and definitions, prevent meaningful comparisons and conclusions. Batsakis attempted to review the literature from a pathologist’s perspective and draw attention to deficiencies.1 He also emphasised the need for proper definitions, and considered tumour site, anatomical restrictions, biological characteristics and extent of surgery all influenced the adequacy of the resection. The material in the present investigation was homogeneous in relation to its source, and conformation to protocols both in clinical management, operative techniques and presentation of the
resection specimen. Potential influences such as radiotherapy and obvious multifocal mucosal disease were eliminated. However, the inclusion criterion of a neck dissection meant that small and/ or superficial tumours amenable to laser ablation or conservative excision and primary closure are not considered. Nevertheless, more than 300 suitable cases were available and despite the small number of cases at some anatomical sites (Table 1), the material is sufficient for an evidence-based report. The laboratory protocols for macroscopic inspection, anatomical dissection and selection of tissue slices for processing and histological examination are well established in Liverpool.5,7–9 Experience gathered prior to and following publication of the Guidelines2 shows that several points merit particular emphasis. Firstly, thorough slicing of the complete resection specimen, with slices of no more than 4 mm in thickness, is essential. Secondly, the need to develop consistent methods that enable optimal assessment of the advancing tumour front while preserving, or reconstructing, the true anatomical relationships after trimming of tissue slices for routine processing, thus reducing the risk of misinterpretation. Thirdly, the adoption and maintenance of a diligent approach to routine histological assessment supplemented
A histopathological appraisal of surgical margins in resection specimens by the use of step–serial sectioning and immunohistochemistry as appropriate. It is difficult to compare our data on the frequency of involved, close and clear margins with other reports due to the variation in terminology and the indirect approach favoured by authors who allude to ‘‘positive margins’’ when presenting data on local recurrence.10–13 In addition, the frequency of close and involved margins is related to the stringency of the pathological assessment that most authors do not detail. Nevertheless, our data indicates that anatomical site is an important determinant. Our finding of involved margins in only 11% of the oral tongue resections is surprising given the poor survival of patients with tumours at this site.5 One possible explanation is that the anatomy permits the design and adoption of a hemiglossectomy adequate for achieving clear margins in most cases. In contrast, anatomical constraints and difficult access reduce the scope for wide resection margins in sites such as the oropharynx and retromolar region. Anatomical features could also account for a high proportion of involved margins in floor of mouth. Probably, the presence of loose areolar tissue around and deep to the sublingual gland, and the deep localisation of muscle bulk, provide little resistance to infiltrating tumour.14 In addition, structures passing through the zone such as the lingual nerve and sublingual ganglion can be invaded and become potential sources of further dissemination. The submucosa and muscle of the cheek overlying the mandible and maxilla were also shown to be high-risk sites (accounting for 17% of all involved cases in our material). Possible explanations include the desire to preserve the facial skin unless there is obvious spread into the dermis and the natural laxity of a split-thickness cheek resection, which leads to excessive tissue shrinkage following delivery of the resection specimen from the patient prior to and during fixation. It has been reported that shrinkage depends on the site and can reduce the width of the surgical margin by as much as 46%,1,15 a vagary that is not accounted for in standardised guidelines. The finding of a significant relationship between involved margins and pT, pN and p Stage Grouping is not surprising. It is logical that large tumours are more difficult to resect given the anatomical restraints that operate at many sites within the oral cavity and oropharynx. In addition, the relationship with both pT and pN status probably reflects the inherent biological characteristics of the tumour. For example, the incidence of involved margins was increased in patients with any degree of neck metastasis, a traditional marker of a biologically
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aggressive tumour.14 The exception of oral tongue where neck disease is common,9,14,16 but the incidence of involved margins is low has already been commented upon. The high percentage of bone resections and the frequency of pT4 bone status at the Regional Centre for Oral & Maxillofacial Surgery, Aintree, have been discussed in previous reports.6,17,18 Histopathological assessment of the resection margins in specimens that include bone is complex. Pathological T4 status due to bone involvement was demonstrated in 100 of the 175 specimens. In the other cases, tumour was confined to the outer aspect of the cortical plate, or the adjacent periosteum/soft tissues. As detailed in the results, the tumour front in the bone may involve the cancellous bone at the truncated base of rim resections, and in all bone resections, the anterior and posterior margins may be involved either in relation to the periosteum overlying the cortical plates or within the cancellous bone. We find consecutive slices taken in the frontal plane following demineralisation of the specimen permit assessment of these aspects of the tumour front, and preserve the natural relationship between the bone and the adjacent soft tissue, including the afore-mentioned high-risk buccal sulcus/cheek region. The delay associated with the demineralisation and the consequent deterioration in the quality of the soft tissue elements are disadvantages of this approach. In order to overcome these disadvantages, we find routinely prepared sections of the soft tissue and periosteum dissected off the buccal and lingual cortical plates are useful when an urgent preliminary