Jeffrey D. Spiro

Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth

In this review of 105 consecutive patients who underwent operation for previously untreated, N0 squamous carcinomas arising in the oral tongue or the floor of the mouth, 86 percent of the determinate patients remained alive and well 2 years after treatment. Included were 48 patients, 49 patients, and 8 patients who had T1, T2, and T3 tumors respectively. Elective cervical lymphadenectomy was performed in about a third, but tumor staging did not facilitate selection of those who were most likely to have occult metastases. For this reason, we retrospectively assessed the impact of tumor thickness using an optical micrometer to measure the thickness in millimeters of the excised tumors in routinely prepared paraffin sections. Disease-related death appears to be unusual when oral tumors are thin (2 mm or less), regardless of the tumor stage. Multivariate analysis confirms that increasing tumor thickness, rather than tumor stage, had the best correlation with treatment failure and survival. These findings need to be verified in prospective studies involving a larger patient population and other head and neck sites, but they strongly suggest that measurement of tumor thickness may be a better way to select those oral cancer patients who are most likely to benefit from elective treatment of the N0 neck.

Critical assessment of supraomohyoid neck dissection

During a recent 5-year period, 115 patients had 131 supraomohyoid neck dissections. Eighty-one percent of these procedures were performed for squamous carcinoma. Seventy-nine percent of the primary tumors were located in the oral cavity and 16 percent arose in the oropharynx. Almost 80 percent of the necks dissected for primary squamous carcinoma were clinically N0, and occult nodal disease was discovered in 31 percent of these neck specimens. When the supraomohyoid neck dissection specimen showed no involvement, the overall incidence of treatment failure in the neck at 2-year follow-up was 5 percent. Almost all patients with occult squamous carcinoma in the supraomohyoid neck dissection specimen received postoperative radiotherapy, and the failure rate in the neck was 15 percent. When neck nodes were both clinically and pathologically involved, neck recurrence developed in 29 percent of the patients despite the addition of adequate postoperative radiotherapy. Among those patients with nonsquamous primary tumors and a pathologically negative supraomohyoid neck dissection specimen, there was only one subsequent treatment failure in the neck. Supraomohyoid neck dissection appears to be a valid staging procedure for clinically N0 patients with primary squamous carcinomas located in the oral cavity or oropharynx, with an appropriate yield of occult nodal disease, and infrequent treatment failure in the dissected neck when the supraomohyoid neck dissection specimen is pathologically uninvolved. When nodal disease is clinically obvious, treatment failure is more frequent, even with the addition of postoperative radiotherapy. The role of supraomohyoid neck dissection in this setting deserves further study.

The management of chyle fistula

Over a recent 4‐year period, 823 neck dissections that included the lower jugular lymph nodes were performed. Of the 823, 14 (1.9%) patients developed chyle fistulas. Two other patients developed fistulas, one after undergoing a gastric transposition, and the other after a scalene node biopsy. All 16 patients were initially managed conservatively with closed‐wound drainage and low‐fat nutritional support; this was successful in only 4 patients, 3 of whom had peak 24‐hour chyle drainage of less than 600 cc. The remaining 10 patients required open‐wound management, which included operative ligation in 4 instances. Continued conservative treatment with an open neck wound resulted in significant additional hospitalization. Our experience indicates that closed‐wound management of a chyle fistula is likely to fail when peak 24‐hour fistula output exceeds 600 cc. Considering the cost and morbidity of conservative treatment, early reoperation may be appropriate in those patients with high fistula output.

Vascular endothelial growth factor expression in head and neck squamous cell carcinoma

BACKGROUND Angiogenesis is an essential process required for growth and metastasis in cancer. In breast, gastric, and prostate cancer, vascular endothelial growth factor (VEGF) has been implicated in angiogenesis; however, little is known about VEGF in HNSCC. In this study, we hypothesize that VEGF is present in elevated levels in HNSCC and may therefore play a role in promoting angiogenesis. METHODS We obtained tumor tissue from 63 HNSCC patients undergoing primary resection. All tissue samples were analyzed by immunohistochemistry (IHC) techniques for the presence and localization of VEGF; however, only 36 had sufficient amounts of tissue for quantitative analysis of VEGF by ELISA. Nine control specimens taken from patients undergoing uvulopalatopharyngoplasty were also analyzed. RESULTS In all 63 of our patient samples we found VEGF to be present and localized to the cancer cells and endothelial cells. The poorly differentiated cancer cells stained more intensely in comparison with the well-differentiated ones. There was a 20-fold increase in the patient levels when compared with controls levels (P > or =0.05). Analysis by enzyme-linked immunosorbent assay revealed elevated mean levels of VEGF (241 +/- 326 pg/mg total protein [TP]) with a range of 2 to 1484 pg/mg TP. The control specimens had mean levels of 13 +/- 11 pg/mg TP and a range of 1 to 78 pg/mg TP. Patients who exhibited higher levels of VEGF tended to have a higher rate of disease recurrence (P < or =0.048) and shorter disease-free interval (P < or =0.05). CONCLUSIONS The expression of VEGF in elevated levels in the HNSCC tumor microenvironment appears to be associated with more aggressive disease. Based on our results, VEGF may be an important angiogenic factor associated with cancer cells and endothelial cells in HNSCC. Further studies are needed to better define the role of VEGF in HNSCC and its role as a potential target for therapeutic intervention.

Coexpression of interleukin-8 receptors in head and neck squamous cell carcinoma

BACKGROUND Interleukin 8 (IL-8) is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies. We hypothesize that IL-8 plays an important role in the cellular proliferation and angiogenesis seen in head and neck squamous cell carcinoma (HNSCC) and set out to identify its receptors, IL-8RA and IL-8RB. METHODS Immunohistochemical analysis was performed on specimens from 38 HNSCC patients with stage I to IV disease and control tissues. RESULTS All of cancer specimens demonstrated positive staining for IL-8RA. The IL-8RA staining of microvessel endothelial cells was seen in 51%. The IL-8RB pattern was similar to the IL-8RA pattern in that 97% of cancer sections demonstrated positive cancer cell staining, and 74% of the specimens demonstrated positive staining for microvessel endothelial cells. CONCLUSION Our studies demonstrate that IL-8 receptors are expressed by cancer cells and microvessel endothelial cells in HNSCC, suggesting that IL-8 may act in an autocrine/paracrine fashion to stimulate cellular proliferation and angiogenesis.

Oral and laryngeal muscle coordination during swallowing

The objective of this experiment was to determine the relative contributions and patterns of activity of different muscles involved during the oral phase of swallowing. Electromyographic (EMG) signals were recorded from the orbicularis oris inferior, masseter, palatal elevator, anterior and posterior genioglossus, mylohyoid, anterior belly of the digastric, and vocalis muscles of 12 normal adult subjects. Each subject swallowed 15 mL of water, under normal and bite block conditions, 15 to 20 times. The integrated EMG signals for each subjects swallows were ensemble averaged. The results of the analyses showed that swallowing function varies from individual to individual in terms of the specific muscles used and how the various muscle activity patterns are coordinated. These results suggest that swallowing is a highly complex adaptive motor activity which probably relies more on higher‐level control mechanisms than previously believed.

Role of angiogenic factors : Coexpression of interleukin-8 and vascular endothelial growth factor in patients with head and neck squamous carcinoma

Objective/Hypothesis: Angiogenesis has been used as a prognostic indicator in a variety of cancers and is believed to be controlled by angiogenic factors, including the cytokines interleukin‐8 (IL‐8) and vascular endothelial growth factor (VEGF). We hypothesized that the in vivo coexpression of both IL‐8 and VEGF in head and neck tumors contributes to perpetuating tumor growth and metastasis by enhancing angiogenesis. Methods: Immunohistochemical analysis for IL‐8 and VEGF was performed using specimens from 33 cancer patients and 6 control patients. We quantitatively evaluated levels of IL‐8 and VEGF in tumor tissue homogenates from those same patients using enzyme‐linked immunosorbent assay and radioimmunoassay. Comprehensive histories of each patient were taken and later analyzed for clinical correlations with IL‐8 or VEGF levels. Results: IL‐8 and VEGF were found to be colocalized within the head and neck squamous cell carcinoma (HNSCCA) tumor cells. In the head and neck tumor specimens, IL‐8 levels ([38,152 ± 1.8] × 10 5 pg/mg total protein [TP]) were 22‐fold greater than controls (1,721 ± 2,122 pg/mg TP). The tumor levels of VEGF (1,304 ± 6,037 pg/mg TP) were nearly fourfold higher than the controls (317 ± 400 pg/mg TP. Interleukin‐8 and VEGF levels were found to have a positive correlation (P ⩽ .0001). Patients exhibiting high levels in picograms per milligram of TP and/or number of moles of IL‐8 and VEGF were found to clinically have more aggressive disease manifested by higher TNM stage, more recurrences, and shorter disease‐free intervals (P ⩽ .03) Conclusions: Marked increase in HNSCCA of IL‐8 and VEGF underscores the importance of these angiogenic factors in this disease. Understanding the roles and interplay of angiogenic factors such as IL‐8 and VEGF may have value in the treatment of HNSCCA.

