(ral Oncology (2006) 42, 229-239 oNcoLocy ELSEVIER http /intlelcevierhealth.com/journals/oron! REVIEW Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma Julia A. Woolgar * Oral Pathology, Liverpool University Dental Hospital, Pembroke Place, Liverpool L3 5PS, United Kingdom Received 9 May 2005; accepted 24 May 2005 KEYWORDS ‘Summary Histopathological assessment of the surgical resection specimen con- Oral and oropharyngeal tinues to provide information that is central to determining the post-operative cancer; treatment needs and prognosis for an individual patient with oral/oropharyngeal Squamous cell ‘squamous cell carcinoma. This review describes the prognostic value of histopathol- carcinoma; ‘gical features related to the primary tumour and the cervical lymph nodes, and Histopathology; considers their relative merits. In addition, a brief overview of more general patient Prognosticators factors is included. Throughout the review, guidance is offered on practical aspects Of the histopathological assessment together with brief mention of potential inaccu- racies. Emphasis is given also to the importance of the partnership between the sur- ‘geon and the pathologist, the need for standardisation during all stages of the histopathological assessment, and the value of accurate documentation of the find- ings. (© 2005 Elsevier Ltd. All rights reserved. Introduction Although in recent years, numerous biological and molecular factors have been proposed as prognosti- cators in oral and oropharyngeal squamous cell car- cinomas (OSC), these have yet to impact on routine clinical care, and detailed histopatholo- sical staging of surgical resection specimens re~ mains an important determinant of post-operative ‘management and prognosis prediction. This review 5 fax: +44 151 706 5240, E-mail address: jawaliverpoolac.k details histopathological prognosticators related to the primary tumour and the cervical lymph nodes, and considers their relative merits, and summarises the significance of distant metastases, general pa- tient factors, and locoregional relapse. Prognostic features related to the primary tumour Tumour site The gradual decrease in the five-year survival for more posteriorly located tumours has been 1368;8375/S - see front matter © 2005 Elsevier Ltd. All rights reserved. 4ol:10.101615.oraloncology.2005.05.008230 JA. Woolgar recognised for many years.’ This association be~ ‘tween tumour site and survival is largely explained by tumour site’s influence on nodal metastasis, and to a lesser extent, stage at presentation; histolog- ical grade and features of the advancing tumour front including the pattern of invasion and perinet ral invasion; vascular invasion; the surgeon’s ability to achieve clear resection margins, and the occur- rence of second primary tumours. ~7 Nodal metas- tases were diagnosed histologically in 59-64% of, tumours of the tongue, retromolar area and oro- pharynx compared to 22% of buccal tumours and less than 7% of gingival/alveolar tumours in the study reported by Woolgar et al.” Between 38% ‘and 41% of patients with retromolar, oropharyngeal and lateral tongue tumours had died of with OSCC ‘compared to only 10—17% of patients with floor-of- mouth and buccal tumours. Tumour size The size of the primary tumour affects both the choice and outcome of treatment. Tumour size is ‘an important factor in determining the surgeon's ability to obtain tumour-free margins, and the dose necessary to effect a cure in patients treated by radiotherapy.” Large size at presentation is associated with an increased risk of local recur- increased cervical lymph node * and poor survival.!"~1? Surface greatest dimension—'"tumour diame- ter’”—is used to indicate tumour size in the TNM staging classification system" although tumour thickness is now recognised as a more accurate his- tological prognosticator."°-° In pathological assessment of resection specimens*'”*, the maxi- mum diameter and thickness are measured to the nearest millimetre using an optical micrometer to supplement the macroscopic inspection of the resection specimen. No account is made for tissue shrinkage during fixation and processing even ‘though this amounts to around 15% of the fresh tis- sue volume.” Care must be taken to differentiate between epithelial dysplasia/carcinoma-in-situ and invasive carcinoma, and to include all satellite ‘stands and individual tumour cells ahead of the main tumour front. Thorough sampling by slicing the complete resection specimen into thin (3— 4mm) slices is essential to ensure that any streaks or satellites (for example due to lymphovascular or neural invasion) are not overlooked. In difficult cases, immunohistochemical staining for pan-cyto- keratins is useful for hightighting stray islands and individual tumour cells. Tumour thickness is mea- sured to an imaginary reconstructed mucosal sur- face, thus compensating for any ulceration or exophytic growth component.”* Other—more com= plex—histological indicators of the size of the pri- mary tumour include pathological cross-sectional area, exophytic/endophytic ratio, shape and form (ulcerative, nodutar papillary, etc)."® Several unconnected studies,"°2° have shown that tumour thickness is the only size criterion to have independent predictive value on multivariate analysis, particularly when the tumours are from a single intra-oral site or restricted to TNMT1 and T2 categories (diameter less than 40 mm), and it is now widely accepted that thickness is a more accu- rate predictor of sub-clinical nodal metastasis, local recurrence and survival than diameter."® Nev- ertheless, the critical thickness differs widely in different reports and it is highly site dependent. For example, the critical thickness in relation to metastasis in floor-of-mouth tumours was only 1.5mm in the study by Mohit-Tabatabai et al.”” compared to 6mm for tumours of the buccal mucosa. In tumours of the oral tongue, the criti- cal thickness is less for tumours of the ventral as- pect than the lateral border, possibly due to differences in the depth, calibre and richness of the lymphatic vessels at the two sites.”