report is required. These rountinely-prepared sections provide good visualisation of the tumour as it spreads around the cortical plates and at its soft tissue margins within the buccal sulcus and lingual sulcus/floor of mouth. However, correct interpretation becomes more difficult because of the loss of the innate anatomical orientation and relationships. Our findings indicate that involved bone margins are rare—10 (14%) of the 70 involved cases, of which seven also had an involved mucosal or deep soft tissue margin. Hence, just over 1% the series of 301 specimens had solely an involved bone margin (Table 2). Of the 12 mandibular rim resections showing destruction of the cortical plate, tumour was present at the truncated cancellous bone margin in three cases. Although the majority of the segmental bock resections were pT4 status, only six had an involved bone margin. Hence, the present study indicates that the pre-operative and surgical protocols at the Aintree Unit are justified.6,17,18 Our results also show that involved mucosal margins are rare—11 (16%) of the 70 involved cases, of
1042 which six also had an involved deep soft tissue or bone margin (Table 2). Hence, less than 2% of the series of 301 resection specimens had solely an involved mucosal margin. Unexpected multifocal early OSCC/synchronous primary tumours, both indicative of ‘‘field cancerization’’19–22 and only histologically apparent, account for all except two of the 10 cases. In one of the latter two cases, the resection of the primary tumour involved the mandible and a ‘‘deficiency’’ was apparent in the mucosa adjacent to the tumour leaving the bone exposed. This raised the possibility of loss of mucosa during the operation or manipulation of the specimen on/ following its delivery from the patient, thus resulting an artifactually involved mucosal margin. By contrast, involved deep margins are more of a problem. An involved deep soft tissue margin was present in 61 (87%) of the 70 cases with involved margins, and was the sole cause of the involvement in 50 cases—17% of the series of 301 resection specimens (Table 2). Anatomical restraints are more likely to affect the deep margins. Also, it is difficult to ‘‘visualise’’ particular growth patterns and other features of the deep advancing tumour front, both pre- and intra-operatively, since those particularities are only evident on microscopy (Table 3). The features depicted in Table 3 support the policy of the guidelines2 to denote a margin of less than 1 mm as involved. Invasion pattern 3/4 was the most common explanation of a deep involvement and it is well recognised that cellular groups in poorly-cohesive tumours are often separated by distances approaching 1 mm.23,24 Although single streaks and satellites, and lymphovascular and neural invasion, were additional problems (Table 3), these were often only evident in a single tissue slice despite thorough 4–5 mm slicing of the complete resection specimen. Whether these features represent specific biological characteristics of the tumour or the result of anatomical factors such as lines of least resistance, proximity to nerves, etc, is uncertain. Research assessments using serial sections and immunohistochemistry may well reveal an increased frequency. It is important to remember that the procedures used in the present study are routine guidelines designed to be used in the clinical service laboratory where research possibilities have to be balanced with the limitations of increased workload and cost. In summary, the present study has yielded an insight into the frequency and type of involved margins in routinely assessed OSCC resection specimens, and attempted to provide a histological explanation. Although in the future, molecular assessment of resection margins may become rou-
J.A. Woolgar, A. Triantafyllou tine, it is unlikely that histological procedures will be superseded in the present decade.
Acknowledgement We acknowledge Mr E.D. Vaughan, Mr J.S. Brown and Mr S.N. Rogers, Consultant Oral and Maxillofacial Surgeons, Aintree Hospitals NHS Trust.
References 1. Batsakis JG. Surgical excision margins: a pathologist’s perspective. Adv Anat Pathol 1999;6:140–8. 2. Helliwell T, Woolgar JA. Standards and minimum datasets for reporting common cancers. Minimum dataset for head and neck histopathology reports. London: The Royal College of Pathologists; 1998. 3. Calman K, Hine D. A policy framework for commissioning cancer services: A report by the expert advisory group on cancer to the chief medical officers of England and Wales. London: DoH; 1995. 4. Sobin LH, Wittekind C. Head and neck tumours. In: TNM classification of malignant tumours. 6th ed. New York: Wiley-Weiss; 2002 p. 19–56. 5. Woolgar JA, Rogers S, West CR, Errington JS, Brown JS, Vaughan ED. Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 1999;35:257–65. 6. Shaw RJ, Brown JS, Woolgar JA, Lowe D, Rogers SN, Vaughan ED. The influence of the pattern of mandibular invasion on recurrence and survival in oral squamous cell carcinoma. Head Neck 2004;26:861–9. 7. Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 1995;17:463–72. 8. Woolgar JA. Detailed topography of cervical lymph-node metastases from oral squamous cell carcinoma. Int J Oral Maxillofac Surg 1997;26:3–9. 9. Woolgar JA. T2 carcinoma of the tongue: the histopathologist’s perspective. Br J Oral Maxillofac Surg 1999;37: 187–93. 10. Looser KG, Shah JP, Strong EW. The significance of ‘‘positive’’ margins in surgically resected epidermoid carcinomas. Head Neck Surg 1978;1:107–11. 11. Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg 1990;160:410–4. 12. Van Es RJJ, Amerongen NN, Slootweg PJ. Resection margin as a predictor of recurrence at the primary site for T1 and T2 oral cancers. Evaluation of histopathologic variables. Arch Otolaryngol Head Neck Surg 1996;122:521–5. 13. Spiro RH, Guillamondegui O, Paulino AF, Huvos AG. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck 1999;21:408–13. 14. Batsakis JG. Clinical pathology of oral cancer. In: Shah JP, Johnson NW, Batsakis JG, editors. Oral Cancer. London: Martin Dunitz; 2003. p. 77–129. 15. Johnson R, Sigman JD, Funk GF. Quantification of surgical margin shrinkage in the oral cavity. Head Neck 1997;19: 281–6. 16. Silver CE, Moisa II. Elective treatment of the neck in cancer of the oral tongue. Semin Surg Oncol 1991;7:14–9.
