Biomedical subjects
A K el-Naggar
Publications and source records attributed to A K el-Naggar.
Frequent loss of imprinting at the IGF2 and H19 genes in head and neck squamous carcinoma.
Genomic imprinting is an inherited epigenetic phenomenon that results in parental-origin-specific gene expression in somatic cells. Relaxation or loss of this feature in certain genes has been demonstrated in several pediatric and adult neoplasms, suggesting an association with tumorigenesis. We analysed 64 primary untreated head and neck squamous carcinoma for the loss of imprinting in the IGF2 and H19 genes to determine the implications of this alteration in the development and progression of these tumors. Forty-nine (77%) of the 64 tumors were informative for imprinting analyses of these genes. IGF2 and H19 were imprinted in all normal squamous epithelium examined. Twelve (37.5%) of 32 tumors informative for H19 and 11 (40.7%) of 27 tumors informative for IGF2 manifested loss of imprinting. Ten tumors were informative for both genes, of which four maintained the constitutional imprinting and six showed loss of imprinting at either H19 or IGF2. These data suggest that loss of imprinting at the IGF2 and H19 loci play a role in the oncogenesis of head and neck carcinoma.
Comparative cytologic and histologic study of fifteen salivary basal-cell tumors: differential diagnostic considerations.
Cytologic results of preoperative fine-needle sampling (FNS) of 15 salivary basal-cell tumors are presented, described, and compared with histologic results. Eleven of the FNAS showed individual and clusters of homogeneous basaloid cells with scanty cytoplasm, occasional peripheral palisading, and naked nuclei and were diagnosed as basal-cell adenoma. Four samples showed, in addition, three-dimensional cell clusters with mild cytonuclear atypia, occasional mitosis, and/or focal necrosis and were diagnosed as basal-cell adenocarcinoma. Basal-cell tumors must be diagnostically differentiated from adenoid cystic carcinoma and metastatic basal-cell carcinoma. Although the adenomas diagnosed by cytologic examination and four suspected carcinomas in our series were verified by histologic testing, the bland cytologic features of basal-cell adenocarcinoma may not always allow diagnosis on cytologic examination.
Limited nonrandom chromosomal aberrations in a recurrent adenoid cystic carcinoma of the parotid gland.
We present the cytogenetic, interphase fluorescence in-situ hybridization (FISH) and DNA content findings in a clinically aggressive adenoid cystic carcinoma (ADCC) of the parotid gland. The tumor manifested diploid chromosomal and DNA content by cytogenetic, interphase FISH and flow cytometry. G-banding analysis revealed inv(5)(p15.2q33) and t(6;15)(q25;q15) as the only structural alterations in all 30 metaphases examined. The limited structural abnormalities found in this recurrent lesion suggest that they may constitute a primary or early event in the development of this tumor. The involvement of 6q region in our tumor and in some of the previously reported ADCC supports the association between this region and the evolution of at least a subset of these tumors.
Cytogenetic analysis of a primary salivary gland myoepithelioma.
Myoepithelioma, a rare benign salivary gland neoplasm, is a tumor composed entirely of myoepithelial cells. Unlike pleomorphic adenoma, these tumors lack any ductal epithelial differentiation, and manifest a minor stromal element. Previous cytogenetic and molecular genetic studies have mainly investigated pleomorphic adenomas and reported recurring specific chromosomal alterations at 8q12 and 12q13-q15 regions. The cell origin of these alterations, however, remains speculative. We report the cytogenetic analysis of a parotid myoepithelioma and discuss the putative origin for the cells with cytogenetic alterations. Our analysis shows 12q12 involved in a translocation with a previously unreported partner (1q), and nonrandom del(9)(q22.1q22.3) and del(13)(q12q22). Our results indicate that the myoepithelial cell is the source of those cells with chromosomal alterations, and that myoepithelioma shares 12q alterations reported in a subset of pleomorphic adenomas.
Genetic alterations in oral squamous cell carcinoma of young adults.
The underlying molecular abnormalities associated with head and neck squamous cell carcinoma in young adults (< 40 years) are unknown. We analyzed DNA extracted from paired microdissected samples of normal squamous epithelia and invasive oral squamous cell carcinomas from 36 young adults at microsatellite loci commonly found in older patients and correlated the results with clinicopathologic parameters and outcome. Our results showed that 30 of the 36 (83%) tumors manifest loss of heterozygosity (LOH) in at least one marker. Microsatellite instability was manifested in only six tumors (< 17%). The highest incidences of alterations were noted at markers D9S168 (9p23-22), TP53 (17p13), and D17S799 (17p11) on the short arms of chromosomes 9 and 17. In general, the incidences of LOH at 3, 9 and 17p regions in young adults were similar to those found in older patients. No correlation between LOH at chromosomes 3, 9, and 17p and clinicopathologic parameters was found. Our study indicates that chromosomal regions with frequent genetic alterations involved in young adult squamous tumorigenesis are similar to those reported in older patients. Further studies of other chromosomes in this population are underway to define the novel molecular features of these tumors.
Proliferative verrucous leukoplakia and its related lesions.
Proliferative verrucous leukoplakia (PVL) is a unique type of clinical oral leukoplakia. Enigmatic in etiology, PVL behaves in a far more aggressive fashion than other forms of leukoplakia. Its aggressiveness relates not only to a high recurrence rate, but more so to a very high level of and relentless progression from a localized simple keratosis to extensive oral disease and squamous carcinomas of verrucous, or conventional squamous cell type. Diagnosis is often late in the protracted course of PVL with the disease in an advanced stage when it is especially refractory to treatment. Within the histologic spectrum that is seen in PVL, usually as a function of time, are: (1) verrucous hyperplasia (VH), a histologically defined lesion; (2) varying degrees of dysplasia; and (3) three forms of squamous cell carcinoma: verrucous, conventional and, according to some, papillary squamous cell carcinoma. Each of these are discussed both within and outside the context of PVL. VH is a forerunner of verrucous carcinoma and the transition is so consistent that the hyperplasia, once diagnosed, should be treated like verrucous carcinoma. VH is not only an oral lesion; it can occur in the upper airway (sinonasal tract and larynx) where it is not usually found within a maternal soil of PVL. Papillary squamous cell carcinoma has been a loosely defined neoplasm, more often considered a verrucal type of malignancy. It nonetheless is a distinct clinicopathologic entity, separate from verrucous carcinoma and without a predilection for the oral cavity or an association with PVL.
Diagnostic molecular pathology comes of age.
Specific and consistent chromosomal translocations, identified in several lymphoreticular, neuroectodermal, and soft tissue neoplasms, generally result in the development of novel fusion transcripts.
Advances in clinical investigations of salivary gland tumorigenesis.
Advances in molecular techniques, tumor genomics and tissue acquisition offer, new opportunities in exploring the genesis and the submicroscopic features of salivary gland neoplasms. Studies integrating these techniques and information may lead to better understanding of the histogenesis and the pathobiological heterogeneity of these tumors.
Myoepithelium in salivary and mammary neoplasms is host-friendly.
This commentary relates to ameliorative effects of myoepithelial cells in carcinomas of salivary glands and the breast as viewed not only by proliferative characteristics, but also by laboratory experiments and clinicopathologic evidence. The tumor suppressor action of myoepithelium is, in part, associated with its matrix-synthesizing and proteinase inhibitor properties. Loss of the myoepithelial phenotype yields a more aggressive carcinoma with enhanced invasive and metastatic capability.
Genetic alterations in acinic cell carcinoma of the parotid gland determined by microsatellite analysis.
We investigated, for the first time, the genetic alterations at certain chromosomal loci in 25 primary parotid acinic cell carcinomas to define the most frequently altered chromosomal regions and their association with pathologic features and DNA content analysis. Our results showed that 21 (84.0%) of the tumors had alteration in at least one of the loci tested. In general, chromosomal regions at chromosomes 4p, 5q, 6p, and 17p were more frequently altered than those on chromosomes 1p and 1q, 4q, 5p, and 6q. Certain markers at 4p15-16, 6p25-qter, and 17p11 regions showed the highest incidence of LOH, suggesting the presence of tumor suppressor genes associated with the oncogenesis of these tumors. LOH was significantly associated only with tumor grade. No apparent correlation between LOH and other clinicopathologic and DNA content characteristics was identified. Our study broadly defined the chromosomal arms and loci that may be targeted for further localization of the minimally deleted regions involved in the tumorigenesis of these tumors.
Multiple unrelated translocations in a metastatic epimyoepithelial carcinoma of the parotid gland.
We report the cytogenetic, fluorescence in-situ hybridization (FISH) and DNA flow cytometric analysis of a rare metastatic epimyoepithelial carcinoma of the parotid gland to the lung with a clinical course of 29 years. DNA content and FISH analyses of tumor and short-term culture cells showed diploid DNA content and lack of numerical chromosomal abnormalities. Immunohistochemical analysis of the short-term culture cells showed predominantly keratin positive and sparse desmin staining supporting an epithelial rather than myoepithelial origin. Cytogenetic analysis showed 46,XY karyotype with clonal translocations of t(3;22)(q13.2;q13.1), t(1;7)(q21;q22), t(8;9)(p10;p10), and t(5;6) (q35;q21). Our findings indicate that these alterations developed in a diploid stemline during tumor progression and in the epithelial component of this tumor.
Concurrent cytogenetic, interphase fluorescence in situ hybridization and DNA flow cytometric analyses of a carcinoma ex-pleomorphic adenoma of parotid gland.
We report the cytogenetic, fluorescence in situ hybridization (FISH), and DNA ploidy analyses of a high grade carcinoma ex-pleomorphic adenoma of the submandibular gland. Our overall combined analyses showed a marked DNA aneuploidy and numerical abnormalities involving all chromosomes. Cytogenetic analysis revealed a near tetraploid modal chromosomal number with tetraploid loss of chromosomes Y, 1, 6, 9, 11, 14, 15, 17, and 19-21 and hypertetraploid gain of chromosomes 7, 8, and 22. The structural abnormalities included der(1;14)(q10;q10), del(6)(q15q34), +del(6)(q15q34), +der(8) t(1;8)(q12;q12.2),der(9;19)(q10;q10),add(14)(p11.2),i(20)(q10),der(21) t(8;21)(q11.2;q22.3),+der(21)t(8;21) (q11.2;q22.3). Interphase FISH of the primary and short-term cultured cells using directly labeled pericentromeric probes for chromosomes 6-12, 17, 18, and Y resulted in alterations corresponding to the cytogenetic findings. DNA ploidy analysis of both the primary and cultured tumor cells showed a hyperdiploid stemline with DNA indices of 2.6. The results indicate that: (1) marked numerical, structural chromosomal, and DNA content abnormalities are present in this tumor; and (2) alteration at 8q and 6q regions, together with previous results, suggest an association between these events and the development and/or progression of this tumor.
Telomerase activity in cancer: a magic bullet or a mirage?
Telomerase is an important enzyme required for maintenance of chromosome ends (telomeres) during cell division. Since elevated activity of telomerase has been selectively demonstrated in a large number of human cancers, it has generated considerable excitement as a potential cancer marker, a prognostic factor, and a target of possible anticancer strategy. This article details diagnostic, prognostic, and therapeutic prospects linked to the measurement of telomerase activity and the growing complexity of its regulation and function.
Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma.
PURPOSE: Standard therapies of head and neck squamous cell carcinoma (HNSCC) often cause profound morbidity and have not significantly improved survival over the last 30 years. Preclinical studies showed that adenoviral vector delivery of the wild-type p53 gene reduced tumor growth in mouse xenograft models. Our purpose was to ascertain the safety and therapeutic potential of adenoviral (Ad)-p53 in advanced HNSCC. PATIENTS AND METHODS: Patients with incurable recurrent local or regionally metastatic HNSCC received multiple intratumoral injections of Ad-p53, either with or without tumor resection. Patients were monitored for adverse events and antiadenoviral antibodies, tumors were monitored for response and p53 expression, and body fluids were analyzed for Ad-p53. RESULTS: Tumors of 33 patients were injected with doses of up to 1 x 10(11) plaque-forming units (pfu). No dose-limiting toxicity or serious adverse events were noted. p53 expression was detected in tumor biopsies despite antibody responses after Ad-p53 injections. Clinical efficacy could be evaluated in 17 patients with nonresectable tumors: two patients showed objective tumor regressions of greater than 50%, six patients showed stable disease for up to 3.5 months, and nine patients showed progressive disease. One resectable patient was considered a complete pathologic response. Ad-p53 was detected in blood and urine in a dose-dependent fashion, and in sputum. CONCLUSION: Patients were safely injected intratumorally with Ad-p53. Objective antitumor activity was detected in several patients. The infectious Ad-p53 in body fluids was asymptomatic, and suggests that systemic or regional treatment may be tolerable. These results suggest the further investigation of Ad-p53 as a therapeutic agent for patients with HNSCC.
Leukoplakia: still a gallimaufry or is progress being made?--A review.
