Spontaneous hemorrhage in an intraorbital arteriovenous malformation.

OBJECTIVE: To report the clinical findings and management of spontaneous hemorrhage in an unsuspected intraorbital arteriovenous malformation. DESIGN: Interventional case report. METHODS: Review of clinical findings, radiologic studies, and treatment of the patient. RESULTS: A 75-year-old woman sought treatment for the rapid onset of severe proptosis. Orbital exploration of a "mass" imaged on computed tomography scan and magnetic resonance imaging resulted in massive intraoperative hemorrhage. Subsequent arteriographic and histopathologic analysis confirmed an underlying orbital arteriovenous malformation. CONCLUSIONS: Spontaneous intraorbital hemorrhage from an arteriovenous malformation is extremely rare, but should be considered in the differential diagnosis of rapidly progressive proptosis.

Thyroid transcription factor-1, thyroglobulin, cytokeratin 7, and cytokeratin 20 in thyroid neoplasms.

Thyroid transcription factor-1 (TTF-1), a member of the NKx2 family of homeodomain transcription factors, is a mediator of thyroid-specific transcription of the thyroglobulin (TG) gene. The combined immunohistochemical profile of TTF-1, TG, cytokeratin 7 (CK7), and cytokeratin 20 (CK20) in neoplasms of the thyroid gland and their metastases to other sites has not been defined previously. Formalin-fixed tissue of 43 thyroid tumors, including 31 carcinomas and 12 adenomas, and 16 metastasic lesions were immunostained using monoclonal antibodies to TTF-1, TG, CK7, and CK20. Immunoreactivity of the primary tumors (adenomas and carcinomas) for TTF-1 was seen in 32 cases (74%), TG 32 (74%), and CK7 34 (79%), whereas none (0%) showed positivity for CK20. The distribution of reactivity in the 31 carcinomas for TTF-1, TG, and CK7, respectively was papillary (8/8), (8/8), and (8/8); poorly differentiated (6/7), (4/7), and (6/7); oncocytic (Hürthle) cell (2/6), (6/6), and (4/6); follicular (4/4), (3/4), and (3/4); medullary (1/2), (0/2), and (1/2). One of four anaplastic carcinomas was focally immunoreactive showing positivity for TTF-1 only. Of the six follicular adenomas, five were positive for TTF-1, six for TG, and six for CK7. Among the six oncocytic cell adenomas, five were reactive for TTF-1, five for TG, and all six for CK7. Twelve (75%) of the 16 metastatic tumors were positive for TTF-1, 10 (63%) for TG, 15 (94%) for CK7, and none (0%) for CK20. In summary, TTF-1 and TG are demonstrable by immunohistochemistry in the majority of thyroid neoplasms. Compared with TG, an antibody to TTF-I is a similarly sensitive marker for thyroid tumors. Moreover, TTF-1 is a more sensitive marker for poorly differentiated carcinomas and metastasis. In most cases, its nuclear pattern of immunoreactivity facilitates interpretation. Thyroid tumors are CK7+/CK20-. The panel of antibodies for TG, TTF-1, CK7, and CK20 is useful when the thyroid origin of a metastatic tumor is a consideration.

Esthesioneuroblastoma and sinonasal undifferentiated carcinoma: impact of histological grading and clinical staging on survival and prognosis.

