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«Pitfalls and procedures in the histopathological diagnosis of oral and oropharyngeal squamous cell carcinoma and a review of the role of pathology in ...»

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Pitfalls and procedures in the histopathological

diagnosis of oral and oropharyngeal squamous cell

carcinoma and a review of the role of pathology in


Julia Anne Woolgar, Asterios Triantafyllou

Oral Pathology, School of Dental Sciences and Dental Hospital, University of

Liverpool, Pembroke Place, Liverpool L3 5PS, United Kingdom

Tel.: +44 151 706 5245 (JAW), +44 151 706 5243 (AT); fax: +44 151 706 5240

E-mail address: jaw@liverpool.ac.uk, A.Triantafyllou@liverpool.ac.uk

2 Summary Histopathological assessment of formalin-fixed biopsy tissue and surgical resection specimens remains the cornerstone of cancer diagnosis and pathological staging in routine clinical practice. In recent years, standard protocols for reporting head and neck cancer have been widely used and these have improved the general level of the pathological assessment.

In this article, we look beyond the standard protocols and deal with potential difficulties and pitfalls in the assessment of incisional biopsy specimens, surgical resection specimens and neck dissections. We draw attention to possible shortcomings and issues requiring clarification. Emphasis is given to precise histopathological definitions, histopathological detection and differential diagnosis. The approach is a practical one - a consideration of common experiences and dilemmas faced by the reporting pathologist, and where possible, we offer guidance and practical tips. The article concludes with a brief consideration of the prognostic value of accurate histopathological staging.


Oral cancer;

Oropharyngeal cancer;

Squamous cell carcinoma;

Histopathology 3

1. Introduction Although, molecular biology is being increasingly used in the investigation of oral and oropharyngeal squamous cell carcinoma (OSCC), histological assessment of surgically-removed formalin-fixed tissues remains the cornerstone of its diagnosis and pathological staging in routine clinical practice. In recent years, standardised pathological protocols1 and regular multidisciplinary team meetings (MDTs) have become routine and are essential for a high quality service. Nevertheless, problems may occur at all stages of the histopathological diagnosis and staging, from the processing of received tissues to the generation of the final report. They may result from inherent limitations of histopathological definitions, diagnosis and staging;

inaccuracies in histological detection and histological misinterpretation. The present article concentrates on such problems. Our aims were: 1) to illustrate potential pitfalls by considering common experiences during the pathological assessment of the initial and subsequent diagnostic / incisional intra-oral biopsy specimens, surgical resection specimens (Fig. 1) and neck dissections (NDs) (Fig. 2); 2) to draw attention to possible shortcomings and issues needing clarification; and 3) to suggest, where possible, practical solutions, improvements and areas of further research. Finally, the impact of detailed, accurate pathological staging in prognosis prediction of OSCC is considered.

2. Problems related to incisional biopsies and surgical resections ofprimary OSCCs

Questions and potential problems are expected to arise when the pathologist assesses incisional biopsies and surgical resections of the primary tumour. Some of the questions and experiences overlap, while others merit only brief consideration, and hence, some of the situations can be grouped and addressed in conjunction.

Table 1 summarises the groupings and indexes the topics which we discuss.

2.1 Proliferative squamous epithelial dysplasia

–  –  –

2.2 Histological subtypes of OSCC In addition to the conventional and instantly recognised OSCC, several subtypes presenting varying diagnostic challenges have been recognised.3 While some are addressed here it was deemed appropriate to discuss the remainder in other sections (see Table 1). It is not our intention to repeat descriptions in standard references3 and emphasis is given to personal approaches, experience and observations.

The OSCC subtypes often occur alone (‘pure’ forms). However, ‘hybrid’ OSCCs, combining varying ratios of more than one subtypes, are now being increasingly recognised and are attributable to proliferation of individual clones expressing different phenotypes. Cervical node metastases of hybrid OSCCs may consist wholly or predominantly of one subtype.

It has been repeatedly stated that the acantholytic SCC could be misdiagnosed as adenocarcinoma, adenosquamous carcinoma, and 4 mucoepidermoid carcinoma. With awareness and increased experience the prompt recognition of the subtype is not difficult, particularly when it is considered that the acantholytic changes, which result in the formation of pseudolumens / pseudoglandular spaces (Fig. 3), are usually not extensive and asymmetrically distributed, preferentially close to the advancing front of the tumour. The presence of malignant acantholysis within surface dysplastic epithelium and experience with cutaneous SCCs wherein the acantholytic subtype is more often seen would be of further help. The recognition can be confirmed by special staining for mucosubstances, eg. Alcian Blue (AB) pH 2.5 followed by periodic-acid/Schiff (PAS), as these are absent from pseudolumens. Malignant acantholysis usually affects the central part of advancing cellular aggregates and a ‘basal’ layer is preserved (Fig. 3).

We have, however, observed tumours where the latter becomes focally affected and dyscohesive. This results in collections of malignant keratinocytes occurring as individual units subadjacent to the advancing front, which can be highlighted by immunohistochemistry for cytokeratins (using a panel of pan-keratin antibodies) (Fig.

4). We do not report these as acantholytic SCCs, but as conventional SCCs with dyscohesive foci at the advancing front. It is not known whether this phenomenon is of prognostic significance, but see section 2.3.