A histopathological appraisal of surgical margins in resection specimens 17. Brown JS, Lowe D, Kalavrezos N, D’Sousa J, Magennis P, Woolgar JA. Patterns of invasion and routes of tumour entry into the mandible by squamous cell carcinoma. Head Neck 2002;24:370–83. 18. Brown JS, Kalavrezos N, D’Sousa J, Lowe D, Magennis P, Woolgar JA. Factors that influence the method of mandibular resection in the management of oral squamous cell carcinoma. Br J Oral Maxillofac Surg 2002;40: 275–84. 19. Bouquot JE, Gnepp DR. Epidemiology of carcinoma in situ of the upper aerodigestive tract. Cancer 1988;61: 1685–90. 20. Bouquot JE, Kurland LT, Weiland LH. Carcinoma in situ of the upper areodigestive tract. Cancer 1988;61:1691–8.
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21. Jovanovic A, van der Tol IGH, Schulten EA. Risk of multiple primary tumours following oral squamous cell carcinoma. Int J Cancer 1994;56:320–3. 22. Jovanovic A, van der Tol IGH, Kostense PJ. Second respiratory and upper digestive tract cancer following oral squamous cell carcinoma. Oral Oncol 1994;30:225–9. 23. Bryne M, Koppang H, Lilleng R, Kjaerheim A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol 1992;166:375–81. 24. Martinez-Gimenco C, Rodrigeuz EM, Vila CN, Varela CL. Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope 1995;105:728–33.
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A histopathological appraisal of surgical margins in oral and oropharyngeal cancer resection specimens Julia Anne Woolgar *, Asterios Triantafyllou Oral Pathology, Liverpool University Dental Hospital, Pembroke Place, Liverpool L3 5PS, UK Received 6 May 2005; accepted 7 June 2005
KEYWORDS
Summary Standardised reporting of head and neck cancer resections according to guidelines issued by the UK Royal College of Pathologists was introduced as a routine procedure in 1998. The guidelines include definitions of ‘‘mucosal’’, ‘‘deep’’, ‘‘clear’’, ‘‘close’’ and ‘‘involved’’ surgical margins. This study of routine diagnostic material describes the frequency, type and morphological features of involved margins, and assesses the influence of tumour site and pathological T and N stage. 301 consecutive radical resection specimens for oral/oropharyngeal squamous cell carcinoma assessed according to the guidelines were appraised. 70 resections (23%) had involved margins. The frequency was related to primary tumour site, and pathological T and N stage. Mucosal involvement was evident in 11 resections, bone in 10, and deep soft tissue in 61–12 resections had multiple category involvement. Both anatomical factors and histological ‘‘markers’’ of tumour characteristics influence the status of surgical resection margins. c 2005 Elsevier Ltd. All rights reserved.
Oral cancer; Oropharyngeal cancer; Squamous cell carcinoma; Resection margins; Histopathology
Introduction
Assessment of the resection margins forms an important part of the pathological examination of surgical specimens in patients undergoing surgery with curative intent for most forms of malignant disease, including squamous cell carcinoma of the mouth and oropharynx (OSCC). Although the histo* Corresponding author. Tel.: +44 151 706 5245; fax: +44 151 706 5845. E-mail address: [email protected] (J.A. Woolgar).
