Xli

Fig. 3.10 Squamous cell carcinoma (SCC). A Well differentiated SCC. B Poorly differentiated SCC.

the tracheostoma, is a well recognized, but infrequent complication after total laryngectomy. Patients with subglottic and postcricoid involvement and advanced stage of the primary SCC are at risk to develop this complication.

Local and distant metastases

Laryngeal, hypopharyngeal and tracheal SCC are likely to metastasize to the regional lymph nodes. The location and frequency of lymph node metastases depends upon the site of the primary tumour. Extracapsular spread (ECS) refers to carcinoma penetrating the lymph node capsule and infiltrating extracapsular tissue. Extracapsular spread is further divided into macroscopic and microscopic ECS {337}; macroscopic ECS is evident to the naked eye and appears as matted lymph nodes. Microscopic ECS is only evident on histologic examination and is usually limited to the adjacent perinodal fibro-adipose tissue.

Clinically relevant haematogenous metastases are infrequent but may occur in late stages of the disease. The most common site for spread is the lung, and less commonly, liver and bones {2435}. In patients with blood-borne metastases, regional lymph node metastases are usually also present or have been treated.

Staging

Tumours of the larynx and hypopharynx are staged by the TNM system (AJCC and UICC) {947,2418}. Tracheal tumours are not included in the TNM system. In the definition of the N classification, the specified 3.0 cm and 6.0 cm measurements include the total tumour mass in the area (lymph node mass) and not just the individual lymph node size {2801}.

Histopathology

Squamous differentiation, often seen as keratinization with variable "pearl" formation, and invasive growth are the prerequisite features of SCC. Invasion is manifested by disruption of the basement membrane, and extension into the underlying tissue, often accompanied by stro-mal reaction. Angiolymphatic and per-ineural invasion are additional signs of malignancy.

The tumours are traditionally graded into well-, moderately-, and poorly differentiated SCC. Well differentiated SCC resembles closely normal squamous epithelium. Moderately differentiated SCC contains distinct nuclear pleomor-phism and mitotic activity, including abnormal mitoses; there is usually less keratinization. In poorly differentiated SCC, immature cells predominate, with numerous typical and atypical mitoses, and minimal keratinization. Although ker-atinization is more likely to be present in well- or moderately-differentiated SCC, it should not be considered an important histological criterion in grading SCC. Most SCC are moderately differentiated, so grading by differentiation is really of limited prognostic value, as compared to pattern of invasion.

Invasive front

Tumour growth at the invasive front can show an expansive pattern, an infiltrative pattern, or both. Expansive growth pattern is characterised by large tumour islands with well-defined pushing margins and is associated with a better prog nosis. Infiltrative growth pattern is characterized by scattered small irregular cords or single tumour cells, with poorly defined infiltrating margins and is associated with a more aggressive course {290}. Some guidelines recommend categorizing tumours into cohesive, and non-cohesive fronts, (Reporting Guideline for the Royal College of Pathologists).

Stromal reaction

Invasive SCC is almost always accompanied by stromal reaction that consists of desmoplasia with deposition of extracellular matrix and proliferation of myofibroblasts {2907}. Neovascularization is frequently seen.

Immunoprofile

SCC expresses epithelial markers such as cytokeratins. The patterns of expression of cytokeratin subtypes may change during malignant transformation and relate to the histologic grade, degree of keratinization, and the likelihood of metastases. Low-grade SCC expresses medium-high molecular weight (MW) cytokeratins, but not low MW cytoker-atins, similarly to normal squamous epithelium. In contrast, high-grade SCC tends to lose the expression of mediumhigh MW cytokeratins, and express low MW cytokeratins {1617}. High-grade SCC may express vimentin {2668}.

Electron microscopy

SCC exhibits desmosomes and attached tonofilaments {880}.

Differential diagnosis

The diagnosis of SCC is usually not prob

Fig. 3.11 Exophytic squamous cell carcinoma. Small fibrovascular cores are seen in the centre of papillary projections of squamous cell carcinoma.

lematic. However, the exophytic variant of SCC must be distinguished from papillary and verrucous SCC. The exophytic SCC is composed of broad-based neo-plastic fronds, and in contrast to papillary SCC, lacks prominent branched fibrovascular cores {171,2602}. Verrucous SCC is composed of papillary projections and bulbous invaginations, lacking cytological atypia. Well-differentiated SCC must also be distinguished from pseudoepitheliomatous hyperplasia, a benign hyperplastic epithelial condition composed of irregular elongated rete pegs extending deeply into the stroma. It typically occurs in association with chronic infections (tuberculosis, mycosis), trauma, and classically, granular cell tumours. The cytological features of malignancy are not found in pseudoepitheliomatous hyperplasia.

Distinguishing SCC from radiation changes can be difficult. Radiation can result in ulceration, epithelial and stromal atypia, inflammation and vascular changes. The seromucinous glands may be atrophic. Squamous metaplasia and hyperplasia of ducts, can mimic SCC. Preservation of ductal lumens and lobular architecture aid in making this distinction.

Moderately or poorly differentiated SCC must be distinguished from various subtypes of SCC. The differential diagnosis also includes other malignant tumours, such as adenocarcinoma, neuroendocrine carcinoma, melanoma and lymphoma. The correct diagnosis is best achieved by the use of appropriate immunohistochemistry.

Precursor lesions

Precursor lesions are defined as altered epithelium with an increased likelihood for progression to SCC {847,852,1253, 1581}. Epithelial dysplasia is the term used traditionally to describe these microscopic alterations, although other terms have been proposed (see section on epithelial precursor lesions). Pathologists are frequently asked to assess epithelial dysplasia, because it is believed to be an important indicator of malignant potential. The likelihood of malignant change directly relates to the severity of dysplasia. However, it is clear that malignancy can develop from any grade of dysplasia or even from morphologically normal epithelium.

Histogenesis

SCC originates from the squamous mucosa or from ciliated respiratory epithelium that has undergone squa-mous metaplasia.

Somatic genetics

Cytogenetics and comparative genomic hybridization (CGH)

The most frequent chromosomal alterations detected by CGH are +3q, +5p,

+8q, +11q13, +17q, and -3p. Additional alterations, such as +1q, +7p, +7q +9q, + 14q, +18p, and -4p, -5q, -11qter, and -18q are also frequent {1074,1145}. These alterations are very similar to those reported with conventional karyotyping analysis of early passage cells from laryngeal carcinomas {1219}. Predictive models based on hierarchical branching and distance-based trees indicate +3q21-29 as the most important early chromosomal alteration, followed in importance and chronology by -3p {1145}. High-level amplifications are found at 3q24-qter and, less frequently 11 q 13, 18p, 18q 11.2, 8q23-24, and 11q14-22. Some of these amplifications are at loci containing known oncogenes (CCND1 for 11q13) {1074}. Metastazising tumours show a higher number of DNA copy losses than non-metastazising tumours. Losses at 8p, 9q, and 13 are more frequent in metastatic than in primary tumours {1381}.

Molecular genetic alterations

Neoplastic transformation implies modulation of a large number of genes {1810} as well as telomerase re-activation as indicated by hTERT expression {1588}. CCND1 is amplified and overexpressed mostly in advanced cases {811,1207}. MYCand EGFRare amplified in 6-25% of cases although amplification is not related to overexpression {612,794,811}. Loss of RB1 expression is seen in less than 20% of tumours {1208,2546} although LOH at 13q14 is present in 60% or more of tumours, suggesting the existence of other(s) tumour suppressor gene(s) neighbouring RB1 {2857}. TP53 mutations are found in 13-50% of laryngeal tumours. The excess of G to T transversions and the codons more frequently affected are both attributed to the carcinogenic effect of tobacco smoking {1939,2027}. TP53 alterations are found in premalignant lesions indicating participation early in the neoplastic transformation process {847,1809}. However, neither TP53 overexpression nor CDKN1A expression are reliable markers for TP53 mutations. Instead, CDKN1A expression is clearly related to squa-mous differentiation {1811}. TP73L, a TP53 homologue with oncogenic potential, maps to 3q27-28, a region with frequent gains. In primary carcinoma, low-copy number TP73L amplification has been detected by fluorescent in-situ hybridization (FISH) {2837}. The role of HPV infection in laryngeal carcinoma may be overestimated {1810}. The use of PCR-based techniques for the detection of HPV-DNA has yielded variable results (for a review see {1523}). In fact, the virus has even been demonstrated in more than 12-25% of non-neo-plastic samples examined {2008}. CDKN2A can be inactivated by mutation, homozygous deletion, and promoter hypermethylation {1208,2168}. CDKN2A mutations can occur in cases with mRNA and/or protein overexpression {1209}. Significant levels of MMP13 mRNA are detectable in some laryngeal tumours, restricted to those that retain features of squamous differentiation. MMP13 expression is coordinated with MMP2 and MMP14 overexpression, two molecules that can efficiently activate MMP13. Both MMP13 expression and MMP14 overexpression are associated with advanced tumours, indicating a more aggressive behaviour {348}. CDH1 expression is lower in metastatic tumours {798}. In addition, gene expression silencing of CDH1 by promoter hyperme-thylation is more frequent in metastatic (77%) than in primary laryngeal tumours (40%) {95}.

Prognosis and predictive factors

The overall 5-year survival rate is 80-85% in glottic SCC, 65-75% in supraglottic SCC, about 40% in subglottic SCC {126}, 62.5% in hypopharyngeal SCC {2434}, and 47% in tracheal SCC {2143}.

Clinical predictive factors

Stage

TNM remains the most significant predictor of survival.

Localization

Tumour localization is important {754}. The best prognosis has been reported for glottic SCC, and the worst prognosis for hypopharyngeal, subglottic and tracheal SCC.

Other factors that can have an impact on the presentation and outcome of SCC include age, {428,2374}, comorbidity (concurrent diseases) {402} and performance status {428}.

Histopathological predictive factors

Resection margins

The complete excision of tumour is the most important principle of oncologic surgery. Negative resection margins are generally associated with decreased recurrence and improved survival {1557, 2403}. Although controversial, a distance of a few millimeters may be adequate in selected glottic SCC {2462,2738}. For supraglottic, advanced glottic, and hypopharyngeal SCC, resection margins have not been precisely defined but distances of at least 5 mm or greater are desired {841}.

Proliferation

Proliferation fraction determined immunohistochemically with antibodies against Ki67 and proliferating cell nuclear antigen (PCNA) have been reported to correlate strongly with the degree of differentiation in SCC {1372,2906} and the presence of lymph node metastases {798}. However, proliferation fraction is not an independent prognostic factor {1372}.

Lymphovascular and perineural invasion

The penetration of tumour cells into lymphatic and/or blood vessels is associated with an increased propensity for lymph node and/or distant metastases. It tends to occur in aggressive SCC and is associated with recurrence and poor survival {2853}. Similarly, perineural invasion is associated with increase local recurrence, regional lymph node metastases and decrease survival {708,2853}.

Extracapsular spread in lymph node metastases

Lymph node metastasis is the single most adverse prognostic factor in head and neck SCC {750}. Recent studies have shown that the presence of extra-capsular spread in lymph nodes is strongly associated with both regional recurrence and distant metastases, resulting in decreased survival {750, 1094,2507}.

DNA ploidy

The prognostic significance of DNA ploidy has been studied extensively and the results are controversial. Some studies have shown that aneuploid tumours are associated with a higher rate of lymph node metastases and decreased survival {652,2545,2805} while others have not confirmed this {139,574}. Conflicting results have also been reported regarding the predictive value of DNA

ploidy and treatment response {2545, 2774}.

Genetic predictive criteria

The prognostic value of p53 abnormalities is generally inconclusive for laryngeal carcinoma {79,1809,1914}. CCND1 amplification is related to poor prognosis independent of stage {192}. Simultaneous CDK4 and CCND1 overexpression is associated with poor prognosis {615}. In patients with locally advanced laryngeal cancer, CDKN2A mutations have prognostic significance in predicting adverse outcome {183}

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