A

Fig. 1.11 Basaloid squamous cell carcinoma. A Typical comedo-type necrosis. B Small gland-like structures.

with intraepithelial neoplasia, invasive SCC, or islands of squamous differentiation among the basaloid cells {2036}. The proliferative activity is higher than in typical SCC. However, basaloid squamous cell carcinoma is also characterized by a high rate of apoptosis and its prognosis does not differ significantly from that of the ordinary oesophageal SCC {1663}.

Precursor lesions

Most studies on precursor lesions of oesophageal SCC have been carried out in high-risk populations, especially in Iran and Northern China, but there is no evidence that precursor lesions in low-risk regions are substantially different. The development of oesophageal SCC is thought to be a multistage process which progresses from the conversion of normal squamous epithelium to that with basal cell hyperplasia, intraepithelial neoplasia (dysplasia and carcinoma in situ), and, finally, invasive SCC {354, 1547, 377}.

Intraepithelial neoplasia. This lesion is about eight times more common in high cancer-risk areas than in low-risk areas {1547}, and is frequently found adjacent to invasive SCC in oesophagectomy specimens {1154, 988}. Morphological features of intraepithelial neoplasia include both architectural and cytological abnormalities. The architectural abnormality is characterized by a disorganisation of the epithelium and loss of normal cell polarity. Cytologically, the cells exhibit irregular and hyperchromatic nuclei, an increase in nuclear/cytoplasmic ratio and increased mitotic activity. Dysplasia is usually graded as low or high-grade. In low-grade dysplasia, the abnormalities are often confined to the lower half of the epithelium, whereas in high-grade dys-plasia the abnormal cells also occur in the upper half and exhibit a greater degree of atypia. In carcinoma in situ, the atypical cells are present throughout the epithelium without evidence of maturation at the surface of the epithelium {1154}. In a two-tier system, severe dysplasia and carcinoma-in-situ are included under the rubric of high-grade intraepithelial neo-plasia, and may have the same clinical implications {1055}.

Epidemiological follow-up studies suggest an increased risk for the subsequent development of invasive SCC for patients with basal cell hyperplasia (relative risk: 2.1), low-grade dysplasia (RR: 2.2), moderate-grade dysplasia (RR: 15.8), high-grade dysplasia (RR: 72.6) and carcinoma in situ (RR: 62.5) {377}.

Fig. 1.12 Low-grade intraepithelial neoplasia with an increase in basal cells, loss of polarity in the deep epithelium and slight cytological atypia.
Fig. 1.13 High grade intraepithelial neoplasia of oesophageal squamous epithelium. Architectural disarray, loss of polarity and cellular atypia are much greater than shown in Fig. 1.12. Changes in D extend to the parakeratotic layer of the luminal surface.
Fig. 1.14 Squamous cell papilloma of distal oesophagus. This lesion was negative for human papillomavirus by in situ hybridisation.

Basal cell hyperplasia

This lesion is histologically defined as an otherwise normal squamous epithelium with a basal zone thickness greater than 15% of total epithelial thickness, without elongation of lamina propria papillae {377}. In most cases, basal cell hyperplasia is an epithelial proliferative lesion in response to oesophagitis, which is frequently observed in high-risk populations for oesophageal cancer {1547}.

Squamous cell papilloma (ICD-O 8052/0)

Squamous cell papilloma is rare and usually causes no specific symptoms. It is a benign tumour composed of hyper-plastic squamous epithelium covering finger-like processes with cores derived from the lamina propria. The polypoid lesions are smooth, sharply demarcated, and usually 5 mm or less in maximum diameter {249, 1428}. Rarely, giant papil-lomas have been reported, with sizes up to 5 cm {2037}. Most squamous cell papillomas represent single isolated lesions, typically located in the distal to middle third of the oesophagus, but multiple lesions occur.

Histologically, cores of fibrovascular tissue are covered by mature stratified squamous epithelium. The aetiological role of human papillomavirus (HPV) infection has been investigated in several studies, but the results were inconclusive {248}. Malignant progression to SCC is extremely rare.

In Japan, oesophageal squamous cell carcinoma is diagnosed mainly based on nuclear criteria, even in cases judged to be non-invasive intraepithelial neoplasia (dysplasia) in the West. This difference in diagnostic practice may contribute to the relatively high rate of incidence and good prognosis of superficial squamous cell carcinoma reported in Japan {1682}.

Grading

Grading of oesophageal SCC is traditionally based on the parameters of mitotic activity, anisonucleosis and degree of differentiation.

