Stromal control of oncogenic traits expressed in response to the overexpression of GLI2, a pleiotropic oncogene.

Hedgehog signaling is often activated in tumors, yet it remains unclear how GLI2, a transcription factor activated by this pathway, acts as an oncogene. We show that GLI2 is a pleiotropic oncogene. The overexpression induces genomic instability and blocks differentiation, likely mediated in part by enhanced expression of the stem cell gene SOX2. GLI2 also induces transforming growth factor (TGF)B1-dependent transdifferentiation of foreskin and tongue, but not gingival fibroblasts into myofibroblasts, creating an environment permissive for invasion by keratinocytes, which are in various stages of differentiation having downregulated GLI2. Thus, upregulated GLI2 expression is sufficient to induce a number of the acquired characteristics of tumor cells; however, the stroma, in a tissue-specific manner, determines whether certain GLI2 oncogenic traits are expressed.

Molecular biology of squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (HNSCC) is a heterogeneous but largely preventable disease with complex molecular abnormalities. It arises from a premalignant progenitor followed by outgrowth of clonal populations associated with cumulative genetic alterations and phenotypic progression to invasive malignancy. These genetic alterations result in inactivation of multiple tumour suppressor genes and activation of proto-oncogenes, including p16(ink4A), p53, cyclin D1, p14(ARF), FHIT, RASSF1A, epidermal growth factor receptor (EGFR), and Rb. Intramucosal migration and clonal expansion of transformed cells with formation of abnormal genetic fields appear to be responsible for local recurrences and development of second primary tumours.

Expression of mismatch repair proteins, beta catenin, and E cadherin in intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Despite their histological resemblance to colorectal adenocarcinomas, there is little information about the molecular events involved in the pathogenesis of intestinal-type sinonasal adenocarcinomas (ITACs). AIMS: To evaluate the possible role of DNA mismatch repair (MMR) gene defects or disruptions of the E cadherin-beta catenin complex in ITAC by investigating the immunohistochemical expression of the MMR gene products, beta catenin, and E cadherin in a group of sporadic ITACs. METHODS: Ten sporadic cases of ITAC were stained with antibodies against MLH1, MSH2, MSH3, MSH6, beta catenin, and E cadherin. RESULTS: Nine cases showed strong nuclear expression of MLH1, whereas one case showed moderate staining. All 10 cases were strongly positive for MSH2 and MSH3. MSH6 was strong in nine cases, and moderate in one. Membranous beta catenin expression was strong in all 10 cases, and no case showed cytoplasmic or nuclear staining. E cadherin was strong in seven cases, and moderate in three cases. CONCLUSIONS: The preserved nuclear expression of MLH1, MSH2, MSH3, and MSH6 suggests that mutations or promoter methylation of MMR genes do not play a role in the pathogenesis of ITAC. The strong membranous staining for E cadherin and beta catenin and lack of abnormal cytoplasmic or nuclear expression is in keeping with the preservation of E cadherin-beta catenin complexes and beta catenin pathways.

Expression pattern of CK7, CK20, CDX-2, and villin in intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is an uncommon neoplasm, which resembles adenocarcinoma of the gastrointestinal tract. ITAC occurs sporadically or in association with occupational exposure to hardwood dust and other agents. AIMS: To investigate the phenotype and possible pathogenetic mechanisms of primary sinonasal and nasopharyngeal adenocarcinomas by staining for cytokeratin 7 (CK7), CK20, CDX-2, and villin. METHODS: Twelve sporadic sinonasal and nasopharyngeal adenocarcinomas were stained with monoclonal antibodies to CK7, CK20, CDX-2, and villin. The ITACs were classified as papillary, colonic, solid, mixed, or mucinous types. RESULTS: The diagnosis of ITAC was confirmed in 10 cases: five were colonic type and five were papillary. One was a sinonasal papillary low grade adenocarcinoma, and one a papillary nasopharyngeal adenocarcinoma, and these tumours were CK7 positive, but CK20, CDX-2, and villin negative. All ITACs were positive for CK20, CDX-2, and villin, and six were CK7 positive. One ITAC had a focus of intestinal metaplasia away from the invasive carcinoma. CONCLUSIONS: Sinonasal ITACs have a distinctive phenotype, with all cases expressing CK20, CDX-2, and villin. Most ITACs also express CK7, although a proportion of tumours are CK7 negative. ITAC seems to be preceded by intestinal metaplasia of the respiratory mucosa, which is accompanied by a switch to an intestinal phenotype. Although ITACs are morphologically similar, differences in cytokeratin expression patterns suggest two distinct types. The expression pattern of CK7, CK20, CDX-2, and villin positive may be useful in separating these tumours from other non-ITAC adenocarcinomas of the sinonasal tract and nasopharynx.

Marsupialization as a definitive treatment for the odontogenic keratocyst.

PURPOSE: We sought to show that marsupialization can be a definitive treatment for the odontogenic keratocyst (OKC). MATERIALS AND METHODS: Ten patients (10 males and 4 females) between the ages of 11 and 64 with biopsy-proven OKC (8 mandibular and 2 maxillary) measuring between 2 and 8 cm were treated by marsupialization consisting of excision of the overlying mucosa and the opening of a 1-cm window into the cystic cavity and, where possible, suturing of the cyst lining to the oral mucosa. Immunohistologic determination of bcl-2 was done for all samples of cyst lining. The cavities were kept open either by vigorous use of a home syringe by the patient or by suturing into place the flange and short length of a nasopharyngeal airway. Once the cyst had largely filled in, histologic material was taken from the base of the residual depression and studied by light microscopy and bcl-2 expression. RESULTS: In the 10 patients, the OKCs completely resolved both clinically and radiographically. The time taken for resolution varied from 7 to 19 months. In all cases, the histologic material obtained after marsupialization showed normal epithelium only, with no signs of cystic remnants, daughter cysts, or budding of the basal layer of the epithelium. At initial biopsy, bcl-2 was expressed in the keratocyst lining, but not in the histologic material obtained after marsupialization. Follow-up time ranged from a minimum of 1.8 years to a maximum of 4.8 years. Teeth at the periphery of the cysts were observed to upright and erupt. CONCLUSIONS: All 10 OKCs resolved completely after marsupialization. Teeth within the cyst were found to be upright and erupt. Marsupialization requires a cooperative patient who will irrigate the cavity and keep it open. It appears that the cyst lining is replaced by normal epithelium during this treatment.

Observer agreement in the grading of oral epithelial dysplasia.

OBJECTIVES: To determine the extent of observer agreement in diagnosis of oral epithelial dysplasia (OED). Published studies of OED examiner agreement report relatively low agreement levels; however, these studies were limited by the methodologies employed. METHODS: For this study, 64 slides were each independently examined twice by three oral pathologists. Consistency was assessed by determining intra- and interexaminer agreement. Conformity was assessed by using the modal diagnosis as a gold standard. RESULTS: The group showed moderate interobserver agreement when grading the presence or absence of OED with a group-simple kappa (Ks) of 0.51 (95% CI = 0.42-0.61), and substantial agreement when using a 5-point ordinal scale with a group-weighted kappa (Kw) of 0.74 (95% CI = 0.64-0.85). The group showed fair to substantial intraexaminer agreement when assessing the presence or absence of OED, with Ks ranging from 0.22 to 0.78, and showing almost a perfect agreement using a 5-point ordinal scale, with Kw ranging from 0.82-0.96. Conformity with the comparison standard modal diagnosis was almost perfect, with pairwise Kw ranging from 0.81 to 0.92. CONCLUSION: Overall, there was substantial intra- and interobserver consistency and almost perfect conformity in the grading of OED. Appropriate statistical methods are necessary to determine the degree of observer agreement.

Lingual nerve damage due to inferior alveolar nerve blocks: a possible explanation.

BACKGROUND: An explanation for the predominance of injuries to lingual nerves over those to inferior alveolar nerves as a result of inferior alveolar nerve blocks may be due to the nerves' fascicular pattern. A unifascicular nerve may be injured more easily than a multifascicular nerve. METHODS: The authors unilaterally dissected lingual and inferior alveolar nerves from 12 cadavers. They cut the specimens 2 millimeters above the lingula for both the lingual nerve and inferior alveolar nerve and opposite the site of the middle of the third molar for the lingual nerve, and they counted the number of fascicles at each site. RESULTS: For the lingual nerve at the lingula, the mean number of fascicles was three (range, one to eight). Four of the 12 nerves (33 percent) were unifascicular at this point. Opposite the third molar, the lingual nerve had a mean of 20 fascicles (range, six to 39). In every case, there were more fascicles in the third molar region than above the lingula in the same nerve. At the lingula, the inferior alveolar nerve had a mean of 7.2 fascicles (range, three to 14). CONCLUSION: This study may explain the observation that when an inferior alveolar nerve block causes permanent nerve impairment, the lingual nerve is affected about 70 percent of the time and the inferior alveolar nerve is affected only 30 percent of the time. In 33 percent of cases, the lingual nerve had only one fascicle at the lingula; a unifascicular nerve may be injured more easily than a multifascicular one. CLINICAL IMPLICATIONS: There is no known way to avoid the remote possibility of nerve damage resulting from an inferior alveolar nerve block. The lingual nerve may be predominantly affected because of its fascicular pattern.