Molecular and biomarker analyses of salivary duct carcinomas: comparison with mammary duct carcinoma.

Salivary duct carcinoma (SDC) is a rare high-grade aggressive neoplasm that manifests close histologic features with invasive ductal carcinoma of the breast (IDC). In contrast to SDC, extensive molecular studies have been performed on IDC and led to the identification of certain biological markers. To investigate the underlying molecular and biologic characteristics of SDC, we performed molecular analyses using microsatellite markers on chromosomal arms 6q, 16q, 17p, and 17q, DNA flow cytometry and immunohistochemical staining for androgen receptor (AR) and p53 expression on 28 examples of these tumors in comparison to 24 IDC cases. Our results show that generally similar allelic alterations, elevated p53 and androgen receptor expressions, and high frequency of DNA aneuploidy are manifested in both SDCs and IDCs. Differences at certain markers on 6q, 17p and 17q chromosomal loci, however, were observed between the two entities. Certain loci on 6q were more frequently altered in SDC than IDC which loci on chromosomes 17p and q arms were more seen in IDCs than SDCs. The majority of SDCs had high AR expression while most of IDCs were AR negative. Our study indicates that: i) SDC may share some genetic alterations with IDC, ii) high AR expression in SDC may play a role in tumor progression, and iii) p53 overexpression and DNA aneuploidy in both entities reflect their aggressive behavior.

Phase I/II trial of radiation with chemotherapy "boost" for advanced squamous cell carcinomas of the head and neck: toxicities and responses.

PURPOSE: Extrapolating from our experience delivering a "boost" field of radiation concurrently with fields treating both gross and subclinical disease at the end of a course of radiation therapy, we developed a regimen to deliver concurrent chemotherapy during the last 2 weeks of a conventionally fractionated course of radiation. PATIENTS AND METHODS: Patients had stage III or IV biopsy-proven squamous cell carcinoma originating from a head and neck mucosal site. The regimen was 70 Gy delivered over 7 weeks with concurrent fluorouracil (5-FU) and cisplatin given daily with each radiation dose during the last 2 weeks. A phase I study was performed to determine the maximum-tolerated dose (MTD) before a phase II study was conducted. RESULTS: The MTD was 400 mg/m(2) per day for 5-FU and 10 mg/m(2) per day for cisplatin. Mucositis persisting more than 6 weeks after therapy was the dose-limiting toxicity. A total of 60 patients were treated on the two phases of the study. Eighteen patients (35%) treated at the MTD developed prolonged mucositis. There were two cases of neutropenic sepsis, including one fatality. The actuarial 2-year rates for overall survival, freedom from relapse, and local control were 62%, 59%, and 80%, respectively. CONCLUSION: Preliminary locoregional control rates seem to be higher than those reported for treatment with radiation alone. Toxicity was also greater than that seen with radiation alone, but the regimen was designed to deliver an intense treatment schedule, which could be completed without significant interruptions, and to obtain high control rates above the clavicles. These end points were achieved.

Antibiotic prophylaxis in head and neck oncologic surgery: the role of gram-negative coverage.

Many studies have elucidated the risk factors associated with peri-operative infection following head and neck cancer surgery (HNS), the implications of infection for total treatment cost, and the clinical benefits of successful antimicrobial prophylaxis. The most appropriate antibiotic use is achieved by focusing on patients with clean, contaminated wounds. Thereafter, the usefulness of an antibiotic agent depends on its antimicrobial spectrum, tolerability profile, and cost. Successful antimicrobial prophylaxis requires antimicrobial activity against gram-positive, gram-negative, and anaerobic organisms. The beta-lactam/beta-lactamase inhibitor combination, sulbactam-ampicillin, has just such an antimicrobial spectrum. A double-blind, randomized clinical trial, involving patients undergoing HNS, recorded a lower post-operative infection rate among patients receiving peri-operative sulbactam-ampicillin 0.5 g/1.0 g i.v. q6h compared with those receiving clindamycin 600 mg i.v. q6h (13.3 vs. 27.1%; P = 0.02). Culture of strains from infected individuals indicated a significantly lower proportion of gram-negative organisms for sulbactam-ampicillin than for clindamycin (32 vs. 81%; P < 0.05). There was a significant difference in the median duration of surgery between infected and non-infected individuals (8.5 vs. 5.9 h; P < 0.0001). These data support the use of sulbactam-ampicillin to reduce the incidence of post-operative infection following HNS.

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.

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.

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.

Phase II trial of paclitaxel, ifosfamide, and cisplatin in patients with recurrent head and neck squamous cell carcinoma.