pathologic status of the resection margins has long been used as a potential indicator of local recurrence and survival, there is still considerable uncertainty concerning many aspects of resection margins including their nomenclature and definition, and the influence of anatomical and histological factors.1 The UK Royal College of Pathologists issued guidelines and a minimum dataset for head and neck carcinomas in 19982 in an attempt to improve and standardise cancer services in line with the Calman–Hine Report.2,3 The Guidelines divided the surgical margins into ‘‘mucosal’’ and ‘‘deep’’
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A histopathological appraisal of surgical margins in resection specimens and in each category, defined a histological distance from invasive carcinoma to surgical margins of more than 5 mm as clear, 1–5 as close and less than 1 mm as involved. Involved cases may, or may not, show histological cut-through.2 However, to date, there have been no studies of resection specimens reported according to those criteria. In particular, there is no information on the morphological features of ‘‘involved’’ margins. A retrospective review of the Oral Pathology Diagnostic Service at the Liverpool University Dental Hospital showed that 301 surgical resection specimens for OSCC have been reported since the introduction of the Guidelines. This material provided us with the opportunity to remedy the aforementioned deficiencies and the present investigation was undertaken. Our aims were (1) to determine the relative frequency of involved versus close and clear margins; (2) to assess the influence of tumour site and pathological T and N status, and pathological stage4 on the relative frequency of the three categories; (3) in the cases of involved margins, to determine the relative frequency of involved mucosal and deep margins; and (4) to seek possible histological explanations for the involved status.
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Materials and methods The 301 resection specimens were consecutive cases from patients with histologically-confirmed OSCC. None of the patients had known multiple primary OSCCs nor had received previous radiotherapy, chemotherapy or surgery other than biopsy, and all cases underwent radical surgical resection of the primary tumour (with curative intent) together with selective or comprehensive neck dissection. Of the 301 specimens, 175 (58%) included bone (67 mandibular rim resections; 73 mandibular segmental block resections; 24 partial maxillectomies; 11 complex specimens including both mandibular and maxillary bone). All the operations were carried out by one of three consultant teams at the Regional Centre for Oral and Maxillofacial Surgery, Aintree Hospitals NHS Trust, Liverpool, where well-established standard management protocols are in place.5,6 The series comprised 190 males (63%) and 111 females (37%) with a mean age of 60 years (SD 11.50, range 30–88 years). The site of the primary tumour, and the pathological T and N status, and pathological stage4 are shown in Table 1. The fixation, orientation and
Table 1 Histological status of margins of resected primary tumour in relation to site, and pathological (p) TN classification and staging in 301 resection specimens of OSCCs Site
Floor of mouth
Total
81
Margin status
Total
pT
pN
T1
T2
T3
T4
N0
N1
N2b
N2c
Clear Close Involved
22 44 15
8 11
9 16 2
5 3
5 12 10
14 19 5
4 7 4
4 14 3
4 3
2 1 1
1 9 3
30 15 4
3 6
6 4 3
1 3 1
3 4 9
6 5 2
2 4
4
8 20 6
7 16 2
1 3 2
2 2
1 2 4
1 2 1
1
1 1 3
Oral tongue
76
Clear Close Involved
40 28 8
15 9 1
22 9 3
Retromolar
26
Clear Close Involved
7 9 10
1
3 5
Clear Close Involved
8 21 6
Clear Close Involved
2 4 5
Mandibular alveolus
Maxillary alveolus
35
11
pStage
1 1 1 2 1
1
24
Clear Close Involved
10 6 8
3
4 4 3
1 1
2 1 5
7 3 6
2 2
1 1 2
Oropharynx
48
Clear Close Involved
14 16a 18
3 3 2
7 4 1
1 4 4
3 5 11
9 4 7
2
3 9 5
One tumour was classified as N3.
3
II
III
IV
7 5
5 6 1
2 8 2
8 25 12
15 9 1
14 2 2
3 2
8 15 5
1
3 2 1
2
Buccal
a
I
1
8 20 6
1 1 1
1
1
2 3
3 6 9
1 3 4
2
4 2 2
1 2
3 2 6
3
3 2 2
2 1 3
6 13 12
1
1036 laboratory dissection of the specimens were carried out according to the Guidelines and details are reported elsewhere.5 During histological assessment of the routinely prepared sections, the status of the resection margins (clear, close, involved or involved with cut-through of tumour epithelium) was noted together with a descriptive account of the tumour invasive front and its distance from the margins. In involved cases, the site of involvement—mucosal or deep or both—was noted. Mucosal margins were considered involved when the primary tumour was cut-through or less than 1 mm from the margin; dysplasia or carcinoma-in situ did not qualify. ‘‘Deep’’ included the submucosa and skeletal muscle, bone, etc, both around and underneath the tumour. In cases with involved deep margins without histological cut-through, features of the invasive front—the patterns of invasion as defined in the Guidelines;2 the presence of single streaks or satellite nodules of tumour; lymphovascular emboli/permeation; and perineural/intraneural invasion—were noted. In addition, in cases that included mandibular and/or maxillary bone, the status of the bone and periosteal margins in demineralised tissue sections was recorded.