* A useful “average critical thickness” for oral and oropha- ryngeal tumours is 4mm with thicker tumours hav- ing a fourfold increased risk of metastasis than thinner tumours.” In. predicting survival, the reconstructed thickness measurement is robust. For example, in the study of Woolgar et al.,” the ‘tumours were from diverse sites within the mouth and oropharynx, yet the mean thickness in patients dying of with OSCC was twice that of survivors/ patients dying free of OSCC. Histological grade of conventional OSCC It has been customary to grade OSCC according to the method originally described by Broders,** and adopted by the WHO"? which takes into account a subjective assessment of the degree of keratinisa~ tion, cellular and nuclear pleomorphism, and mitotic activity. The WHO grading system”? recom- mends three categories: grade 1 (well differenti- ated); grade 2 (moderately differentiated) and grade 3 (poorly differentiated). In a tumour show- ing different grades, the higher grade determines the final categorization. Similar terminology is rec- ‘ommended by the UICC pTNM system." Although inHistopathological prognosticators in OSCC 231 the 1970s several large studies'?°3" reported a correlation between histological grade and sur- vival, most authorities now recognise that Broders’/WHO grade alone shows poor correlation with outcome and response to treatment in an indi- vidual patient."*?° The subjective nature of the assessment; small biopsies from tumours showing histological heterogeneity and inadequate sam- pling; reliance on structural characteristics of the tumour cells rather than functional ones; and evaluation of tumour cells in isolation from the supporting stroma and host tissues have all been cited as possible explanations for the disappointing findings.”*The main reason, however, is probably the lack of discrimination inherent’ in the Bro- ders/WHO system—over 90% of oral and oropha- ryngeal tumours are grade 2. Multifactorial and invasive front histological malignancy grading In an attempt to overcome some of the problems associated with the Broders’ /WHO grading system, Jakobbson et al.” introduced the multifactorial histological malignancy grading system in which multiple features of both the tumour cells and the interface between the tumour cells and the host tissues are assigned points according to strictly defined criteria. Several modifications fol- lowed, *3- the most successful being “invasive front grading’’—that is, consideration of solely the most dysplastic areas at the deep advancing edge of the tumour,”*'*” and several independent workers have found invasive front grading useful in predicting nodal _metastasis, local recurrence and survival.’**8~ For example, in a study of 102 tumours from different intra-oral sites, Sawair et al."' found that the total score was the best pre- dictor of overall survival while the pattern of inva~ sion was the best predictor of nodal metastasis Pattern of invasion correlates with several in vitro markers of malignancy such as loss of contact inhi- bition, tumour cell mobility and secretion of prote- lytic’ enzymes,*? and its observation in routine histological preparations provides a simple mea- sure of tumour behaviour. Grade 1 tumours have a well-defined edge composed of broad, bulbous bands and islands of tumour cells while grade 4 tumours consist of single, non-cohesive tumour cells, which form an ill-defined edge often with sa- tellite islands well ahead of the main tumour front. Improved reproducibility was one of the aims of multifactorial histological malignancy grading and several workers have reported good levels of in- tra-observer agreement but inter-observer agree ment is less satisfactory." Suggestions to improve reproducibility include simplification of the categories, clarification of definitions, and omission of less reproducible features. In addition to tumour factors such as histological heterogene- ity, differences in experiences of the assessors, varying interpretation of the category definitions, subconscious baseline-shift and fatigue which can all affect the quality of the assessment” are diffi cult to eliminate and hence, limit the validity and predictive value of invasive front grading in the clinical setting. Lymphovascular invasion Assessment of the presence and extent of lympho vascular invasion was part of the multifactorial grading system proposed by Jakobbson et al.” Later systems™9” omitted this characteristic since they considered it was difficult to define and recognise with certainty. Nevertheless, an assessment of lym- phovascular invasion Is still thought valuable since its detection in random tissue sections statistically implies a considerable number of tumour cells are entering the vascular compartment, thus increasing the likelihood of successful metastatic growth,2"22** Qur own studies—in which lym Phovascular invasion was defined as the presence of aggregates of tumour cells within endothelial lined channels or invasion of the media of a vessel with ulceration of the intima—have shown a significant association with tumour site, diameter and thickness; perineural invasion; invasive front multifactorial histological malignancy score and pattern of invasion; nodal metastasis; status of resection margins; local recurrence; and survival.>*24 Perineural invasion Our studies®*" show that infiltration of the peri neural space of nerves at the advancing front of the tumour (taking care to exclude mere juxtapo- sition) is related to the site, the diameter and thickness of the tumour, pattern of invasion at the advancing tumour front, presence of nodal metastasis; close/involved resection margins and survival. Similar findings have been reported by Fagan et al.” and Rahima et al.”® who showed the association with both regional recurrence232 JA. Woolgar and distant metastasis was maintained on multi- variate analysis. The failure to demonstrate the prognostic value of perineural invasion in earlier studies such as that of Carter et al.” is likely due to their inclusion of salvage post-radiotherapy cases where extensive perineural invasion is al- most ubiquitous. Bone involvement In the TNM staging classification," involvement of bone with penetration of the mandibular or maxit- lary cortical plate to involve cancellous bone qual- iffes for T4, stage IVA status, with its implied poor prognosis. Bone involvement influences the type and extent of treatment, but it is uncertain whether the stage IVA status is justified.