Considerable difficulties could arise when the malignant acantholysis affects most of the tumour and the histology becomes that of individual cells of variable / ‘bizarre’ phenotypes, which are extensively insinuating between normal tissue elements rather than the cellular aggregates with pseudoluminal arrangements seen in typical acantholytic SCC. Increased index of suspicion and immunohistochemistry 5 for cytokeratins would overcome the difficulties. We are characterising these as noncohesive SCCs, but we are unable to comment on prognostic significance, because they are rare (see section 2.3).

In the context of non-cohesive SCCs, we have to consider the pseudovascular SCC that can be mistaken for angiosarcoma and the giant cell carcinoma of the mouth. Immunohistochemistry for cytokeratins and endothelial markers would be helpful in recognising the former,5 whereas the very rare giant cell carcinoma may show multinuclear cells resembling osteoclasts or pleomorphic giant cells.3 When this presents in the mouth, it is important to exclude a metastasis from, for example, thyroid or lung, the usual sites of giant cell carcinoma.6 Aptly named, the basaloid SCC (Fig. 5) is characterised by ‘basaloid’ cell phenotypes and variable peripheral palisading.3 It can bear a resemblance to ameloblastoma, which could cause confusion for tumours centred on the alveolar processes, and occurs either as pure or hybrid forms (Figs. 5, 6). This could be a confounding factor in studies attempting to ascribe different grades to particular subtypes and it is conventionally accepted that basaloid SCCs are of a worse prognosis (see section 4.1.8).

The diagnostic challenges presented by spindle cell carcinoma (Fig. 7) are well known and, although mandatory, immunohistochemistry is not consistent.

Cytokeratin immunoreactivity is often focal or variable (40-85%)7 and it is essential to use a panel of antibodies. The need for careful search for a surface origin, epithelial dysplasia or foci with discernible squamous / squamoid phenotypes has been emphasised, but an incisional biopsy could be lacking such features and a high index of suspicion to prompt further investigation is a sine qua non for mistakes to be avoided. Myofibroblastic reactions (Fig. 8) and the ‘bizarre’ stromal cells often seen in florid granulation tissue, occasionally following previous biopsy, or at sites following radiotherapy such as brachytherapy, have also been considered as possible diagnoses when biopsies show ‘suspicious spindle cells’.8.9 We feel, however, that the recognition of these cells is less difficult than that of malignant keratinocytes showing spindled or ovoid phenotypes and occurring as individual units.

Myofibroblasts often have discernible borders, eosinophilic cytoplasm, fascicular arrangement, low mitotic activity and, if any doubt, immunoreactivity for smooth muscle actin (SMA) (Fig. 7b), whereas the ‘bizarre’ stromal cells, in comparison with malignant keratinocytes, are usually elongated and lack rounded / ‘epithelioid’ phenotypes (Fig. 7b).

Intra-oral carcinomas may show a variable component exhibiting features similar to the nasopharyngeal non-keratinising carcinoma10 with a lymphoplasmacytic inflammatory infiltrate. When the latter is brisk, the designation ‘lymphoepithelial carcinoma’ may be preferred. The histology is distinctive and comprises sheets and cellular masses composed of cells with ill-perceived borders (resulting in the characteristic ‘syncytial’ arrangement),10 and vesicular nuclei with obvious nucleoli (Fig. 9).

Apart from the nasal cavity and paranasal sinuses, carcinomas showing a transitional phenotype may arise as primaries in oral / oropharyngeal sites, eg. the base of tongue (Fig. 10a) and tonsil.11 Keratinisation is absent or minimal (occasional small and poorly-formed keratin pearls or squamous ‘eddies’) and a correct diagnosis should be prompted by the distinctive histology. This comprises multilayered cellular masses in characteristic garland- or ribbon-like arrangements (Fig. 10b), which are usually affected by central comedo-necrosis, surrounded by variably discernible basement membrane and composed of mitotically active non-keratinising cells that, peripherally, may have their long axis oriented vertical to the underlying basement membrane (Fig. 10c). Pure or hybrid forms are seen (Fig. 11).

Finally, the rare pigmented intra-oral carcinomas12 are histopathological curiosities rather than of clinical significance. They correspond to conventional SCCs that have been ‘colonised’ by dendritic melanocytes synthesising and transferring melanin to adjacent malignant keratinocytes (Fig. 12). The phenomenon is similar to that seen in basal cell carcinomas, adnexal tumours and Bednar’s tumour.13 Although many subtypes of SCC are considered rare or very rare in the mouth and oropharynx, we believe that they will become increasingly recognised with centralisation of cancer services and sharing of cases between oral and Ear Nose and Throat (ENT) pathologists. Although currently sub-typing may be considered largely ‘academic’, it is essential that it is accurate and well documented so that information on management and prognosis can be shared (see section 5.1.8).

2.3 Grading systems of conventional OSCC, growth patterns and measurements The histopathological grading of conventional OSCC as well- (pG1), moderatelypG2) or poorly differentiated (pG3),14 enjoys popularity because it is simple. The degree of ‘differentiation’ (resemblance to normal oral / oropharyngeal surface epithelium) is subjectively assessed and in terms of keratinisation, cellular pleomorphism, mitotic activity and nuclear aberrations.14 Application of the system, which evolved from Broders’ original classification15, indicates that 50% of oral and 90% of oropharyngeal SCCs are moderately differentiated.14 Increased 7 discrimination is, however, desirable and the World Health Organisation (WHO) is now recommending that grading by differentiation is supplemented by assessment of the pattern of invasion. Hence, it is important that an incisional biopsy is of sufficient size and depth to include part of the advancing front of the tumour. Ideally, the deep front should be included, but if not, as in large tumours, the peripheral (lateral) front is often sufficiently representative to allow provisional assessment.

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