Results The status of the resection margin in relation to the site of the primary, and the pathological T and N status, and pathological stage, is given in Table 1. In this table, no distinction is made between mucosal and deep and bone resection margins, and the ‘‘worst’’ category (involved > close > clear)—whether mucosal or deep or bone or a combination—is recorded. Overall, 70 resections (23%) had involved margins, 38 (13%) with histological cut-through; 128 (43%) were close and 103 (34%) were clear. The percentage of involved margins was higher in maxillary alveolar (45%), retromolar (38%) and oropharyngeal tumours (38%); intermediate in tumours of the buccal mucosa (33%); and lower in tumours of the floor of mouth (19%), mandibular alveolus (17%) and oral tongue (11%). Involved margins were present in only four (7%) of the 58 pT1 tumours and in 10 (10%) of the 96 pT2 tumours, compared with eight (35%) of the 23 pT3 and 48 (39%) of the 124 pT4 tumours. Involved margins were present in 27 (16%) of the 165 patients with a pN0 neck compared to 14 (30%) of the 46 patients with a pN1 neck and 29 (32%) of the 90 patients with a pN2/3 neck. Involved margins were present
J.A. Woolgar, A. Triantafyllou in only two (4%) of the 45 p Stage Group I tumours compared with eight (15%) of the 53 p Stage Group II, six (21%) of the 28 p Stage Group III and 54 (31%) of the 175 p Stage Group IV tumours. Statistical tests showed there were significant differences in the number of involved cases in relation to pT stage (pT1/2 versus pT3/4, v2 = 37.1, p < 0.001, df = 1), pN status (pN0 versus pN1-3, v2 = 8.9, p < 0.01, df = 1), and p Stage Group (p Stage Group I/II versus p Stage Group III/IV, v2 = 14.9, p < 0.001, df = 1). Of the 70 cases designated ‘‘involved’’, only 11 (16%)—four oropharyngeal, two floor-of-mouth, two oral tongue, two retromolar and one maxillary alveolus—had an involved mucosal margin. Three of the oropharyngeal tumours, one of the retromolar tumours and the maxillary alveolar tumour also had an involved deep soft tissue margin, and one of floor-of-mouth cases had an involved bone margin (Table 2). In six of the eleven cases, the mucosal margin cut through superficially invasive tumour that was not obvious macroscopically. In these six cases, the histological edge of the primary tumour was ill-defined due to the presence of multiple foci of invasion against a background of carcinomain situ, dysplasia or epithelial atrophy (Fig. 1). In a further three cases, the mucosal margin was involved due to histological presence of a second (clinically undiagnosed) primary tumour (Fig. 2). Cut-through of the clinically and macroscopically obvious primary tumour accounted for the remaining two cases. Of the 301 resection specimens, 100 (33%) qualified for pT4 status on account of invasion through the cortical bone and into marrow spaces.4 Twelve were mandibular rim resections; 66 were mandibular segmental block resections; 11 were partial maxillectomies and the remaining 11 cases were the complex resections including both mandibular and maxillary bone. In ten of the 100 cases with pT4 bone status (14% of the 70 cases with involved margins), the bone margin was involved. The site of the primary tumour in these cases was mandibular alveolus (3); retromolar region (2); floor of mouth (2); oral tongue (1); buccal mucosa (1); oropharynx (1). Five of the ten cases also had an involved deep soft tissue margin and as mentioned above, one had an involved mucosal margin (Table 2). In four of the 10 cases with an involved bone margin, the resection specimen was a mandibular segmental block with tumour present within cancellous bone at either the posterior (3 cases) or anterior (1 case) resection margin (Fig. 3). In a further three mandibular segmental blocks, macroscopically undetected tumour had crept along the alveolar (‘‘occlusal’’) periosteal surface to reach the
50
Figure 1 SCC of lateral/ventral aspect of tongue. The rectangular demarcated area shows spreading of invasive elements below atrophic surface epithelium and lateral to the tumour bulk (asterisk). Part of the area is magnified in the inset wherein tumour islands and cords are indicated by arrows (objective magnification · 4). (M, mucosal excision margin; D, deep excision margin; E, surface epithelium; t, tonsil; n, nerve; skm, skeletal muscle; sgl, salivary gland.)
3 5 5 70 All sites
3
1
1
1 1
Floor of mouth Oral tongue Retromolar Mandibular alveolus Maxillary alveolus Buccal Oropharynx
1
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6 1
1 1
12 5 6 3 4 7 13 1 1 2 1 1
1 2 1
15 8 10 6 5 8 18
Involvement of mucosal and deep soft tissue margins Involvement of mucosal margin only Total number of involved cases Anatomical site of primary tumour
Table 2
Histopathological type of involvement in relation to site of primary tumour
Involvement of bone margin only
Involvement of bone and mucosal margins
Involvement of bone and deep soft tissue margins
Involvement of deep soft tissue margin only
A histopathological appraisal of surgical margins in resection specimens
Figure 2 SCC of soft palate/oropharynx. The asterisk indicates part of the clinically obvious tumour. The thick arrow indicates a second, clinically undiagnosed tumour that involves a mucosal excision margin. The mucosa between the tumours is indicated by the thin arrow and was of normal appearances on step-serial sectioning. (ln, lymph node free from tumour.)
posterior bone resection margin. Three remaining involved bone specimens were mandibular rim resections with tumour involving cancellous bone at the resection base, and one was a partial maxillectomy. In 50 of the 70 involved resections (71%), there was involvement of only the deep soft tissue margin. The site of the primary tumour in the 50 cases is shown in Table 2. In three of the eight retromolar
1
2 6 11
1 1 2 3
61 All sites
39
1 2 1
12 6 8 5 3 8 17 Floor of mouth Oral tongue Retromolar Mandibular alveolus Maxillary alveolus Buccal Oropharynx
7 3 6 5 1 6 9
3 1 1
1
1
1
1 2
Lymphovascular invasion ‘‘Spidery showering’’ Invasion pattern 1, <1 mm Satellite nodule Single ‘‘streak’’ Invasion pattern 3, 4 Total number with involved soft tissue deep margin Anatomical site of primary tumour
Histopathological explanation of soft tissue deep involvement in relation to site of primary tumour
tumours with involved deep margin (Table 2), this was due to involvement of the submucosa or muscle of the buccal sulcus, while in the other five, the tumour extended to the opposite side of the mandible to involve the lingual sulcus, floor-ofmouth or tongue margin. In the involved mandibular alveolar tumours, the tumour involved the buccal sulcus in four cases and the lingual sulcus in one case. Tumour involved the submucosa/ muscle of the buccal sulcus in all five maxillary alveolar tumours. Hence, in total, 12 resections (17% of all involved cases) involved the submucosa/muscle of the buccal sulcus. In the eight involved buccal mucosal tumours, the site of involvement involved the buccinator deep to the centre of the tumour. Of the 17 oropharyngeal tumours with involved deep margin (Table 2), the site of the involvement was base of tongue (10), tonsillar bed (3), glossotonsillar fossa (2) and soft palate (3). In total, 61 of the 70 involved resections (87%) had involvement of the deep soft tissue margins and the histological cause of the involvement is shown in Table 3. As shown there, the most common histological cause of involvement was patterns of invasion 3 and 4 (Fig. 4), followed by a single streak of tumour extending ahead of the main invasive front (Fig. 5). Satellite nodules were seen in six cases (Fig. 6). Less common pathological causes included a well-defined tumour front (pattern 1) at a distance less than 1 mm; lymphovascular emboli/permeation (Fig. 7); extension along vascular bundles (Fig. 8); and peri-/intraneural invasion (Fig. 9). In a single case, the growth pattern was extraordinary, consisting of
Table 3
Figure 3 SCC of maxillary alveolar process. Tumour islands (arrows) involve the marrow spaces. Artifactitious shrinkage that should not be confused with lymphovascular invasion, affects the islands indicated by the horizontal arrow. Objective magnification ·4.
1
J.A. Woolgar, A. Triantafyllou
Neural invasion
1038
A histopathological appraisal of surgical margins in resection specimens
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Figure 4 SCC of lateral aspect of tongue, patterns 3(a) and 4(b). The arrows indicate invasive tumour. Note Involvement of deep excision margin (a) and malignant keratinocytes invading as individual units (b, lower right). Objective magnification ·20 (a), ·40 (b).
Figure 7 SCC of oropharynx. Vascular invasion. Objective magnification · 20.
Figure 5 SCC of base of tongue. The arrows outline a tumour streak that extends below the clinically obvious tumour bulk (asterisk) and through the musculature, to involve deep excision margin.
Figure 8 SCC of floor of mouth. The rectangular demarcated area shows spreading of invasive elements lateral to the tumour bulk (asterisk). Part of the area is magnified in the inset wherein tumour islands and cords are indicated by arrows (objective magnification · 4).
Figure 6 SCC of floor of mouth. The arrows outline part of satellite tumour nodules below the clinically obvious tumour (asterisk), which are involving the deep excision margin.
Figure 9 SCC of soft palate/oropharynx. Involvement of deep excision margin through invasion of nerve fascicles (thick arrow) and skeletal muscle (thin arrow). The asterisk indicates the tumour bulk.
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J.A. Woolgar, A. Triantafyllou
Figure 10 SCC of oropharynx. Ulcerated granulation tissue (ugr) replaces mucosal surface; there is no evidence of tumour bulk in this or any of the multiple blocks processed from the resection. Invasive tumour elements that are demarcated or indicated by arrows, involve the deep excision margin. Part of the square and rectangular areas is magnified in (b) and (c) respectively. Irregular tumour islets (vertical arrow) surrounded by lymphoid inflammatory infiltrates invade fat and muscle (b; objective magnification · 4). Variably acantholytic tumour aggregates invade a nerve fascicle (c; objective magnification · 2). (f, fat; h, haemorrhage).
diffuse islands and spidery cords without the usual tumour bulk (Fig. 10).