°°" Tumours of the gingiva and alveolar ridge are most likely to involve bone, but the risk of nodal metas tases in these sites is low,”* leading to the antic- ‘pation that T4NO tumours involving bone have a better prognosis than the other stage IVA catego- ries. In our studies of mandibular resections from previously untreated patients,“ an infiltrative, but not an erosive, pattern of invasion was predic” tive for local recurrence and survival even after taking into account the prevailing soft tissue prog- nasticators. These findings may explain the previ- ‘ous uncertainties on the prognostic significance of bone involvement and we advocate a change in the pathological TNM staging classification so that the infiltrative pattern is a prerequisite for pT4 status.°¢ Sialoadenotropism and ductal invasion The influence of sialoadenotropism (extension of dysplasia down the orifices of minor salivary glands) and ductal invasion on survival is uncer- tain but both features are associated with in- creased local recurrence and second primary ‘tumours.°” Skin involvement Direct spread to the skin in conventional OSC is indicative of a poor prognosis—Cole and McGuirt™* reported a median survival of seven months. Lymphatic spread to the skin (‘carcinoma en cuirasse”’) was an even more ominous sign with a median survival of only three months. Histological subtypes of OSCC In addition to conventional OSCC, several subtypes are occasionally encountered in the mouth/oro- and these are listed in Table 1. Verrucous carcinoma, characterised by a predomi- nantly exophytic growth of well-differentiated ker- atinising epithelium and a locally destructive pushing margin at its interface with the underlying connective tissue is the best known. The prognosis of verrucous carcinoma and carcinoma cunicula~ tum is generally good since nodal metastases do not occur. However, in 20% of cases, verrucous car- cinoma co-exists with conventional squamous cell carcinoma with a consequent reduced prognosis. ‘Adenosquamous carcinoma and basaloid squamous cell carcinoma have a poor prognosis due to exten- sive local spread and early regional and distant metastases." The prognosis of the other sub- types is uncertain. This is due, at least in part, to inconsistent recognition and documentation, and the lack of guidance on specific diagnostic criteria such as what proportion of the tumour should show the specific features to qualify for sub-categorisa- tion; how to deal with hybrid tumours showing mul- tiple subtypes, etc. This is one area where accurate standardised reporting and exchange of informa- tion between centres should provide useful information. Status of the resection margins ‘The resection margins include both the surface mu- cosa at the edge of the tumour and the submucosal and deeper connective tissues all around the de- fect, yet few authorities state which aspect is unsatisfactory. The distinction is important. Unsat= isfactory mucosal margins are more amenable to Table 1 Histological subtypes of oral/oropharyngeal squamous cell carcinoma Verrucous carcinoma Carcinoma cuniculatum Papillary squamous cell carcinoma ‘Adenoid (acantholytic) squamous cell carcinoma ‘Adenosquamous carcinoma Basaloid squamous cell carcinoma Spindle cell carcinoma Giant cell (pleomorphic) carcinoma Undifferentiated carcinomaHistopathological prognosticators in OSCC 233 surgical revision and recurrences due to re-growth of the OSCC at the superficial margin are usually evident on clinical inspection and can often be suc- cessfully treated.® in contrast, recurrences due to re-growth of tumour cells left behind at the deep margin may grow undetected under the skin-flap or reconstruction and thus, they tend to be large at diagnosis, and their size and position makes them less amenable to salvage surgery. Studies on the prognostic importance of the surgical resection margin have been further hampered by the lack of agreement on what constitutes a satisfactory mar- gin.” In routine assessment, no account is made for tissue shrinkage which can result in a reduction of 30-47% in the margin width when the clinical pre-incision (in situ) width is compared with the margin seen in the microscope slide. The UK guidelines (which we follow) record the status of both the mucosal and deep margins and designate margins of 5 mm or more as clear, 1-5 mm as close and less than 1 mm as involved.”*?? Other author' ties apply less stringent criteria and classify close margins as 2mm*" or even 1mm, and involved margins as only those with tumour cut-through. Our experience suggests that even 5mm may not be "clear" when the pattern of invasion is highly unfavourable with widely separated tumour cells/ {slands. An appraisal of 301 resection specimens re- ported according to the UK guidelines’ showed a mucosal involvement in only 11 cases (4%) and nearly all were due to an unexpected synchronous primary tumour or muttifocal carcinoma rather than failure to clear the index tumour. The deep soft tissue margin was involved in 61 resection specimens (20%) and the bone margin in 10 cases (3%) and a histological explanation related to the tumour growth pattern could be discerned in nearly all cases. In our studies, *“*°°"'" the status of the resection margin is a robust prognosticator. At five years, only 11% of patients with an involved margin were ‘alive and well/dead free of disease, com: pared with 47% of those with close margins and 78% with clear margins. The relative risk of death associated with even a close margin was similar to that associated with nodal metastasis.® Adjuvant post-operative radiotherapy does not appear to de- crease the risk of local recurrence in patients with involved/close margins to a level similar to par tients with clear margins.“ Even a positive mar- gin on evaluation of the initial intra-operative frozen section increases the risk of local recur: rence, despite a negative result being achieved fon frozen-section evaluation of the revised margin.