OBJECTIVES: Hyams proposed a histological grading system for esthesioneuroblastoma in which grade I tumors have an excellent prognosis and grade IV tumors are uniformly fatal. The Hyams grading system predated advanced craniofacial techniques, extensive use of immunohistochemistry, and the recognition of sinonasal undifferentiated carcinoma (SNUC) as a distinct entity. Therefore we aimed to determine whether Hyams classification is useful in predicting outcome for esthesioneuroblastoma and SNUC. STUDY DESIGN: A retrospective review of cases from 1970 to 1999. METHODS: Twenty-six patients (12 with esthesioneuroblastoma and 14 with SNUC) were reviewed. The Kadish clinical stage was determined, and histopathological slides were reviewed and graded using the Hyams system. RESULTS: Kadish staging was available for 26 patients (2 patients with stage A tumors; 7 with stage B; and 17 with stage C). Of the 8 evaluable patients with Kadish stage A or B tumors, 6 remained disease free for more than 2 years compared with only 5 of the 17 Kadish stage C tumors. Slides were available for Hyams grading in 21 patients (2 patients with grade I tumors; 4 with grade II; 4 with grade III; and 11 with grade IV). Of the 6 patients with Hyams grade I or II tumors, 4 remained disease free for more than 2 years compared with only 4 of the 15 patients with Hyams grade III or IV tumors. Of note, three patients with Kadish stage C tumors (two with esthesioneuroblastoma, one with SNUC) and two patients with Hyams grade IV tumors (one with esthesioneuroblastoma and one with SNUC) survived for more than 5 years. CONCLUSIONS: Both the Hyams grading system and the Kadish staging system can be used as independent predictors of outcome. Although limited by small numbers, the results of this study demonstrate that patients with either advanced clinical stage or pathological grade of esthesioneuroblastoma or SNUC have poor prognosis, but that long-term survival is possible in these patients if aggressive treatment is used.

Frequent loss of heterozygosity at chromosome 3p14.2-3p21 in human pancreatic islet cell tumours.

OBJECTIVE: Pancreatic islet betacell tumours occur either sporadically or as part of inherited neoplastic syndromes, most commonly multiple endocrine neoplasia (MEN) type 1. Recently, a transgenic mouse model has been established in which the expression of the SV40 large T antigen was targeted to betacells by the rat insulin promoter, leading to the development of multiple pancreatic betacell tumours. In the advanced stages of tumour evolution, these tumours exhibited a high prevalence of loss of heterozygosity (LOH) on mouse chromosomes 9 and 16, at regions syntenic with regions 3q, 3p21, 6q12, 15q24 and 22q of the human genome. DESIGN: Loss of heterozygosity in human islet cell tumours was analysed in a PCR based approach at regions of the human genome syntenic with the mouse loci linked to pancreatic betacell tumours as well as the MEN1 gene on chromosome 11q13. These included 35 microsatellite markers in the human chromosomal regions 3q, 3p21, 6q12, 11q13, 15q24 and 22q. PATIENTS: 21 patients diagnosed with insulinoma were analysed. Histologically, 16 tumours were benign, while 5 were malignant insulinomas. RESULTS: Thirteen of 21 (62%) tumours were found to have loss of genetic material on chromosome 3. The shortest region of overlap implicated a deletion at 3p14.2-3p21 region, corresponding to the marker D3S1295. We did not detect a substantial frequency of LOH in the other syntenic regions, except for the region of MEN 1 gene on 11q13 found to be deleted in 6 (29%) cases, including 3 of 4 tumours from MEN 1 families. Deletions of 3p14. 2-3p21 were observed in 8 of 15 (53%) benign tumours, and in 5 of 6 (83%) malignant neoplasms. CONCLUSIONS: These results indicate the high frequency of 3p14.2-3p21 deletions in human pancreatic betacell neoplasms. These finding suggest the presence of a tumour suppressor gene in this region, that may be important in the microevolution of these tumours towards malignancy.

Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression.

We have previously reported that loss of p53 tumor suppressor protein results in centrosome hyperamplification, which leads to aberrant mitosis and chromosome instability. Since p53 is either deleted or mutated in human cancers at a high frequency, we investigated whether human cancers showed centrosome hyperamplification. Screening of advanced stage breast ductal carcinomas and squamous cell carcinomas of the head and neck (SCCHN) revealed that centrosome hyperamplification is frequent in both tumor types. Moreover, through the analyses of p53 in SCCHN samples by direct sequencing and by loss-of-heterozygosity test, we found that p53 mutations correlated with occurrence of centrosome hyperamplification. However, in some cases, we observed centrosome hyperamplification in tumors that retained wild-type p53. These tumors contained high levels of Mdm2. Since Mdm2 can inactivate p53 through physical association, we investigated whether Mdm2 overexpression induced centrosome hyperamplification. We found that Mdm2 overexpression, like loss of p53, induced centrosome hyperamplification and chromosome instability in cultured cells.