Well differentiated tumours have cytolo-gical and histological features similar to those of the normal oesophageal squa-mous epithelium. In well differentiated oesophageal SCC there is a high proportion of large, differentiated, keratinocyte-like squamous cells and a low proportion of small basal-type cells, which are located in the periphery of the cancer cell nests {1055}. The occurrence of kera-tinization has been interpreted as a sign of differentiation, although the normal oesophageal squamous epithelium does not keratinize.

Poorly differentiated tumours predominantly consist of basal-type cells, which usually exhibit a high mitotic rate. Moderately differentiated carcinomas, between the well and poorly differentiated types, are the most common type, accounting for about two-thirds of all oesophageal SCC. However, since no generally accepted criteria have been identified to score the relative contribution of the different grading parameters, grading of SCC suffers from a great interobserver variation.

Undifferentiated carcinomas are defined by a lack of definite light microscopic features of differentiation. However, ultrastructural or immunohistochemical investigations may disclose features of squa-mous differentiation in a subset of light-microscopically undifferentiated carcinomas {1881}.

Fig. 1.15 Squamous cell carcinoma. A Moderately differentiated. B Well differentiated with prominent lymphoid infiltrate. C Well differentiated areas (left) contrast with immature basal-type cells of a poorly differentiated carcinoma (right).

Fig. 1.15 Squamous cell carcinoma. A Moderately differentiated. B Well differentiated with prominent lymphoid infiltrate. C Well differentiated areas (left) contrast with immature basal-type cells of a poorly differentiated carcinoma (right).

Genetic susceptibility

Familial predisposition of oesophageal cancer has been only poorly studied except in its association with focal non-epidermolytic palmoplantar keratoderma (NEPPK or tylosis) {1279, 1278, 752}. This autosomal, dominantly inherited disorder of the palmar and plantar surfaces of the skin segregates together with oesophageal cancer in three pedigrees, two of which are extensive {456, 1834, 693}. The causative locus has been designated the tylosis oesophageal cancer (TOC) gene and maps to 17q25 between the anonymous microsatellite markers D17S1839 and D17S785 {1594, 899}. The genetic defect is thought to be in a molecule involved in the physical structure of stratified squamous epithelia whereby loss of function of the gene may alter oesophageal integrity thereby making it more susceptible to environmental mutagens.

Several structural candidate genes such as envoplakin (EVPL), integrin |34 (ITGB4) and plakoglobin have been excluded as the TOC gene following integration of the genetic and physical maps of this region {1595}. The importance of this gene in a larger population than those afflicted with the familial disease is indicated by the association of the genomic region containing the TOC gene with sporadic squamous cell oesophageal carcinomas {2020, 823}, Barrett adenocarcinoma of the oesophagus {439}, and primary breast cancers {549} using loss of heterozygosity studies.

Genetics

Alterations in genes that encode regulators of the G1 to S transition of cell cycle are common in SCC. Mutation in the TP53 gene (17p13) is thought to be an early event, sometimes already detectable in intraepithelial neoplasia. The frequency and type of mutation varies from one geographic area to the other, suggesting that some TP53 mutations may occur as the result of exposure to region-specific, exogenous risk factors. However, even in SCC from Western Europe, the TP53 mutation spectrum does not show the same tobacco-associated mutations as in lung cancers {1266}. Amplification of cyclin D1 (11q13) occurs in 20-40% of SCC and is frequently detected in cancers that retain expression of the Rb protein, in agreement with the notion that these two factors cooperate within the same signalling cascade {859}. Inactivation of CDKN2A occurs essentially by homozygous deletion or de novo methylation and appears to be associated with advanced cancer. Other potentially important genetic alterations include transcriptional inactivation of the FHIT gene (fragile histidine triad, a

Chromosome 17

STS Markers

Chromosome 17

STS Markers

Fig. 1.16 Location of the tylosis oesophageal cancer gene on chromosome 17q.

presumptive tumour suppressor on 3p14) by methylation of 5' CpG islands, and deletion of the tylosis oesophageal cancer gene on 17q25 {2020, 1264}. Furthermore, analysis of clones on 3p21.3, where frequent LOH occurs in oesophageal cancer {1274}, recently led to identification of a novel gene termed DLC1(deleted in lung and oesophageal cancer-1) {365}. Although the function of the DLC1 gene remains to be clarified, RT-PCR experiments indicated that 33% of primary cancers of lung and oesophagus lacked DLC1 transcripts entirely or contained increased levels of nonfunctional DLC1 mRNA. Recent evidence suggests that LOH at a new, putative tumour suppressor locus on 5p15 may occur in a majority of SCC {1497}. Amplification of several proto-oncogenes has also been reported (HST-1, HST-2, EGFR, MYC) {1266}. How these various genetic events correlate with phenotypic

Physical Map

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment