Pathology of the Head and Neck

28 N. Gale · N. Zidar11.6 Molecular Pathologyof Squamous Cell CarcinomaMalignant tumours arise clonally from transformedcells that have undergone specific genetic alterations intumour suppressor genes and proto-oncogenes [117], aswell as telomerase re-activation [225, 226, 256]. Loss ofchromosomal region 9p21 is the most common geneticchange in head and neck carcinogenesis with consequentinactivation of the p16 gene [168, 169]. A frequentevent is also mutation of the p53 gene located at 17p13;it occurs in approximately 50% of patients with SCCsof the head and neck [255, 257, 270]. Loss of retinoblastomagene (Rb1) expression is seen in less than 20% ofcases, although LOH at 13q14 is present in 60% or moreof SCCs, suggesting the existence of (an)other tumoursuppressor gene(s) neighbouring Rb1 [256].The activation of oncogenes also occurs, such as cyclinD1 amplification, which has been described in one-thirdof patients with SCCs of the head and neck, and is associatedwith advanced disease [167, 272]. Amplification ofother oncogenes, e.g. c-myc and epidermal growth factorreceptor, has also been described in 6–25% of patientswith SCCs of the head and neck [119, 121, 269], while rasmutations probably do not play a significant role in thedevelopment of head and neck SCCs [119].Molecular pathology has significantly deepened ourinsight into genetic alterations occurring in and beingprobably responsible for cancer development. Moreover,it offers the opportunity for tissue characterisation, i.e.detection of tumour cells, distinction between multipleprimary tumours and metastatic disease, and the risk ofprogression of premalignant lesions, going beyond morphologicaltechniques that have been used in pathologyuntil now. The question remains, however, whetherthere is any practical impact of these new techniques regardingdiagnosis, prognosis and management.1.6.1 Detecting Tumour CellsThe introduction of methods more sensitive than histologyfor detecting tumour cells in surgical margins andlymph nodes could be helpful in obtaining better treatmentresults for patients with SCCs of the head and neck[53, 261, 361]. Their application, however, requires somecritical remarks.First, if histology is inadequate for reliable margin assessment,a lot of cases of SCC of the head and neck thathave been classified as tumour-free after surgery by thismethod should nevertheless show recurrence at the sitefrom which the tumour was removed.Secondly, the usefulness of molecular detection of tumourcells in lymph nodes should be demonstrated bytransferring patients from the histopathologically assessedN0 stage to the N+ stage. Merely detecting additionalpositive nodes in patients already classified as N+is of debatable value.In the third place, genetically altered cells are not alwaystumour cells. The whole epithelial lining of the upperaerodigestive tract bears the genetic burden of thecarcinogenetic agents that cause SCCs and, therefore,these cells could have arisen independently from the invasivetumour [50, 268].Also, there is no uniformity as to what constitutesa positive or negative surgical margin [26]. There is abroad spectrum of histological appearance betweennormal epithelium and fully developed SCC. If geneticallyaltered cells are found in areas free of tumour butwith atypical hyperplasia (severe dysplasia), molecularpathology does not provide any information comparedwith conventional microscopical examination.In a recently published study, the value of molecularpathology was compared with traditional histology inthe assessment of surgical margins and neck nodes in patientswith SCCs of the head and neck [326]. It was foundthat from patients with microscopically positive margins,22% had recurrence at the primary site. In contrast, of thecases with histologically tumour-free margins, only 4%showed recurrence of the tumour at the primary site. Theauthors concluded that conventional histology adequatelyidentifies patients with SCCs of the head and neck atrisk of local recurrence, leaving only very limited roomfor improvement using more sophisticated methods.Regarding the neck, local recurrence was observedin 12 out of 107 cases in which a previous neck dissectionwas reported to be tumour-free. These neck recurrencescould be due to the presence of micrometastasesnot detected by microscopy and improved methods fordetecting them may reduce this number. However, it isstill uncertain whether micrometastatic disease has thesame clinical significance as metastatic disease detectedby conventional methods [104].The authors concluded that the added clinical valueof molecular pathology over histology in detecting tumourcells in surgical margins in SCCs of the head andneck does not justify the effort. For lymph nodes, suchan added value is still under discussion [326].1.6.2 Clonal AnalysisPatients with SCCs of the head and neck are at risk of thedevelopment of multiple primary SCCs, not only in thehead and neck region, but also in the lung. Therefore, itis not always clear whether a patient who has multiplelesions either synchronically or metachronically suffersfrom one single disseminated disease or from multipleprimary cancers. If all tumour deposits show SCC, histologycannot distinguish between both possibilitieswhereas both situations require different treatment approaches.If histologically similar tumours differ geneti-