Pathology of the Head and Neck

Lesions of Squamous Epithelium Chapter 1 27Extracapsular spread is a significant predictor ofboth regional recurrence and the development of distantmetastases resulting in decreased survival [109, 155, 175,335, 337]. In some studies, ECS has been shown as a betterpredictor than the resection margins. It has thereforebeen suggested that ECS should be incorporated into thestaging system for surgically managed patients [380].Some studies, on the contrary, have not confirmed theindependent prognostic significance of extracapsularspread [230, 280].1.5.3.2 Metastases in the Soft Tissueof the NeckIn some patients, an SCC in the soft tissue of the neck isfound, with no evidence of lymph nodes being present.These soft tissue metastases may be the result of eithertotal effacement of a lymph node by the SCC, or extralymphaticspread of the SCC [176].It has been shown that the presence of soft tissue metastasesis associated with an aggressive clinical courseand poor survival [176, 368]. In a study of 155 patients,survival was significantly shorter for patients with softtissue metastases than those without nodal metastasesand those with nodal metastases without extracapsularspread; it was similar to that for patients with lymphnode metastases with extracapsular spread [176].1.5.4 Distant MetastasisDistant metastases in patients with head and neck cancerare usually defined as metastases below the clavicle,and may be the result of lymphogenic or haematogenousspread. Lymphogenic spread results in distant lymphnode metastases; the most commonly affected distantnodes are the mediastinal, axillary and inguinal nodes[7]. Haematogenous spread results in distant metastases,most commonly to the lung, liver and bones, followed bythe skin and brain [84, 157, 198, 208, 337, 362, 387]. Metastaseshave been also described in the small intestine[384], spleen [3] and the cavernous sinus [362].Distant metastases in head and neck SCCs are infrequent,but may occur in the late stages of the disease,with the reported incidence between 3 and 8.5%[337, 387]. Postmortem studies have shown a higher incidenceof distant metastases, ranging from 24 to 57%[266, 325, 393].The incidence of distant metastases depends on thesite of the primary tumour, as well as the initial size ofthe tumour and the presence of nodal metastases [59,198, 253]. The highest incidence of distant metastaseshas been reported in hypopharyngeal SCCs, followed bythe SCCs of the tongue [198].Most distant metastases become clinically apparent2 years after diagnosis of the initial tumour. The averagesurvival once distant metastases are diagnosed rangesbetween 4 and 7 months [208].1.5.5 MicrometastasisMicrometastasis is defined as a microscopic deposit ofmalignant cells, smaller than 2–3 mm, that are segregatedspatially from the primary tumour [193]. The fateof micrometastases is uncertain; the majority of themare probably destined for destruction or dormancy, andonly a small percentage of circulating tumour cells surviveand initiate a metastatic focus [1].The fundamental characteristic of micrometastasisis the absence of a specific blood supply. Micrometastasesare thus dependent on passive diffusion for oxygenand nutrient supply. Experimental studies haveshown that without new blood vessel formation (neoangiogenesis),the growth of tumour cells is limited to2–3 mm and may remain dormant for months or evenyears. During dormancy, the proliferation is balancedby an equivalent rate of cell death by apoptosis. Afterinduction of neoangiogenesis, apoptosis is significantlyreduced, but the proliferation rate remains unchanged,and the growth of the clinically overt metastasiscan occur because of the increased survival of thetumour cells [158].Micrometastases can be detected anywhere in thebody, but most frequently in the lymph nodes, in thesurgical margins, in the blood and in bone marrow[112]. Their detection can be accomplished by serial sectioninglight microscopy, immunohistochemistry, and/or molecular analysis [35, 112, 130, 146].The clinical and prognostic implication of micrometastasesis still uncertain. It has been suggested that residualmicrometastatic tumour cells may increase therisk of tumour recurrence, thus resulting in failure ofthe primary treatment. Furthermore, the presence of tumourcells in the blood and/or bone marrow may be anindicator of a generalised disease with possible disseminationto many organs [163]. Several studies have demonstratedthat lymph node micrometastases are associatedwith a high risk of recurrence and poor survivalin patients with carcinoma of the breast, oesophagus,stomach, colon and lung [163], but few studies have beenfocused on the clinical significance of micrometastasesin SCCs of the head and neck [112, 379].It appears that the detection of micrometastases isa promising approach that might enable us to identifycandidates for adjuvant treatment strategies [163]. However,further studies are needed to define more preciselythe clinical implication of micrometastases, as well asthe most appropriate method for their detection.