Alloantigen gene therapy for squamous cell carcinoma of the head and neck: results of a phase-1 trial.

OBJECTIVE: To determine the safety and efficacy of an immunogenic gene therapy using a drug designed to produce expression of a foreign class I major histocompatibility complex protein in patients with head and neck cancer. DESIGN: Phase 1 prospective clinical trial. SETTING: Academic medical setting. PATIENTS: Nine patients with advanced head and neck squamous cell carcinoma who had failed conventional therapy and did not express HLA-B7, a class I major histocompatibility complex protein. INTERVENTION: Patients were treated with Allovectin-7 (Vical Inc, San Diego, Calif) by direct intratumoral injection. Allovectin-7 contains a plasmid complementary DNA complexed with a cationic lipid, which results in expression of HLA-B7. MAIN OUTCOME MEASURES: Patients were assessed for any toxic effects and for any change in tumor volume. Biopsy specimens obtained before and after therapy were evaluated by immunohistochemistry to detect HLA-B7 expression and with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay to detect any induction of apoptosis. RESULTS: There were no toxic effects of the gene therapy. In 4 of these 9 patients there was a partial response to treatment, evidenced by a gradual reduction in tumor size. One patient has remained alive for more than 17 months since commencing treatment, with no clinical evidence of disease but with persistent histological evidence of cancer. Analysis of the biopsy specimens from 2 of the patients who responded to therapy demonstrated HLA-B7 expression. The TUNEL assay demonstrated extensive apoptosis in both of these patients, suggesting that this may be the mechanism of tumor reduction. CONCLUSIONS: These data demonstrate the potential efficacy and lack of toxicity of this form of alloantigen gene therapy. A multi-institutional study has been initiated to expand on these findings.

Hypersensitivity pneumonitis in a machinist.

Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is a patchy, interstitial lung disease that involves an immunologic reaction of the lung to repeated inhalation of foreign antigens. In this report, we describe a machinist with exposure to metalworking fluids (MWFs) and biopsy-confirmed HP. Return to work, which could be equated with a retrospective workplace-specific bronchoprovocation test, proved that working within an environment in which MWFs were used was associated with clinical deterioration in the patient's pulmonary status and with clinical improvement after removal from exposure.

Tracheal chondrosarcoma: a case report.

BACKGROUND: Tracheal neoplasms are extremely rare, representing only 0.2% of malignancies of the respiratory tract. A case of tracheal chondrosarcoma, with airway obstruction, seen in the Department of Otolaryngology Head and Neck Surgery at the University of Cincinnati is presented. Review of the literature was undertaken, revealing 10 previously described cases. Clinical presentation and treatment options are described. METHODS: A literature review of all reports of tracheal chondrosarcoma was undertaken. RESULTS: From this review, we identified only 10 single case reports. The majority of patients were elderly men, with lesions in the mid to distal trachea. Treatment predominantly consisted of tracheal resection. Recurrence was associated with failure to achieve complete resection. CONCLUSIONS: We conclude that tracheal chondrosarcoma is an exceedingly rare upper airway neoplasm. Treatment should be aimed at complete surgical removal.

Prognostic indicators for squamous cell carcinoma of the oral cavity: a clinicopathologic correlation.

Fifty-three patients with T1 squamous cell cancer of the floor of mouth and ventral surface of the tongue with a known clinical outcome were retrospectively analyzed and arbitrarily divided into "aggressive" and "nonaggressive" groups based on their clinical behavior. Various host and tumor factors were then evaluated in an attempt to determine whether the tumor behavior could have been predicted. The paraffin-embedded tumor specimens were evaluated for tumor differentiation, tumor thickness and tumor invasion, microvessel density, and p53 expression. In addition, a composite morphologic grading score was obtained by combining cell differentiation, nuclear polymorphism, mitosis activity, depth of infiltration, type of infiltration, and lymphatic infiltration. No single technique appeared capable of identifying "aggressive" behavior, although possibly an evaluation of composite factors might show promise in the future.