Leukoplakia as a medical term has been encumbered by a hodgepodge of synonyms and interpretations. It also has been a term associated with strong emotions with respect to an implied malignant potential. It now is regarded as potentially malignant, with varying degrees of risk for transformation. Leukoplakia at its major anatomic site of occurrence, the oral cavity, recently has been redefined, classified, and staged as a preamble to a more rational approach to the clinicopathologic study of leukoplakia. These changes are presented, as are current assessments of proliferative verrucous leukoplakia, verrucous hyperplasia, palatal white lesions, effects of smokeless tobacco on the oral mucosa, hairy leukoplakia, and lichen planus.
Postoperative radiotherapy for malignant tumors of the parotid gland.
PURPOSE: To update our experience using postoperative irradiation in selected patients with carcinomas of the parotid gland. Outcomes of treatment with a focus on the effectiveness of the two primary techniques of radiation used for treating these tumors were evaluated. METHODS AND MATERIALS: A retrospective analysis of 166 patients with parotid gland malignancies treated in the Department of Radiotherapy at the University of Texas M. D. Anderson Cancer Center between 1965-1989 was performed. All patients were treated following surgery and did not have macroscopic disease at the time of their radiation. The most common histologies were mucoepidermoid carcinoma (28%) and adenocarcinoma (27%). Pathologic features constituting indications for postoperative radiotherapy included: inadequate margins, 104 (63%) cases; extraglandular disease extension, 82 (49%); perineural invasion 57 (34%); and nodal disease 43 (26%). Radiation was delivered through an ipsilateral field of predominantly high energy electrons in 142 patients (86%). Wedged paired 60Co fields were used to treat 19 patients. The median dose was 60 Gy, typically delivered at 2 Gy per fraction. The median follow-up time for surviving patients was 155 months. RESULTS: Forty-seven (29%) patients had disease recurrence, of whom 15 (9%) had disease recur locally and 10 (6%) regionally (neck). There was no association between the dose of radiation and local failure, except for a trend for patients with positive margins and/or named nerve involvement to have improved local control if they received doses > 60 Gy. There was no difference in failure rates in patients treated with wedged pair techniques or ipsilateral fields, but there was a higher complication rate in the former. Overall, 37 patients (22%) developed chronic sequelae attributed to radiation. Twelve patients developed decreased hearing, and 15 patients developed soft tissue or bone necrosis or exposure. CONCLUSIONS: Local and regional control rates for high risk patients with parotid gland carcinomas treated with radiation following surgery were excellent. The technique of using an ipsilateral field encompassing the parotid bed and treated with high energy electrons often mixed with photons was effective with minimal severe late toxicity. The moderate complication rate experienced in this series can be further reduced using modern techniques as described.
Pelvic exenteration for locally advanced rectal carcinoma: factors predicting improved survival.
BACKGROUND: The purpose of this retrospective review was to determine whether a number of clinicopathologic factors (age, gender, type of exenteration, tumor extent, adjuvant therapy, tumor DNA ploidy, and S-phase fraction) that could be determined before operation were useful in predicting survival in patients undergoing pelvic exenteration for rectal cancer. METHODS: Between 1983 and 1992, 40 patients (15 male and 25 female) at our institution underwent pelvic exenteration for rectal adenocarcinoma in which tumor-free pathologic margins were obtained. Twenty-nine patients presented with primary tumors; 11 had recurrent disease. A total exenteration was performed in 20 patients, posterior exenteration in 18 patients, and an anterior exenteration in 2 patients. RESULTS: By multivariate (Cox proportional hazards regression) analysis, age, preoperative chemoradiation therapy, and an S phase of 10% or greater were found to be significant predictors of survival. Age older than 55 years was associated with a relative risk for cancer-related death (RR) of 0.13 (p = 0.02), and chemoradiation had an RR of 0.05 (p = 0.01), indicating their beneficial effect. An S-phase fraction of 10% or greater had an RR of 16.97 (p = 0.03), indicating a poor survival. The clinicopathologic factors listed above were used to derive a prognostic index (PI). A PI of less than 1.37 was associated with a 5-year survival rate of 65% (low risk), whereas patients with a PI of 1.37 or greater had a 5-year survival rate of 20% (high risk) (p = 0.005). CONCLUSIONS: These results indicate that adjuvant chemoradiation may significantly improve survival in patients who require pelvic exenteration for resection of locally advanced rectal carcinoma. An S-phase fraction of 10% or greater is also predictive of a poor outcome. Use of these factors allowed the generation of a PI that identifies high- and low-risk patients. Consideration of the ability to deliver chemoradiation and the determinates of the tumor S-phase fraction in patients requiring pelvic exenteration for rectal cancer may be helpful in predicting outcome and planning therapy.