* Prognostic features related to the cervical (regional) lymph nodes The prognostic importance of the presence and ex- tent of lymph node metastasis has been recognised for many decades. Several independent authorities have reported an association between outcome (in terms of regional recurrence and/or survival) and the features listed in Table 2. Some of the studies, however, present discordant findings and there is no general agreement on which features are the best prognosticators. The lack of agreement may be due to factors influencing the stringency of the pathological assessment (such as multiple pathologists with differing experience and exper tise; lack of standard protocols; subjective inter- pretation of protocols and definitions; and sampling errors); and factors related to the cohort under study. The latter category includes factors such as the criteria for entry into the study (some studies have included irradiated cases, for exam- ple); differing proportions of therapeutic (clinically positive) and elective (clinically negative) neck dis sections; and different protocols for post-operative radiotherapy. The UK Royal College of Pathologists introduced detailed guidelines in 1998 together with a stan- dard minimal dataset proforma (Appendix A). The guidelines’? recommend that neck dissections are orientated and the anatomical levels are marked by the surgeon prior to immersion of the complete specimen in fixative solution. Lymph nodes are identified by inspection and palpation, dissected out and bisected or sliced. If the node ap: pears negative, all slices are processed. "Size of metastasis"” refers to the total profile diameter of the metastatic deposit not the size of the lymph node. When some positive nodes are matted, the Table 2 Prognostic features related to the regional lymph nodes 1 Metastatic status—nodal metastasis present versus absent™*” Laterality of positive nodes**-7" Number of positive nodes*"7?—77 Size of metastatic deposit®*"*”” ‘Anatomical level of involvement?°7"2 Extracapsular spread, ECS, (extracapsular rupture)®479-7.92 7 Embolisation/permeation of perinodal lymphatics’? 8 pNstage™™24 JA. Woolgar “‘number of positive nodes” includes an estimate of the number of nodes contributing to the matted mass. The detection of minor degrees of ECS is aided by harvesting (ymph nodes with their imme~ diate pericapsular adipose tissue in position. The extent of ECS is recorded as "macroscopic’” when it is obvious on laboratory inspection and "*micro~ scopic’ when it is only evident on histological assessment, and the extent is recorded by noting the tissues/structures that are involved by tumour (for example, the internal jugular vein, sternoclei- domastoid muscle, perinodal adipose tissue, imme- diate pericapsular fibrous tissue). Equivocal ‘examples of ECS are upstaged. Only a few studies have used multiple regression analysis to determine the features most predictive of death due to OSCC. In our study of 173 positive neck dissections reported according to the UK Guidelines, ECS was the best prognosticator in the stepwise regression model of Cox. It was even more important than involved margins at the pri- mary site. The Kaplan—Meier survival curves showed patients with macroscopic ECS tended to die within the first year following surgery while pa- tients with microscopic ECS tended to die during the second year so that the survival probability was similar—33% and 36%, respectively—by three years. In contrast, the three-year survival probabil- ity for patients with metastases confined to lymph nodes was 72%—approaching the 81% survival prob- ability seen in patients without metastasis in our previous survival paper.° Hence, our findings chal- lenge the traditional view that the presence of lymph node metastasis per se reduces survival by 50%. It has been suggested that the prognostic sig- nificance of ECS is obliterated by post-operative radiotherapy." This is not our experience. Many of our cases with ECS relapse initially in the mouth rather than in the neck. ECS shows a significant cor- relation with unfavourable histological features at the primary tumour site such as a non-cohesive pattern of invasion, vascular and perineural inva- sion, and close/involved resection margins. Hence, we believe ECS is a simple, readily detectable indi- ator of tumour aggression. It is a sensitive, highly discriminating indicator in an individual patient. Furthermore, it is applicable even in cases with small volume metastatic disease since it occurs in a substantial number of patients with a single posi- tive node (36%) or metastatic deposits of 10 mm or less (34%). The prognostic importance of ECS has also been emphasised by several other recent stud- ies,” and other authorities®*” have acknowledged that the failure to recognise the par- amount importance of ECS in earlier studies was probably due to the lack of standardisation of the pathological assessment and definition of ECS. In spite of the recent convincing evidence on the importance of ECS, the number of positive nodes and size of the metastatic deposit (with its seldom used pN3 category of more than 60 mm) remain pivotal in the TNM staging system," and ECS is not mentioned. In contrast, the prognostic signifi- cance of micrometastases (profile diameter of 2mm or less) and isolated tumour cells (profile diameter of 0.2 mm or less), features that are in- cluded in the latest pTNM classification, "* has yet to be determined. Distant (systemic) metastases Between 5% and 25% of OSC patients have clinical evidence of distant metastases within two years of initial diagnosis." Traditionally, cases initially staged N2 or N3, and those with uncontrolled loco: regional disease were thought to be most at risk,** but more recent reports have shown ECS is the sin- le best predictor.*"-*2* The mean survival follow- ing diagnosis of distant metastases is less than six months and 90% of cases are dead by two years." Additional prognostic features The prognostic importance of general patient features is weak compared with the pathological extent and characteristics of the tumour but, sur- vival is reportedly associated with gender; age; "6791-4 geographical location; race co-morbid conditions secondary to tobacco and alcohol abuse;'*?"6°7 immune _ status;?7"*°? absence of usual risk factors;'°'°" and the development of second (and serial) primary tumours."”""-1% The evidence tends to be incon- sistent and at times contradictory possibly due, at least in part, to the use of different statistical methods, and complex inter-relationships with the possibility of one feature acting as surrogate for one or more other features. Local and regional relapse Local relapse—the re-appearance of SCC within the oral cavity/oropharynx—can be classified as aHistopathological prognosticators in OSCC 235 true recurrence developing from foci of tumour cells left in the operative site (persistent disease); or a new primary (metachronous) SCC developing from the mucosa adjacent to the operative site (of- ten at the edge of the skin-flap used to reconstruct the surgical defect); or elsewhere within the mouth/oropharynx well away from the site of the first (index) tumour.> True recurrences develop much earlier than metachronous tumours and carry the worst prognosis. In our study on 200 patients,” 20 patients developed a true recurrence (median time to diagnosis, eight months) and 18 had died of their disease (median survival, 14 months). in contrast, the median time to diagnosis of metach- ronous SCC was 18 months and only four of the 15 patients had died of disease. Relapse in the neck is a significant cause of death in OScc.*547595 It may result from growth of occult metastases when initial treatment has been confined to the primary site, or it may re- flect metastasis to nodes outside the original field of treatment, or recurrence (persistence) in the operated or irradiated field. It addition, there may be relapse in the contralateral neck. In the study reported by Cunningham et al." 42% of pa- tients with T1/T2 tumours of the oral tongue trea- ted by local therapy alone later developed clinically overt neck disease. The reported fre- quency of recurrent disease in the operated neck ranges from 15—50% of cases.?"®” Factors influenc- ing the rate of recurrence include the pathological extent of metastatic disease at the time of initial surgery; the type of surgical neck dissection proce- dure; and the use of adjuvant therapy.”/7## The cure rates for salvage procedures in patients with recurrent regional disease are poor.*”" In our study,® the median time to diagnosis of recur- rence in the operated positive field was five months (range 1-11 months) and the median survival time was seven months (range 2—15 months). Further- more, no patients survived recurrence in the oper- ated positive field. Peripheral epithelial dysplasia, multifocal carcinoma and second primary tumours Both peripheral epithelial dysplasia and an index (first) tumour of multifocal origin are associated with an increased risk of second (and serial) pri- mary tumours. Second (and serial) primary SCCs have been reported in 733% of oral cancer patients."°" The wide range probably reflects factors as diverse as the criteria for diagnosis and division from recurrent/persistent disease; the duration of the study; the extent of the fol low-up clinical assessment; and the implementa tion and success of _ anti-smoking/drinking campaigns. Second primary tumours are usually diagnosed at a routine follow-up examination and hence, tend to be small and amenable to treatment.” Nevertheless, second, and in particu- lar, serial, primary tumours together with sys temic metastases account for most of the disease-specific deaths occurring after 24 months. >" 199 The way ahead? It fs clear that the identification of accurate prog: nosticators in OSCC has been hampered by the rela. tively small number of cases of the disease, especially in any one treatment centre; the hetero geneity of clinical features such as the extent of the disease at presentation; and, in particular, by the lack of standard clinical, management and labora- tory protocols combined with inconsistent record: ing and reporting of data. Even two of the well-established histological predictive fac tors—tumour thickness and extracapsular spread of nodal metastases—have not become part of the routine TNM pathological staging classification. The introduction of guidelines and minimum data- sets into routine diagnostic pathology should mint mise inconsistencies and produce reliable, standardised data with the potential for realistic multi-centre research, pooling of data, and so on. An “‘evidence-based”” minimum dataset—together with regular audit—prevents, or at least minimises, issues associated with compliance; calibration, con- sistency, clarity and completeness of data; and time and cost efficiency. Other pathways leading to more efficient research and development could include the wider use of standardised computerised dat abases with improved retrieval and exchange of information, and reduced reliance on subjective interpretation with wider use of automated tech- niques and quantitative data, Models combining bio- logical and molecular markers with traditional histological features are an attractive possibility, and fuzzy inference and neural networks are likely to play an increasing role in the future236 JA. Woolgar Appendix A. (Reproduced with the permission of the Royal College of Pathologists) HEAD AND NECK CARCINOMA MINIMUM DATA SET Sumame: Forenames: Date of Birth: Sexi... Hospital Hospital No. Date of receipt, Date of report Report No, Pathologist Surgeon, Clinical TNM stage Previous radiotherapy Yes No Unknown Teese Nowe M. Previous chemotherapy Yes_No__Unknown Primary Tumour Site. ‘Maximum diameter (mm) Subsite(s). ‘Maximum depth of invasion .....(mam) Right Left Midline Distance from invasive tumour to Type of Resection Histological type: squamous carcinoma ‘mucosal margin (mm) Other subtype dcp margin (oom) Differentiation Welt Vasculrinvasion -Yes_—-No Moderate ‘Nerve invasion Yes No ‘oor Boneicartilage invasion Yes No Invasive front cohesive nomeohesive —-Samslsilius invasion Yes No Severe dysplasia at margiaYes__No Right Neck Dinection Yes No Taft Neck Dissection Yes No Comprcheasive Selective Comprehensive Selective Node levels present I Il Ill IV-V VI other | Nodelevels present 1 11 Il IV V VI other Total mimber of nodes Total namber of nodes. Number positive nodes Number postive nodes Levis with metastases Til it IV V V1 other | Levels with metastases fil It TV” VI other Largest metastasis (am) Largest metastasis (one) Extracapsular spread Yes No Extracapsular spread Yes No Levels with ECS Levels with ECS, COMMENTS/ADDITIONAL INFORMATION SUMMARY OF PATHOLOGICAL DATA PINMSTAGE | pT pNosPM TUMOUR SITE, SNOMED CODES New primary Recurrence Notknown : < TUMOUR TYPE. t M RESECTION OF PRIMARY TUMOUR CLEAR CLOSE. INVOLVED, Signed [oars References cancer in relation to pathological features. Ann Cal 1. Arthur K, Farr HW. Prognostic significance of histologic sade in epidermoid carcinoma of the mouth and praryr dm J Surg 1972;124: 489-92. 