Access to emergency care under TennCare: do patients understand the system?

STUDY OBJECTIVE: To determine patient understanding of how to properly gain access to urgent and emergency medical care under TennCare, a government-mandated managed health care initiative designed to replace Medicaid in Tennessee. METHODS: We prospectively surveyed a convenience sample of ED patients at university hospital ED with an annual census of 50,000 during two periods (summer 1994 and summer 1995). In 1994, 250 TennCare patients were enrolled (part 1). In 1995, 199 were enrolled (part 2). RESULTS: Patients from seven different TennCare managed care organizations (MCOs) were interviewed. Thirty-eight percent of part 1 patients and 37% of part 2 patients did not have or did not know the names of their primary care physicians (PCPs). Fifty-eight percent of the part 1 patients who knew their PCPs' names had never visited them. This figure had decreased to 25% by the time part 2 patients were surveyed. Seventy-three percent of part 1 patients interviewed did not call their PCPs before coming to the ED. This figure had decreased to 48% by the time part 2 patients were interviewed. Thirty-two percent of part 1 patients were aware that they were supposed to contact the PCP before visiting the ED, whereas 94% of part 2 patients were aware of this requirement. Thirty-one percent of part 1 patients and 40% of part 2 patients who tried to contact their PCPs were unsuccessful, most often because of a delay on the part of PCPs in returning calls. Fifty-six percent of part 1 patients and 69% of part 2 patients did not know that they might be held responsible for the bill if an ED visit was not considered a true emergency and was not approved by the MCO. CONCLUSION: Improvements in communication of pertinent information must be implemented in managed care systems such as TennCare to better inform participants of the proper use of the system. MCOs will not reduce inappropriate use of the ED if patients are not aware of their responsibilities and do not know their PCPs or how to gain access to them. PCP responsiveness to patients must also be improved.

Tumor angiogenesis as a prognostic indicator in T2-T4 oral cavity squamous cell carcinoma: a clinical-pathologic correlation.

BACKGROUND: Tumor angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis in breast and other cancers. Studies in head and neck cancer have suggested a similar correlation, but results have been inconclusive. This study was performed to determine the correlation between angiogenesis and oral tumor behavior. METHODS: Tumor angiogenesis was evaluated in 31 T2-T4 primary oral cavity squamous cell carcinomas by quantitating the microvessel density with two different anti-endothelial cell antigens, factor VIII antigen (FVIIIAg) and CD-31. The stains were compared to assess whether these antigens yielded complimentary results. The microvessel densities were correlated with T stage and N stage and patient survival. RESULTS: FVIIIAg and CD-31 staining yielded consistent microvessel densities, but FVIIIAg was generally more uniform and easier to interpret. Increasing microvessel density was seen with increasing T stage and N stage; however, there was considerable overlap and no correlation with survival. CONCLUSIONS: These results suggest that oral tumors are less angiogenesis dependent than tumors in other sites. Tumor angiogenesis, as currently measured, is not of value in predicting tumor aggressiveness in patients with oral cavity carcinoma.

Loss of heterozygosity on chromosome 17p13 (p53) and 13q14 (Rb1) in squamous cell carcinoma of head and neck.

Loss of chromosome sequences at 13q14 (Rbl) and 17p13 (p53) associated with squamous cell carcinoma of head and neck (SCCHN) was evaluated in 12 recurrent tumors and 51 primary tumors from 63 patients. The incidence of LOH at 17p13 was 19 of 50 (38%) tumors, and at 13q14 was 21 of 57 (37%). LOH affecting Rbl and/or p53 was observed in 30 of 63 (48%) SCCHN. Coincident LOH at Rbl and p53 was detected in 10 of 46 (22%) tumors. There were nine cases in which primary and metastatic tumors were obtained from the same patient. Of these, seven were informative and five of these (71%) manifested LOH at p53 in both primary and metastatic sites. Examination of Rbl in these same tumors showed LOH in six of the nine metastases, and of these six, only three revealed LOH in the primary tumor. LOH at p53 or Rbl alone showed no correlation with clinical outcome. However, tumors that manifested LOH at both loci were associated with poorer patient outcome and poorer histological differentiation.