Expression of basic fibroblast growth factor and its receptors by head and neck squamous carcinoma tumor and vascular endothelial cells

BACKGROUND Basic fibroblast growth factor (bFGF) is a potent angiogenic factor implicated in tumor growth and metastasis. To determine if bFGF and basic fibroblast growth factor receptor 1 (bFGFR1) and 2 (bFGFR2) are upregulated in head and neck squamous cell carcinoma (HNSCC), we measured the distribution and levels of each in HNSCC specimens and control specimens. METHODS Head and neck squamous cell carcinoma and control tissue specimens were analyzed qualitatively (40 patients, 10 controls) using immunohistochemistry, and quantitatively (26 patients, 8 controls) using immunoassays and graded immunohistochemistry. Control tissue consisted of palatal tissue obtained during uvulopalatopharyngoplasty (UPPP). RESULTS Immunohistochemical analysis revealed that bFGF, bFGFR1, and bFGFR2 antigens were strongly associated with cancer and vascular endothelial cells in HNSCC. Control tissue had moderate staining of vascular endothelium and no stromal staining. Quantitative analysis of bFGF in tissue homogenates indicated that bFGF levels in cancer specimens were significantly elevated compared with control tissues (420.3 +/- 360.9 ng/mg total protein versus 49.2 +/- 48.7, respectively, P < or =0.05). When analyzed by clinical stage, bFGF levels were significantly higher in stage III patients as compared with stage IV patients (P < or =0.01). When immunohistochemistry results were correlated with clinical stage, bFGF (P < or =0.01), bFGFR1 (P < or =0.001), and bFGFR2 (P < or =0.0001) staining was significantly more intense in the cancer cells of stage III versus stage IV patients. CONCLUSION Enhanced expression of bFGF and bFGF receptors by cancer and vascular endothelial cells is present in HNSCC, and may contribute to tumor growth and metastasis in HNSCC by mediating angiogenesis. Strategies aimed at decreasing the expression of bFGF and its receptors may be of therapeutic benefit in HNSCC, particularly at an early stage of disease.

Squamous carcinoma of the nasal cavity and paranasal sinuses

This study retrospectively analyzed 105 patients with squamous carcinoma of the nasal cavity and paranasal sinuses. The primary tumor was located in the maxillary sinus in 65 patients (62 percent), the nasal cavity in 27 (26 percent), the ethmoid sinus in 11 (10 percent), and the sphenoid sinus in 2 (2 percent). Over half of the patients with antral cancer were treated with surgery and radiotherapy, whereas one-third of the remaining patients received combination therapy. Most procedures were radical, including sacrifice of the orbital contents in half of the surgically treated patients. The 5-year determinate cure rate was 45 percent for patients with nasal cavity tumors, 38 percent for those with maxillary sinus lesions, and 13 percent for those with ethmoid tumors. Local recurrence remains a major problem despite aggressive surgery and increased use of adjunctive radiotherapy.

Cancer of the Parotid Gland: Role of 7th Nerve Preservation

Most neoplasms arising in the parotid gland are benign. Patients with cancer of the parotid gland usually present with normal facial nerve function. In these patients, findings at the time of surgery will guide the management of the facial nerve, with most surgeons preserving the nerve unless it is adherent to, or imbedded in, a malignant tumor. In cases where the margins of resection are close to the facial nerve, adjuvant radiotherapy administered postoperatively has significantly improved local control of disease. The minority of patients with parotid cancer who present with facial nerve palsy has a poor prognosis despite extensive surgical resection including the facial nerve.