Discussion To our knowledge, this is the first histopathological appraisal of involved margins in routine OSCC resection specimens reported according to the Royal College of Pathologists Guidelines.2 Surgical margins are frequently mentioned by authors reporting the outcome of OSCC, but rarely defined in detail. For example, often no distinction is made between mucosal and deep margins (as used in the present investigation), and the lack of universally accepted standardised terms and definitions, prevent meaningful comparisons and conclusions. Batsakis attempted to review the literature from a pathologist’s perspective and draw attention to deficiencies.1 He also emphasised the need for proper definitions, and considered tumour site, anatomical restrictions, biological characteristics and extent of surgery all influenced the adequacy of the resection. The material in the present investigation was homogeneous in relation to its source, and conformation to protocols both in clinical management, operative techniques and presentation of the
resection specimen. Potential influences such as radiotherapy and obvious multifocal mucosal disease were eliminated. However, the inclusion criterion of a neck dissection meant that small and/ or superficial tumours amenable to laser ablation or conservative excision and primary closure are not considered. Nevertheless, more than 300 suitable cases were available and despite the small number of cases at some anatomical sites (Table 1), the material is sufficient for an evidence-based report. The laboratory protocols for macroscopic inspection, anatomical dissection and selection of tissue slices for processing and histological examination are well established in Liverpool.5,7–9 Experience gathered prior to and following publication of the Guidelines2 shows that several points merit particular emphasis. Firstly, thorough slicing of the complete resection specimen, with slices of no more than 4 mm in thickness, is essential. Secondly, the need to develop consistent methods that enable optimal assessment of the advancing tumour front while preserving, or reconstructing, the true anatomical relationships after trimming of tissue slices for routine processing, thus reducing the risk of misinterpretation. Thirdly, the adoption and maintenance of a diligent approach to routine histological assessment supplemented
A histopathological appraisal of surgical margins in resection specimens by the use of step–serial sectioning and immunohistochemistry as appropriate. It is difficult to compare our data on the frequency of involved, close and clear margins with other reports due to the variation in terminology and the indirect approach favoured by authors who allude to ‘‘positive margins’’ when presenting data on local recurrence.10–13 In addition, the frequency of close and involved margins is related to the stringency of the pathological assessment that most authors do not detail. Nevertheless, our data indicates that anatomical site is an important determinant. Our finding of involved margins in only 11% of the oral tongue resections is surprising given the poor survival of patients with tumours at this site.5 One possible explanation is that the anatomy permits the design and adoption of a hemiglossectomy adequate for achieving clear margins in most cases. In contrast, anatomical constraints and difficult access reduce the scope for wide resection margins in sites such as the oropharynx and retromolar region. Anatomical features could also account for a high proportion of involved margins in floor of mouth. Probably, the presence of loose areolar tissue around and deep to the sublingual gland, and the deep localisation of muscle bulk, provide little resistance to infiltrating tumour.14 In addition, structures passing through the zone such as the lingual nerve and sublingual ganglion can be invaded and become potential sources of further dissemination. The submucosa and muscle of the cheek overlying the mandible and maxilla were also shown to be high-risk sites (accounting for 17% of all involved cases in our material). Possible explanations include the desire to preserve the facial skin unless there is obvious spread into the dermis and the natural laxity of a split-thickness cheek resection, which leads to excessive tissue shrinkage following delivery of the resection specimen from the patient prior to and during fixation. It has been reported that shrinkage depends on the site and can reduce the width of the surgical margin by as much as 46%,1,15 a vagary that is not accounted for in standardised guidelines. The finding of a significant relationship between involved margins and pT, pN and p Stage Grouping is not surprising. It is logical that large tumours are more difficult to resect given the anatomical restraints that operate at many sites within the oral cavity and oropharynx. In addition, the relationship with both pT and pN status probably reflects the inherent biological characteristics of the tumour. For example, the incidence of involved margins was increased in patients with any degree of neck metastasis, a traditional marker of a biologically
1041
aggressive tumour.14 The exception of oral tongue where neck disease is common,9,14,16 but the incidence of involved margins is low has already been commented upon. The high percentage of bone resections and the frequency of pT4 bone status at the Regional Centre for Oral & Maxillofacial Surgery, Aintree, have been discussed in previous reports.6,17,18 Histopathological assessment of the resection margins in specimens that include bone is complex. Pathological T4 status due to bone involvement was demonstrated in 100 of the 175 specimens. In the other cases, tumour was confined to the outer aspect of the cortical plate, or the adjacent periosteum/soft tissues. As detailed in the results, the tumour front in the bone may involve the cancellous bone at the truncated base of rim resections, and in all bone resections, the anterior and posterior margins may be involved either in relation to the periosteum overlying the cortical plates or within the cancellous bone. We find consecutive slices taken in the frontal plane following demineralisation of the specimen permit assessment of these aspects of the tumour front, and preserve the natural relationship between the bone and the adjacent soft tissue, including the afore-mentioned high-risk buccal sulcus/cheek region. The delay associated with the demineralisation and the consequent deterioration in the quality of the soft tissue elements are disadvantages of this approach. In order to overcome these disadvantages, we find routinely prepared sections of the soft tissue and periosteum dissected off the buccal and lingual cortical plates are useful when an urgent preliminary report is required. These rountinely-prepared sections provide good visualisation of the tumour as it spreads around the cortical plates and at its soft tissue margins within the buccal sulcus and lingual sulcus/floor of mouth. However, correct interpretation becomes more difficult because of the loss of the innate anatomical orientation and relationships. Our findings indicate that involved bone margins are rare—10 (14%) of the 70 involved cases, of which seven also had an involved mucosal or deep soft tissue margin. Hence, just over 1% the series of 301 specimens had solely an involved bone margin (Table 2). Of the 12 mandibular rim resections showing destruction of the cortical plate, tumour was present at the truncated cancellous bone margin in three cases. Although the majority of the segmental bock resections were pT4 status, only six had an involved bone margin. Hence, the present study indicates that the pre-operative and surgical protocols at the Aintree Unit are justified.6,17,18 Our results also show that involved mucosal margins are rare—11 (16%) of the 70 involved cases, of
1042 which six also had an involved deep soft tissue or bone margin (Table 2). Hence, less than 2% of the series of 301 resection specimens had solely an involved mucosal margin. Unexpected multifocal early OSCC/synchronous primary tumours, both indicative of ‘‘field cancerization’’19–22 and only histologically apparent, account for all except two of the 10 cases. In one of the latter two cases, the resection of the primary tumour involved the mandible and a ‘‘deficiency’’ was apparent in the mucosa adjacent to the tumour leaving the bone exposed. This raised the possibility of loss of mucosa during the operation or manipulation of the specimen on/ following its delivery from the patient, thus resulting an artifactually involved mucosal margin. By contrast, involved deep margins are more of a problem. An involved deep soft tissue margin was present in 61 (87%) of the 70 cases with involved margins, and was the sole cause of the involvement in 50 cases—17% of the series of 301 resection specimens (Table 2). Anatomical restraints are more likely to affect the deep margins. Also, it is difficult to ‘‘visualise’’ particular growth patterns and other features of the deep advancing tumour front, both pre- and intra-operatively, since those particularities are only evident on microscopy (Table 3). The features depicted in Table 3 support the policy of the guidelines2 to denote a margin of less than 1 mm as involved. Invasion pattern 3/4 was the most common explanation of a deep involvement and it is well recognised that cellular groups in poorly-cohesive tumours are often separated by distances approaching 1 mm.23,24 Although single streaks and satellites, and lymphovascular and neural invasion, were additional problems (Table 3), these were often only evident in a single tissue slice despite thorough 4–5 mm slicing of the complete resection specimen. Whether these features represent specific biological characteristics of the tumour or the result of anatomical factors such as lines of least resistance, proximity to nerves, etc, is uncertain. Research assessments using serial sections and immunohistochemistry may well reveal an increased frequency. It is important to remember that the procedures used in the present study are routine guidelines designed to be used in the clinical service laboratory where research possibilities have to be balanced with the limitations of increased workload and cost. In summary, the present study has yielded an insight into the frequency and type of involved margins in routinely assessed OSCC resection specimens, and attempted to provide a histological explanation. Although in the future, molecular assessment of resection margins may become rou-
J.A. Woolgar, A. Triantafyllou tine, it is unlikely that histological procedures will be superseded in the present decade.
Acknowledgement We acknowledge Mr E.D. Vaughan, Mr J.S. Brown and Mr S.N. Rogers, Consultant Oral and Maxillofacial Surgeons, Aintree Hospitals NHS Trust.
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21. Jovanovic A, van der Tol IGH, Schulten EA. Risk of multiple primary tumours following oral squamous cell carcinoma. Int J Cancer 1994;56:320–3. 22. Jovanovic A, van der Tol IGH, Kostense PJ. Second respiratory and upper digestive tract cancer following oral squamous cell carcinoma. Oral Oncol 1994;30:225–9. 23. Bryne M, Koppang H, Lilleng R, Kjaerheim A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol 1992;166:375–81. 24. Martinez-Gimenco C, Rodrigeuz EM, Vila CN, Varela CL. Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope 1995;105:728–33.