2. Farr HW, Goldfarb PM, Farr CM. Epidermaid carcinoma of the mouth and pharynx at the Sloan Kettering Cancer Center. Am J Surg 1980;140:563-7. 3. Hldstad ST, Bigelow ME, Remensnyder JP. Scuamous cel carcinoma of the tongue: a comparison of the anterior two-thics with its base. Am J Surg 1983;146:456—61 4. Woolgar JA, Scott J, Vaughan ED, Brown JS, West CR, Rogers S. Survival, metastasis and recurrence of oral Surg Engl 1995;77:325-31. 5. Woolgar JA, Rogers 5, West CR, Errington RD, Brown JS, ‘Vaughan ED. Survival an¢ patterns of recurrence in 200 oral cancer patients teated by radical surgery and neck fisection. Oral Oncol 1999;35: 257-65. 6. Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA. ‘The prognostic implications of the surgical margin In oral scuamous cell carcinoma, Int J Oral Maxillofac Surg 2003;32:30-4. 7. Woolgar JA, Trantafylou A. A histopathological appraisal of surgical resection margins in oral and oropharyngeal cancer resection specimens, Oral Oncol, in press, 4o1:10.1016!).oraloncology.2005.06.008.Histopathological prognosticators in OSCC 237 8. Scholl P, Byers RM, Batsakls JG, Wolf P, Santini H Microscopic cut-through of cancer in the surgical treat- ment of carcinoma of the tongue. Prognostic ané thera peutic implications. Am J Surg 1986;152:354—€0, 9. Bentzen SM, Johansen LV, Overgaard J. Clinical radiobiol ‘ogy of squamous carcinoma ofthe oropharynx Int J Radiat ‘Oncol Biot Phys 1991;20:1197-206, 10. Shaha AR, Spiro RH, Shah JP, Strong EW. Squamous carcinoma of the floor of the mauth. Am J. Surg 1984;148:455-9, 11. Madcox WA. Vicissitudes of head and neck cancer. Am J Surg 1984;148:428—32, 12, Platz, Fries R, Hudec M, TJoa AN, Wagner RR. The prog- nostic felevance of various factors at the time of fst admission ofthe patient. J Maxillofac Surg 1983;11: 3-12 13, Crissman JD, Liu WY, Gluckman JL, Cummings G. Prognos. tic value of histopathologic parameters in. squamous cell carcinoma of the oropharynx. Cancer 1984;54 2395-3001. 14, Sobin LH, Wittekind C. UICC, International Union Against Cancer, TAM classification ‘of malignant tumours. 6th fe. New York: Wiley-Liss; 2002 15. Shinghaki S, Suzuk’ |, Wakajima T. Evaluation of histopa- thologic parameters in predicting cervical lymph node metastasis of oral and oropharyngeal carcinomas. Oral Surg Oral Med Oral Pathol 1988;66:683—8. 16. Nathanson A, Agren K. Evaluation of some prognostic factors in small squamous cell carcinoma of the mobile tongue: a multicenter study in Sweden. Head Neck 1989;11:387-92, 17, Baredes S, Leeman DJ, Chen TS. Significance of tumor thickness in soft palate carcinoma. Laryngoscope 1983;103:289-93. 18, Po Wing Yuen A, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, et al. Prognostic factors of clinically stage | and Il orat tongue carcinoma—a comparative study of stage, thick- ness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimenco score, and pathologie features. Head Neck 2002;24:513-20. 19. Gonzalez-Moles MA, Esteban F, Rodriguez-Arcilla A, Ruiz- ‘Avila |, Gonzales-MolesS. Importance of tumour thickness measurement In prognosis of tongue cancer. Oral Oncol 12002;38:394-7. 20, O-charoenratP, Pillai G, Patel, Fisher C, Archer 9, Eccles Set al. Tumour thicxness predicts cervical nadal metas- tases and survival in early tongue cancer. Oral Oncol 2003;39:386—90, 21. Heliwell T, Woolgar JA. Standards and minimum datasets for reporting common cancers. Minimum dataset for head and neck carcinoma histopathology reports. The Royal College of Pathologists, London, 1988. 22. Heliwell T, Woolgar JA. Minimum dataset for histopathol gy reports on head ane neck carcinomas and salivary neo- plasins. The Royal College of Pathologists, London, in pes 23, Batsakis JG. Surgical excision margins: a pathologist's perspective. Adv Anat Pathol 1999;6:140-8. 24, Woolgar JA, Scott J. Prediction of cervial Iymph node metastasis in squamous cell carcinoma of the tongue/ oor of mouth. Head Neck 1995;17:463-72. 25, Mohit-Tabatabat IMA, Sobel HJ, Rush BF, Mashberg A. Relation of thickness of floor of mouth stage | and 1 cancers to regional metastasis, Am J Surg 1986; 132:351-3 26. Urist MM, O'Brien CJ, Soong SJ, Visscher DW, Maddox WA. Ssquamaus cell carcinama of the buccal mucota: analysis of prognostic factors, Am J Surg 1987;154:411—4, uy. 28 », 20. at. 22. 33. 34, 35. 36. a7. 38. ». 40. 4 2. a. ‘Ambrosch P, Kron M, Fischer G. Micrometastases in ‘earcinoma of the upper aerodigestive tract: detection, Fisk of metastasizing, and prognostic value of depth of invasion, Head Neck 1995;17:473-9, Broders AC. Squamous cell epithetioma of the lip; a study ‘of five hundred and thirty seven cases. JAMA 1920;74:656~64, Pindoorg J, Reichart PA, Smith CJ, van der Waal L. World Health Organisation bistologieal typing of cancer and brecancer of the oral mucosa. 2nd ed. New York: Sprin er; 1997. Shear M, Hawking OM, Farr HW. The prediction of (ymph ode metastases from oral squamous carcinoma. Cancer 1976;37:1901-7. Langdon JD, Harvey PW, Rapicis AD, Patel MF, Johnson NW: Oral cancer: the behaviour and response to treatment of 194 cases. J Maxillofac Surg 1997;5:221-37. Jakobbson PA, Eneroth CM, Killander 0, Noberger , Martenson B. Histologic classification and grading of malignancy in carcinoma of the larynx. Acta Radiol s973;12:1-8, Lund C, Sogaard H, Elbrond 0, Jorgensen K, Andersen AP. Epidermoid carcinoma ofthe tongue. Histologic grading in the clinical evaluation, Acta Radiol Oncol Radiat Phys Biot 1975;14:513-21 ‘Anneroth G, Hansen LS. A methodologic study of histo logic classification and grading of malignancy in oral squamous cell carcinoma. Scand J Dent Res 1984;92: 0468. “Anneroth G, Batsakls J, Luna M. Review of the Uterature and a recommended system of malignancy grading in oral Squamous cell carcinomas. Scand J Dent Res 1987;95:229-49 artinez-Gimenco C, Rodriguez EA, Vila CN, Varela CL Squamous cell carcinoma of the oral cavity: a clinicopath ‘logic scoring system for evaluating risk of cervical mph node metastasis. Laryngoscope 1995;105:728-33. Bryne M, Koppang H, Lilleng R, Kjaesheim A. Malignancy raging of the deep invasive margins of oral squamous cel. ‘carcinomas has high prognostic value. J. Pathol 1992;166:375-81 Odell EW, Jani P, Sherriff mh, Ahluwalia SH, Hibbert J, Levison D, et al. The prognostic value of individual histologic srading parameters in small lingual squamous Cell carcinomas. The importance of pattern of invasion. Cancer 1994;74:789-94, Bryne M, Jenssen N, Boysen M. Histologic grading in the deep invasive front of TI and T2 glottic squamous cel, ‘earcinomas has high prognostic value. Virch Archiv 1995;427:277-81, Okamoto M, OzektS, Watanbe T, lida, TashiraH. Cervical lymph node metastasis in carcinoma of the tongue. Correlation between clinical and histopathological find Ings and metastasis. J Craniomaxllofac Surg. 1988; 6: ie) Sawair FA, Irvin CR, Gordon DJ, Leonard AG, Stephenson 5S, Napier SS. Invasive front’ grading: reliability and Usefulness in the management of oral squamous cell ‘earcinoma. J Oral Pathol Med 2003;32:1-9. Crissman JD. Tumer-hast interactions as prognostic factors in the histologic assessment of carcinomas. Pathol Annu 1986;21:29-52. Piffko J, Bankfalvi A, Tory K, FuzesiL, Bryne M, OfnerD. Molecular assessment of p53 abnormalities atthe invasive front of oral squamous cell carcinomas. Head Neck 1998;20:8-15,238 JA. Woolgar 4“ 4 4". 4 4 50. 1 3 53. 56. 56. 57. 58. 9. 0 6 2. 6. Sugarbaker EV. Cancer metastasis: a product of tumor-host ‘interactions. Curr Probl Cancer 1979;3:1—59, Weiss L, Mayhew E, Glaves-Rapp D, Holmes JC. Metastatic Inefficiency in mice bearing B16 melanomas. Br J Cancer 1982;45:44-50. Close LG, Buns OK, Reisch J. Merovascular invasion in cancer ofthe oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg 1987;143:1191-5, Fagan JJ, Collins B, Barnes L, D'Amico F, Myers EN, Johnson JT. Perineural Invasion in squamous cell care roma of the head and neck. Arch Otolaryngol Head Neck Surg 1998;124:637—40 Rahima 8, Shingaki 5, Nagata M, Saito C. Prognostic significance of perineural invasion in oral and orephary geal carcinoma, Oral Surg Oral Med Oral Patho! Oral Radiol Endod 2004;97:423-31 Carter RL, Pitam MR, Tanner NSB. Pain and dysphagia in patients with squamous carcinomas of the head and neck: the role of perineural spread. J R Soc Med 1982;75:598-606. Jones AS, England J, Hamiiton J. Mandibular invasion in patients with oral and oropharyngeal squamous carcinoma. {lin Otolaryngol 1997;22:239—46 Ash CS, Nason RW, /Abdoh AA, Cohen MA. Prognostic ‘implications of mancibular invasion in oral cancer. Head Neck 2000;22:794~2. Weming JW, Byers RI, Novas MA, Roberts Preoperative assessment for ane outcomes of mandibular conservation surgery. Head Neck 2001;23:1024~30 Woolgar JA. Detailed topography of cervical ymph-node metastases from oral squamous cell carcinoma, Int J Oral Maxillofac Surg 1997;26:3-9. Brown JS, Kalavrezos N, D’Souca J, Magennis P, Woolgar JA. Factors that influence the method of mandibular resection inthe management of oral squamous cel carcinoma. Br J Oral Maxillofac Surg 2002;40:275-B4. Brown JS, Lowe D, Kalavrezos N, D'Souca J, Maggens P, Woolgar J. Patterns of invasion and routes of tumor entry ‘nto the mandible by oral squamous cell carcinoma, Head Neck 2002;24:370~83, Shaw RJ, Brown JS, Woolgar JA, Lowe D, Rogers SN, Vaughan ED. The influence of the pattern of mandibular fvasion on recurrence and survival in oral squamous cel carcinoma, Head Neck 2004;26:861—9 Daley TD, Lovas JGL, Peters E. Salivary gland duct ‘nvalvement in oral epithelial dysplasia and squamous cell carcinoma, Oral Surg Oral Med Oral Pathol Oral Rocio! Endod 1996;81:186-9. Cole RD, MeGuirt WF. Prognostic significance of skin ‘ivalvement for mucosal tumors of the head and neck. Arch Otolaryngol Head Neck Surg 1995;121:1246-8.. Kao GF, Graham JH, Helwig E8. Carcinoma cuniculatum (verrucous carcinoma of the skin): a clinicopathalogic study of 46 cases with ultrastructural observations. Cancer 1982;49:2395—403, Napier $8, Gormley JS, Newlands C. Adenosquamous carcinoma. A rare neoplasm with an aggressive course Oral Surg Orat Med Oral Patho! 1995;79:607—11 Wieneke JA, Heffner DK. Basaloid squamous cell carci rama: an aggressive variant of squamaus cell carcinoma of the head and neck region. Pathol Case Rev 2000;5: 200-5. ‘Johnson RE, Sigman JD, Funk GF. Quantification of surgical, ‘margin shrinkage in the oral cavity. Head Neck 1997;19:281-6 Sheahan P, O'Keane C, Sheahan JN, O'Dwyer TP. Effect of tumour thickness and other factors on the risk of regional 6. 66 67. oe. 6. 7. 1 n. B. 1% ws. %. 7. 7 ns. 0 a isease and treatment of the NO neck in early oral Squamous carcinoma, Clin Otolaryngol 2003;28:461~71 Woolgar JA, Rogers SN, Lowe D, Brown JS, Vaughan ED. Cervical (ymph node metastass in oral cancer: the impor. tance of even microscopic extracapsular spread. Oral Oncot 2003;39:130-7. Woolgar JA. T2 carcinoma of the tongue: the hstopathol ogists perspective. Br J Oral Maxillofac Surg 1999;37:187-93, Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg 1990;160:410—4 Callery CD, Spiro RH, Strong EW. Changing trends in the management of squamous carcinoma of the tongue. Am J Surg 1984;148:449-54, Spiro RH, Alfonso AE, Farr HW, Strang EW. Cervical node metastasis trom epidermoid carcinoma of the oral cavity and oropharynx, A critical assessment of current staging fm J Surg 1974;128:562~7 Schuller DE, MeGuirt WF, McCabe BF, Young 0, The prognostic significance of metastatic cervical lymph nodes, Laryngoscope 1980;90:557—70 Grandi, AlloisioM, MogliaD, Podrecca, Sala L, Salvator P, et al. Prognostic significance of lymphatic spreac in head and neck carcinoras: therapeutic implications. Head Neck Surg 1985;8:67-73. Kowalski LP, Bagietto R, Lara JR, Santos RL, Silva JF, Nagrin M. Prognostic significance of the distribution of neck node metastasis {rom oral carcinoma, Head Neck 12000;22:207-14. Shah JP, Cendon RA, Farr HW, Strong