Squamous cell cancer

Identity

ICD-Morpho	8070/3 Squamous cell carcinoma, NOS
Atlas_Id	5130
Phylum	Lung, Heart, Skin, Other::Squamous cell cancer

Clinics and Pathology

Disease	Squamous cell carcinoma (SCC) accounts for the majority of non-small cell lung cancer, other bronchial tree cancers, and cancers arising throughout the upper aerodigestive tract including the oral cavity, paranasal sinuses, pharynx, larynx, trachea, and esophagus. SCC is the second most common skin cancer. SCC arises at many other sites such as salivary gland, esophagus, bladder, penis, and the female genital tract.
Etiology	Environmental exposures such as tobacco, alcohol, chronic mucosal irritation, certain human papilloma viruses, actinic or low dose radiation, and some occupational chemical exposures increase the risk of developing SCC. The DNA of HPV 16,18, and 31 have been found in human genital cancers and HPV 16 and 18 have been recognized in verrucous carcinomas of the larynx and SCC of the tongue and tonsil. Epstein Barr virus (EBV) is a risk factor for nasopharyngeal SCC in southern China and the Aleutians. Sunlight exposure is the major causal factor in SCC of the skin. In the East and Far East, oral cavity and oropharyngeal cancers account for almost one-half of all cancers. In Bombay, 50% of all cancers are in the buccal mucosa, and is associated with chewing pan. Specific TP53 mutations are associated with tobacco exposure. Deletions and allelic losses of 9p are more common in smoking-associated SCC.
Epidemiology	There is strong evidence that SCC has a genetic basis. For families with smoking-related malignancies, genetic segregation analysis showed strong evidence favoring an autosomal dominant pattern of inheritance for predisposition to malignancy. Some individuals with SCC appear to have a heritable sensitivity to chromosome breakage by certain clastogens. Of mendelian diseases, xeroderma pigmentosum and Bloom syndrome carry a significant risk of skin SCC. Nasopharyngeal carcinomas are 25 times more frequent in Kwang Tung Province, China than in whites with certain HLA haplotypes and familial clustering being identified. Chinese who emigrated from Kwang Tung retain a significantly higher risk of developing nasopharyngeal carcinoma.
Pathology	Histologic grading (tumor, node, metastasis, TNM) and evaluation of tumor thickness have been used to predict survival and to develop algorithms for further treatment. The tissues surrounding an SCC often exhibit genetic damage and premalignant lesions, perhaps secondary to the same carcinogens, and this entire cancerization field appears to be at risk for second primary cancers. DNA content and ploidy are correlated with tumor aggressiveness and responsiveness to some treatments. Abnormal DNA content has been thought to reflect altered proliferation capacity of tumor cells and has been associated with adverse biologic and clinical behavior. Although most studies suggest worse prognosis and more aggressive behavior in aneuploid tumors, these findings are not universal. At some anatomic sites, aneuploid tumors have a better prognosis, and improved response with advanced differentiation.
Treatment	Treatments have resulted in modest improvements in survival in recent years. For head and neck SCC, standardized with traditional therapies relying on surgery, radiation therapy, or combined surgery-radiation therapy treatments. Recent efforts in new treatment strategies have revolved around adjuvant or concomitant chemotherapy. For most skin SCC, surgical excision is standard practice.
Prognosis	largely depends on pathological stage at diagnosis, which in turn depends to a great extent on the anatomic site. For example, skin SCC and larynx SCC have a relatively favorable prognosis because they are frequently identified at an early stage. SCC of the nasopharyngeal area is less often detected early, and the rich blood supply and lymphatic anatomy of the nasopaharynx encourages early metastatic disease and a generally less favorable prognosis.

Cytogenetics

Note	The karyotype is typically very complex, but common features in SCC at one anatomic site are often very similar to SCC at other anatomic sites, irrespective of the initiating events (tobacco and alcohol, pan, human papilloma virus, etc.). These common changes strongly suggest that initiation, development, and progression of squamous epithelial neoplasia are controlled by some of the same genetic pathways, irrespective of anatomic site.
Cytogenetics Morphological	Most early cytogenetic studies of SCCHN relied on analysis of later stage tumors and established cell lines. More recent studies included short term cell cultures, and by-and-large the results have been similar. A common sequence of SCC karyotype evolution appears to be initial loss of chromosomes or segments, followed by tetraploidization, and ultimately loss of previously uninvolved chromosomes from the tetraploid population. The hypotetraploid cell population can have a near triploid or even lower DNA index and number of chromosomes. Many tumors exhibit both diploid and tetraploid cell subclones. As with high DNA content, polyploidy is associated with a more aggressive growth pattern in vitro, high histopathologic grade, and poor survival. Earlier stage tumors tend to have more simple karyotypes. However, within every pathological stage some tumors have more complex karyotypes. It has been difficult to assemble a typical cascade of genetic evolution that has broad applicability in SCC, because most of the recurrent abnormalities have been observed at every histopathologic stage. Nevertheless, some recurrent cytogenetic changes tend to arise earlier in tumor development, and others tend to confer greater prognostic importance. Common early changes in head and neck SCC include 9p and 3p deletion, and 17p mutation, with 5q, 8p, 18q, 21q loss and 11q gain arising later and involved in disease progression. Few specific rearrangements or breakpoints have been documented, and most of those are typically associated with the recurrent gains and losses of chromosome segments. Unbalanced translocations involving bands 1p11-p12, 5q13, 10p11.2, 18q11.2, 11q13, and 7q11.2 were typically associated with deletions. Likewise, isochromosomes 3q, 5p, 7p, 8q, and 9p are typically associated with duplication of the arm involved in the isochromosome, and deletion of the other arm 81. Deletions involving 3p suggest at least three distinct targets of loss. The most universal class of cytogenetic change is deletion, also observed as loss of heterozygosity (LOH) in molecular genetic studies. Loss of segments of 3p, 5q, 8p, 9p, 10p, and 18q are among the most common. The most frequent loss involved 3p. SCC exhibit recurrent gain of segments within 3q, 5p, 7p, 8q, distal 1q, and 11q13-q23. Duplication 11q13-q23 and an apparent homogeneously staining region (hsr) at 11q13 or 11q21 is relatively common. An hsr with amplification of PRAD1/CCND1 can be located in 11q or elsewhere.
Cytogenetics Molecular	FISH analysis of SCC in vivo (from histologic sections) has helped show that the karyotypes observed in established cell lines accurate reflects that of the tumor. FISH has also shown that many apparently independent primary tumors are monoclonal. Comparative genomic hybridization (CGH) studies have generally paralleled classical cytogenetics, although several important differences in findings between the two techniques remain an area of interest.

Genes involved and Proteins

Note

Studies at the molecular level have helped to clarify some of the cytogenetic observations of recurrent gain and loss of specific segments. Allelotype studies, and similar cytogenetic studies, have described a poorer prognosis as genetic losses accumulate. As with cytogenetic studies, allelotype results are fairly similar across anatomic sites, and are even similar to those of adenocarcinomas of the lung. Some genetic abnormalities have been recognized by microsatellite studies that were not common changes in classical cytogenetic studies (e.g., 4q and 15q deletions and 3q amplification). Mismatch repair gene mutations play a negligible role in the etiology and evolution of SCC. Microsatellite instability has been reported, but does not appear to be a major factor in most SCC.

Location

Chromosome arm 3p

Somatic mutation

The most frequent autosomal abnormality is loss of 3p (50-75% of tumors). It appears very early, e.g. in bronchial and esophageal epithelial dysplasias. Isochromosome 3q usually associated with loss of 3p. Other deletions reveal three independent regions of loss at 3p14 ( FHIT/FRA3B), 3p21, and 3p24-p45. Specific targets at 3p21 remain elusive but DCL1 is a candidate. The VHL (von Hipple Lindau) locus may be the target of 3p24-p25 deletion.