The loss of heterozygosity in retinoblastoma and p53 suppressor genes as a prognostic indicator for head and neck cancer.

Inactivation of tumor suppressor genes, including p53 and retinoblastoma (Rb), are commonly found in all cancers, including head and neck squamous cell carcinoma. Alterations at either p53 or Rb, however, are only weakly associated with tumor aggressiveness. In many cancers loss of heterozygosity (LOH) at multiple loci is associated with decreased survival. The polymerase chain reaction and highly informative microsatellite markers were used to compare DNA from matched sets of 63 head and neck squamous cell cancers and normal tissue for LOH at the p53 and Rb loci. At p53, 50 were informative, with LOH occurring in 19 (38%). Of the 57 that were informative at Rb, LOH occurred in 21 (37%). Of the 46 that were informative at both p53 and Rb, LOH occurred in 10 (22%) at both loci. When LOH for p53 and Rb individually was compared to stage, differentiation, and survival, there was no correlation. However, the patients with LOH at both loci had a significantly poorer survival (P = .009). This strongly supports the contention that simultaneous alterations of these two tumor suppressor genes favor tumor aggressiveness and can be used as a prognostic indicator.

Tumor angiogenesis in T1 oral cavity squamous cell carcinoma: role in predicting tumor aggressiveness.

BACKGROUND: Angiogenesis is necessary for tumor growth and metastasis. In breast and other cancers angiogenesis has been shown to correlate with tumor size, metastatic potential, and prognosis. Some studies of head and neck cancer have shown a similar correlation, although results are inconclusive. This study was performed to determine whether tumor angiogenesis can be used as a prognostic indicator for early oral cancers. METHODS: CD-31 immunostaining, the technique of choice for determining microvessel density, was utilized to investigate T1 squamous cell carcinomas of the ventral tongue and floor of the mouth. RESULTS: Adequate staining was achieved in 19 tumors. Seven tumors were deemed aggressive due to either the development of metastases or recurrence. The mean microvessel density in the aggressive patients was 43.1/hpf (range 15--79) and in the nonaggressive patients was 38.6/hpf (range 17--78). Statistical analysis failed to reveal any correlation between tumor aggressiveness and tumor angiogenesis in these early tumors. CONCLUSIONS: Tumor angiogenesis failed to predict tumor aggressiveness in T1 oral cavity carcinoma; however, low levels of neoangiogenesis were seen in all cases. For this reason this technique may prove more valuable in more advanced cancers.

The role of toluidine blue in assessing margin status after resection of squamous cell carcinomas of the upper aerodigestive tract.

OBJECTIVE: To determine the efficacy of toluidine blue in assessing margin status after removal of squamous cell carcinomas of the upper aerodigestive tract. DESIGN: A prospective study of 50 consecutive patients undergoing surgical resection of squamous cell carcinomas of the upper aerodigestive tract was performed during February 1 to December 1, 1993. After tumor resection, toluidine blue was applied directly to the remaining unresected mucosa. The staining characteristics of the mucosa were then compared with those of frozen-section biopsy specimens of the margins and with the permanent histologic findings of the resected tumor specimen. RESULTS: In three cases, toluidine blue identified a positive margin, which was confirmed on frozen and permanent section. In six cases, false-positive staining was noted, which was most frequently related to traumatic handling of the mucosa during the resection. In no case was a positive margin found on histologic staining that failed to stain with toluidine blue. During routine staining of surrounding unresected mucosa, three cases of a second primary tumor that was not seen on routine evaluation before tumor removal were identified with toluidine blue. In one case, a second T1 oral cavity lesion was found, while in the other cases, separate pharyngeal lesions were identified. CONCLUSION: Based on these findings, it appears that toluidine blue improved the ability to assess margin status at the time of resection, and we advocate its use after resection of tumors to the upper aerodigestive tract.