PURPOSE: To assess the activity and toxicity profile of combined taxol (paclitaxel), ifosfamide, and platinum (cisplatin) (TIP) in patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. PATIENTS AND METHODS: Recurrent or metastatic head and neck SCC patients received paclitaxel 175 mg/m2 in a 3-hour infusion on day 1; ifosfamide 1,000 mg/m2 in a 2-hour infusion on days 1 through 3; mesna 600 mg/m2 on days 1 through 3; and cisplatin 60 mg/m2 on day 1, repeated every 3 to 4 weeks. All were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic hematopoietic growth factors were not permitted. RESULTS: Fifty-two patients were assessable for response and toxicity; 53 for survival (local-regional recurrence alone in 57% and distant metastasis with or without local-regional recurrence in 43%). Overall response rate was 58% (30 of 52) of patients; complete response rate was 17% (nine of 52) of patients, with six complete responses that continued for a median 15.7+ months. Median follow-up of all patients was 17.7 months. Median survival was 8.8 months (95% confidence interval [CI] 8.1 to 17.5 months). Toxicity was relatively well tolerated and caused no deaths. The most frequent moderate-to-severe toxicity (90% of patients) was transient grades 3 to 4 neutropenia; neutropenic fever occurred in 27%. Grade 3 peripheral neuropathy occurred in three patients, none had grade 4. Grade 3 mucositis occurred in only one patient, none had grade 4. CONCLUSION: TIP had major activity in this setting, with a 58% objective response rate, 17% complete response rate, durable complete responses (six of nine persisting), and relatively well-tolerated toxicity, with no toxic deaths. The activity of TIP, a novel taxol-cisplatin-based regimen, in recurrent or metastatic head and neck SCC should be confirmed in a phase III trial.

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.

Changing concepts in the pathogenesis and management of thyroid carcinoma.

A wealth of knowledge regarding the molecular causation of thyroid carcinoma has been accumulated over the past five years. This information has already had a significant impact on the management of some forms of thyroid carcinoma. The challenge during the next 10 years will be to incorporate newly acquired information into diagnostic and therapeutic approaches to thyroid carcinoma and to coordinate use of this information with time-tested approaches to further decrease morbidity and mortality from thyroid carcinoma.

Juvenile nasopharyngeal angiofibroma: an update of therapeutic management.

BACKGROUND: Juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor of the nasopharynx composed of fibrous connective tissue and an abundance of endothelium-lined vascular spaces. The name of the disease is derived from the fact that it occurs during adolescence, almost exclusively in boys. METHODS: This study examines the natural characteristics of JNA, the imaging techniques used to diagnose and stage the neoplasm, and the treatment approaches used to manage the disease. RESULTS: Forty-three cases of JNA diagnosed and treated at the University of Texas M. D. Anderson Cancer Center over a 38-year period were reviewed for the study. The cases were divided into two groups, those occurring between 1955 and 1974 and those occurring between 1975 and 1991, to accurately represent the developments in diagnostic and treatment methodology during those time periods. CONCLUSION: The results of our study show that: (1) the imaging techniques used after 1965 (angiography, computed tomography, and magnetic resonance imaging) greatly improve the staging of JNA; (2) morbidity, recurrence, and intraoperative complications decrease when preoperative embolization and skull-based surgical approaches are used; and (3) surgical resection is the most common primary treatment, with chemotherapy and radiotherapy recommended as possible other options.

Head and neck cancer. The problem.

Advanced carcinomas that involve the head and neck present a major therapeutic challenge because of their poor prognosis, the frequently associated medical problems of the patients, and the adverse effect of treatment on oral and pharyngeal function. Collaboration and communication of multidisciplinary teams have had a profound effect on the treatment of head and neck cancer.

Extracranial, extraspinal meningiomas of the head and neck.

The head and neck is the most frequent location for extraneuraxial meningiomas, be they wholly extracranial or extraspinal or extensions of central nervous system meningiomas. Regardless of anatomic site of origin, nearly all meningiomas arise from meningocytes of arachnoid granulations. Ectopic arachnoid cell clusters have a predilection for areas of dural penetration of cranial nerves, and it is in these areas that most extracranial meningiomas are found. Surgical excision is the mainstay of treatment and must be planned by radiologic studies to determine the extent of the tumor and the presence or absence of a companion central nervous system meningioma. The often locally invasive and aggressive behavior of the meningiomas belies their benign histologic appearance.

Carcinomas of the lacrimal drainage system.

Primary carcinomas of the lacrimal drainage system are rare. These malignant neoplasms typically present as noncompressible, nontender masses with low-grade dacyrocystitis and/or unilateral epiphora. Lymph node metastasis may occur late in the disease course. Complete surgical resection is the best treatment choice; extensive procedures such as orbital exenteration and maxillectomy may be necessary for complete tumor extirpation. Further adjunctive radiotherapy may improve local control. We present two cases of carcinoma of the lacrimal drainage system, including one locally controlled tumor with apparent lymph node metastasis that occurred 21 years after primary treatment. A review of the histopathology and literature concerning carcinomas of the lacrimal drainage system is presented.

Predicting occult lymph node metastasis in parotid cancer.

To determine the factors predictive of occult cervical metastases, we retrospectively reviewed the charts of 99 previously untreated patients with a primary parotid malignancy who underwent elective neck dissection between 1960 and 1985. Univariate and multivariate analyses were performed to determine the predictive value of 11 factors. The univariate study found facial nerve paralysis, extraparotid extension, and perilymphatic invasion statistically significant. In the multivariate analysis of preoperative factors, facial nerve paralysis was most predictive of occult disease. If the variable pool was expanded to include a fine-needle biopsy, tumor grade became the most important preoperative variable. When the analysis was further expanded to include a parotidectomy, the most influential factors were patient age, perilymphatic invasion, and extraparotid tumor extension. This report identifies the variables predictive of occult neck disease in parotid cancer.

Intrinsic radiosensitivity of normal human fibroblasts and lymphocytes after high- and low-dose-rate irradiation.

The existence of heritable radiosensitivity syndromes and clinical observations in radiotherapy patients suggests that human cellular radiosensitivity differs among individuals. We report here an in vitro study of radiosensitivity in 30 fibroblast and 29 lymphocyte cultures obtained from cancer patients and controls. In 25 cases, both fibroblasts and lymphocytes were obtained from the same donors. Fibroblasts were cultured from skin biopsy samples, and peripheral T-cell lymphocytes were cultured from blood. Clonogenic survival assays were performed by using high- and low-dose-rate irradiation; lymphocytes were in G0 phase and fibroblasts in confluent plateau phase. Various end points were calculated and compared (i.e., surviving fraction at 2 Gy, initial slope of the survival curve, and doses resulting in 10 and 1% survival, respectively). Depending on the end point, the coefficient of variation of the survival parameters ranged from 31 to 68% for lymphocytes and 21 to 41% for fibroblasts following high-dose-rate irradiation. Similar ranges were obtained after low-dose-rate irradiation. Variance analysis performed on replicate assays in cultures derived from the same patient showed that variation due to technical or sampling errors was significantly lower than variation between individuals (P = 0.00034 and 0.014 for fibroblasts and lymphocytes, respectively). No correlation was observed between the radiosensitivity of lymphocyte and fibroblast cultures derived from the same donors. We conclude that there is significant variation in normal cell radiosensitivity among individuals. On the other hand, comparisons of lymphocyte and fibroblast radiosensitivities suggest that tissue-specific characteristics, such as differentiation status, may variably modulate radiosensitivity.

Salivary gland neoplasms in children.

Of 29 patients, aged 3 to 16 years, with nonvasoformative salivary gland tumors, 21 had malignant tumors. Mucoepidermoid carcinoma was the most common; adenocarcinoma, adenoid cystic carcinoma, and acinic cell carcinoma were equally represented. Pleomorphic adenoma was the exclusive benign lesion, occurring in eight patients. Mean follow-up for patients with malignant lesions was 13.6 years (minimum, 3.5 years). Absolute 2- and 5-year survival rates were 100% and 90%, respectively. Mean follow-up for benign lesions was 15.9 years; none recurred. Superficial or total parotidectomy is the treatment of choice for malignant parotid neoplasms. Benign parotid lesions are adequately controlled with parotidectomy based on extent of disease. Facial nerve sacrifice can often be avoided. We advocate postoperative radiotherapy for high-grade lesions or those with adverse prognostic factors, such as soft-tissue extension and perineural invasion.

Antibiotic prophylaxis in clean-contaminated head and neck oncologic surgery.

The use of antibiotic prophylaxis in head and neck oncologic surgery has greatly reduced the risk of postoperative wound infection and the corresponding increase in morbidity and health care costs. Conversely, inappropriate perioperative use of antibiotics increases costs and risk to patients. Antibiotic prophylaxis is beneficial only in clean-contaminated head and neck surgery; targets are the bacterial flora that commonly inhabit the skin and upper aerodigestive tract, with antibiotics effective against gram-positive aerobic organisms and anaerobic organisms providing the best coverage. Maximum efficacy is achieved with immediate preoperative and short-term (less than 48 hours) postoperative antimicrobial administration in adequate doses. Optimum benefit from prophylaxis in head and neck oncologic surgery depends on appropriate selection and administration of antibiotics in combination with sound, established surgical principles.