Location	Chromosome arm 3q
Somatic mutation	Duplication 3q is often associated with isochromosome formation and there is almost always 3p loss in the same tumor. CGH studies suggest one or more regions of amplification within 3q, and p63, a p53 homolog, is a possible target of gain at 3q27-3q29.

Location	Chromosome arm 5q
Somatic mutation	5q12-q31 deletion is very common, and appears associated with an unfavorable prognosis. Target candidate genes include MCC and APC at 5q21, and the a-catenin locus at 5q31. In esophageal cancer, reduced expression of ·-catenin and E-cadherin have been associated with tumor dedifferentiation, infiltration, and lymph node metastasis.

Location	Chromosome arm 7p
Somatic mutation	Frequent gains of 7p may permit increased activity of EGFR, which is amplified in some SCC. Amplification is associated with lymph node involvement in esophageal SCC.

Location	Chromosome arm 8p
Somatic mutation	Distal 8p loss is a recurrent abnormality, and may target different genes in 8p21, 8p22-p23, and 8p23. FEZ1, a transcription factor residing at 8p22, may be one genetic target for deletion. In lung SCC, 8p deletion is an intermediate event, following after 3p and 9p deletion.

Location	Chromosome arm 9p
Somatic mutation	Loss of 9p is a common and usually early event. The tumor suppressor gene p16/CDKN2/MTS1 at 9p22 is the most likely primary target of deletions. Homozygous deletions and promoter methylation have been identified. In cervical SCC, 9p deletion is associated with lymph node metastasis.

Location	Chromosome arm 10p
Somatic mutation	Loss of 10p has been observed in many SCC.

Location	Chromosome arm 11q
Somatic mutation	The region 11q13-23, commonly duplicated or amplified, includes several probable target genes: HST1, INT2, PRAD1/CCND1, and EMS1. PRAD1/CCND1 and EMS1 are often amplified and over expressed. PRAD1/CCND1 over-expression may be associated with radiosensitivity. An 11q duplication is associated with lower survival in esophageal SCC and disease progression in SCCHN.

Location	Chromosome arm 13q
Somatic mutation	Loss is associated with lymph node metastasis in esophageal SCC. RB1 or BRCA2 may or may not be the target.

Location	Chromosome arm 16q
Somatic mutation	16q deletion is a less common but recurrent finding in SCC at several anatomic sites. E-cadherin is one candidate target.

Location

Chromosome arm 17p

Somatic mutation

TP53 gene mutations are initiating or very early events in SCC regardless of anatomic site, already evident in premalignant lesions and are not usually correlated with tumor aggressiveness or survival. Deletion of 17p is very common and may frequently serve to inactivate the remaining normal homolog in a tumor with a TP53 mutation. In cervical SCC, 17p loss appears to be a late event correlated tumor invasion. The specific mutations are directed by the mutagen involved, e.g, smoking and alcohol in larynx, betel nut in buccal mucosa, and human papilloma virus in vulvar SCC.

Location	Chromosome arm 18q
Somatic mutation	Loss of 18q, specifically 18q21-q22, is a very poor prognostic indicator in SCC at many sites, including the head and neck and the female genital tract. The primary target of loss in SCC is unknown, but probably exclude Smad2, Smad4, and DCC.

Location	Chromosome arm 21q
Somatic mutation	Monosomy 21 is common. Uncommon 21q deletions point to a ubiquitin-specific protease gene as the possible target.

Location	X and Y chromosomes
Somatic mutation	Y loss is observed in about 50% of SCC of males, and loss of the short arm of the inactivated X is common in SCC of females.

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Citation

This paper should be referenced as such :

Van Dyke, DL

Squamous cell cancer

Atlas Genet Cytogenet Oncol Haematol. 2002;6(1):43-46.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/SquamousCellID5130.html

Other genes implicated (Data extracted from papers in the Atlas) [ 5 ]

Genes

BAG1

CCNA1

RAF1

RELA

SEMA4D

External links

arrayMap	arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Disease database	Squamous cell cancer

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed

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