EW. Carcinoma ofthe oral cavity. Factors affecting treatment failure at the primary site and neck. Am J Surg 1976;132:504~7. Kalnins IK, Leonard AG, Sako K, Razack MS, Shedd DP. Correlation between prognosis and degree of lymph node ‘nvalvement in carcinoma of the oral cavity. Am J Surg $977;134:450-4 Snow GB, Annyas AA, van Slooten EA, Bartelink H, Hart AM, Prognostic factors of neck node metastasis. Clin (Otolaryngol 1982;7:185-92. Olsen KD, Caruso M, Foote RL. Primary head and neck cancer. Histopathologic predictors of recurrence after neck dissection in patients with Iymph nade involvement. Arch Otolaryngol Head Neck Surg 1994;420:1370—4 Kokemueller H, Brachvogel P, Eckardt A, Hausamen JE Neck dissection in oral. cancerclinical review and analysis of prognostic factors. Int J Oral Maxillofac Surg 2007;313608—14, Greenberg 45, Fowler R, Gomez J, Mo V, Roberts D, EL Naggar AK, etal, Extent of extracapsular spread, A crtical, rognosticator in oral tongue cancer. Cancer 2003; 97:1464-70 Cachin Y, Sancha-Garnier H,Micheau C, Marandas P. Nodal metastases from carcinomas of the oropharynx. Otolaryn gol Clin North Am 1979;12:145-54, Richard JM, Sancho-Garnier H, Micheau C, Saravane 2, Cachin Y. Prognostic factors’ in cervical lymph node metastasis in upper respiratory and digestive tract carc omas: study of 1,713 cases during a 15-year period. Laryngoscope 1987;97:97—101 Carter RL, Bliss JM, Soo KC, O'Brien CJ. Radical neck lssections for squamous carcinomas: pathologial ndings, and their clinical implications with particular reference to transcapsular spread. Int J Radiat Oncol Biolo Phys 1987;13:828-22 Ayers JN, Greenberg JS, Mo V, Roberts D. Extracapsular spread, A significant predictor of treatment failure inHistopathological prognosticators in OSCC 239 2. 3. 1. a7. 8. 9 2. 9. 9 5s. patients with squamous carcinoma of the tongue. Cancer 2001;92:3030-6 Shinghaki §, Takada M, Sasai K, Bibi R, Kobayashi T, Nomura T. Impact of lymph node metastasis onthe pattern of failure and survival in oral carcinomas. Am J Surg 2003;185:278-B4 Jones AS. Prognosis in mouth cancer: tumour factors. Oral ‘Oncol Eur J Cancer 1994;308:8~15. Calhoun Kit, Fulmer P, Weis R. Distant metastases from head and neck squamous cell carcinomas. Laryngoscope 1994;104:1199-205, Pingolle J, insole V, Majoufre C, Duroux 5, Demeaux H. Prognostic value of histologic findings in neck dissections for squamous cell carcinoma. Arch Otolargol Head Neck Surg 1997;123:145-8, Petruzzelli G. Patterns for neck recurrences, Oral Oncol 2005;1:374, Howaldt HP, Kainz Mm, Euler B, Vorast H. Proposal for modification of the TNM staging classification of cancer of, the oral cavity. J Craniomasillofac Surg 1999;27:275-88. Langdon JD, Rapigis AD. Oral cancer and sex—Why do females do better? J Maxillofac Surg 1979;7:177-81 Constantinides MS, Rothstein SG, Persky MS. Squamous cel. carcinoma in older patients without risk factors. Otolar yngol Head Neck Surg 1992;106:275~7. Franco EL, Dib LL, Pinto DS. Race and gender influences on the survival of patients with mouth cancer. J clin Epidemiol 1993;46:37-46 Funk GF, Karnell LH, Robinson RA. Presentation, treat- ‘ment, and outcome of oral cavity cancer: a National Cancer Database report. Head Neck 2002;24:165-20. Kuriakose M, Sankaranaryanan M, Nait MK. Comparison of tral squamous call carcinoma in younger and older patients in tndia. Oral Oncol Eur J Cancer 1992;28B:113—20. Sarkaria JN, Harari PM. . Oral tongue cancer in young adults less than 40 years of age: rationale for aggressive therapy. Head Neck 1994;16:107—11 Hyam DM, Conway RC, Sathiyaseelan Y, Gebski V, Morgan Gu. Tongue cancer: de patients younger than 40 do worse? Aust Dent J 2003;48:50~4, Carvalho AL, Singh 8 Spiro RH, Kowalski LP, Shah JP. Cancer of the oral cavity: a comparison between institu tions in a developing and a developed nation. Head Neck 2004;26:31-8. Reid BC, Alberg AJ, Klassen AC, Samet JN, Rozier RG, Garcia . Comorbidity and survival of elderly head and neck carcinoma patients. Cancer 2001;92:2109-16. 97. 100, 101 102. 103, 104, 105, 106, 107, 108. 109, De Cassia Braga Ribeiro K, Ribeiro K, Kowalskl LP. Periop ‘erative complications, comorbidities, and survival in oral and oropharyngeal cancer. Arch Otolaryngol Head Neck Surg 2003;129:219-28, Goldman SA, Baker E, Weyant RU, Clarke MR, Myers JN, Lotze MT. Peritumoral CDta-positive dendritic cells are ssociated with improved survival in patients with tongue ceancer. Arch Otolaryngol Head Neck Surg 1998;124: oat—6. )- Reichert TE, Scheuer C, Day R, Wagner W, Whiteside TL ‘The number of intratumoral dendritic cells and zeta-chain ‘expression in T-cells as prognostic and survival biomark- (rs in patients with oral carcinoma. Cancer 2001;91 2136-47. Koch WM, Largo M, Sewell D, Head and neck cancer in non smokers: a distinct clinical and molecular entity. Laryn- -goscope 1999;109:1544—51 Gilson ML, Koch WM, Capone RB. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J. Natl Cancer Inst 2000;92:709-20. Gluckman JL, Crissman JD. Survival rates in 548 patients with multiple neoplasms of the upper aerodigestive tract. Laryngoscope 1983;93:71~4 Kotwall C, Razack MS, Sako K, Rao U. Multiple primary cancers in squamous cell cancer of the head and neck. J Surg Oncol 1989;40:97-9, Jones AS, Morar P, Philips DE. Second primary tumours in patients with head and neck squamous cell carcinoma, Cancer 1995;75:1343—52. Slootweg PJ, Hordik GJ, Koole R. Autopsy Andings in patients with head and neck squamous cell cancer and their therapeutic relevance. Oral Oncol Eur J Cancer 1996;328:413-5, Cunningham MAJ, Johnson JT, Myers EN, Schramm VL, ‘Thearle PB. Cervical \ymph node metastasis after local excision of early squamous call carcinoma of the oral cavity. Am J Surg 1986;152:361-5, Byers RM, Wolf PF, Ballantyne AJ. Rationale for elective modified neck dissection, Head Neck Surg 1988; 10:160~7. Berg JW, Schattenfeld D, Ritier F. Incidence of multiple primary cancer, 3: cancers of the respiratory and upper Aigestive systern as multiple primary cancers. J Natl Cancer int 1970;44:263~74 Carr Ri, Langdon 4D. Multiple primaries in mouth can- cer—The price of success. Br J Oral Maxillofac Sure 4989;27:394-2 Available online at www.sciencedirect.com somnon Goinsor: