Lymphatic vessel density, nodal metastases, and prognosis in patients with head and neck cancer.

OBJECTIVE: To examine the relationship between intratumoral lymphatic vessel density and clinical and pathological variables in patients with head and neck squamous cell carcinoma. DESIGN: Archived paraffin-embedded biopsy specimens were sectioned and stained with hematoxylin-eosin and anti-LYVE-1 antibody, a highly specific marker for lymphatic endothelium. Tumor grade, infiltrating margin, inflammatory infiltrate, and percentage of tumor necrosis were noted and lymphatic vessel density measured using Chalkley point counting. SETTING: Tertiary care center at a university hospital. PATIENTS: A total of 168 previously untreated patients with advanced squamous cell carcinoma (73, larynx; 62, oropharynx; and 33, hypopharynx) treated with primary radiation (with or without planned neck dissection) and salvage surgery from 1992 to 1999. INTERVENTIONS: Measurement of intratumoral lymphatic vessel density in pretreatment tissue biopsy specimen. MAIN OUTCOME MEASURES: Disease-free and disease-specific survival, tumor occurrence, and nodal status. RESULTS: In patients with laryngeal carcinoma there was a significant relationship between the presence of intratumoral lymphatics and nodal metastases at presentation (P = .02) and poorly differentiated tumor grade (P = .02). Patients with high lymphatic vessel density also had a significantly worse disease-specific survival (P = .03). However, this difference was not significant with multivariate analysis. No significant relationship existed between the presence of intratumoral lymphatics and any of the clinical or pathological variables in oropharyngeal and hypopharyngeal carcinoma. CONCLUSIONS: In this patient sample, the development of intratumoral lymphatics in laryngeal carcinoma, but not in oropharyngeal or hypopharyngeal carcinoma, is associated with a spread of the tumor to regional lymph nodes. Detecting tumor lymphatic vessel proliferation is another step in the understanding of tumor biology, and the targeting of lymphatic growth may be of potential therapeutic benefit in selected patients with head and neck squamous cell carcinoma.

Scalp and forehead reconstruction using free revascularized tissue transfer.

OBJECTIVE: To examine the indications for, and the success of, free flap reconstruction in patients with forehead and scalp defects. DESIGN: Case series. SETTING: Two tertiary referral university teaching hospitals. Patients Twenty-six consecutive patients, aged 31 to 85 years, presenting with 26 scalp defects, 5 forehead defects, and 1 combined defect (size, 70-672 cm(2)). Three patients required resection and repair of the dura at surgery. Intervention Patients were staged according to the size of the defect and the viability of surrounding tissue; free flap reconstruction was performed where indicated. MAIN OUTCOME MEASURES: Flap survival, complications, and disease-free and overall survival. RESULTS: Thirty-four free flap reconstructions were performed (24 latissimus dorsi free flaps, 4 scapular free flaps, 3 rectus abdominis free flaps, and 3 radial forearm free flaps). One failed 2 weeks postoperatively, and 2 required exploration (1 for arterial ischemia and 1 for a hematoma). There were 3 cases of donor site morbidity (2 early seromas and 1 late abdominal hernia). One patient died of a pulmonary embolus 1 week postoperatively. Disease-free survival was 48% at 5 years and overall survival was 59% at 5 years, with a median follow-up of 24 months. CONCLUSIONS: Free revascularized tissue transfer is a reliable and safe way of reconstructing large scalp or forehead defects after traumatic injury or neoplastic resection. The muscle-only latissimus dorsi free flap for scalp reconstruction and the cutaneous scapular free flap for the forehead have proved successful in selected patients with a low complication rate and satisfactory cosmesis.

Head and neck reconstruction with anterolateral thigh flap.

OBJECTIVE: Our goal was to present our experience with the free anterolateral thigh flap for reconstruction of various cutaneous and mucosal defects of the head and neck. STUDY DESIGN: We conducted a retrospective review of 37 patients who underwent reconstruction between 1994 and 2002. Outcome measures included ethnicity, flap harvest technique, vascular anatomy, flap success, general surgical complications, and donor site morbidity. RESULTS: The majority of our patients were white (n = 33). The size of the 39 free anterolateral thigh flaps varied from 24 to 252 cm(2). There was 1 arterial failure and flap loss (2.6%) and 2 venous occlusions that were both salvaged. The donor site was closed primarily in 37 cases and with a split-thickness skin graft in 2 cases. CONCLUSIONS: This is the first report on using the free anterolateral thigh flap in whites. This free transfer has proved to be a versatile and reliable flap for reconstruction of the head and neck.

Intratumoral lymphatics and lymph node metastases in papillary thyroid carcinoma.

OBJECTIVE: To examine the relationship between lymphatic vessel density and clinical and pathological variables in patients with well-differentiated papillary thyroid carcinoma. SUBJECTS: Clinical information was retrieved on 109 previously untreated patients with well-differentiated papillary thyroid carcinoma treated with total thyroidectomy and postoperative iodine I 131 ablation. Median follow-up was 38 months. DESIGN: Archived tissue specimens were sectioned and stained with hematoxylin-eosin and anti-LYVE-1 antibody, a highly specific marker for lymphatic endothelium. The size of the tumor and its multifocality were noted and lymphatic vessel density was measured by means of Chalkley point counting. RESULTS: Numerous intratumoral lymphatics were seen in papillary thyroid carcinoma. There was a highly significant association between the presence of intratumoral lymphatics and the presence of neck node metastases (P<.001). There was also a significant association with male sex (P =.03) and the presence of multifocal disease (P =.05). The presence of intratumoral lymphatics remained significantly associated with the presence of nodal metastases at presentation (P =.003) on multivariate analysis. Intratumoral lymphatics were not a significant predictor of tumor recurrence (P =.42, log-rank test). CONCLUSIONS: The development of intratumoral lymphatics in well-differentiated papillary thyroid carcinoma appears to be associated with the spread of tumor to regional lymph nodes. The antimetastatic potential of targeting these lymphatics may be of potential therapeutic benefit in the future.

Predictive value of serum thyroglobulin after surgery for thyroid carcinoma.

OBJECTIVE: To determine the relationship between stimulated serum thyroglobulin levels (taken 3 months after total thyroidectomy) and tumor stage and recurrence in patients with well-differentiated thyroid carcinoma. STUDY DESIGN: Retrospective chart review in a tertiary care institution. METHODS: Two hundred thirteen consecutive patients with well differentiated thyroid carcinoma treated between 1983 and 1998 were identified. Data were collected on clinicopathological variables, stimulated serum thyroglobulin levels obtained 3 months after total thyroidectomy prior to 131I therapy and recurrence. RESULTS: A high postoperative thyroglobulin level was significantly associated with advanced-stage disease at presentation (P =.005, Kruskall-Wallis) but not with any of the other clinicopathological variables. Patients with a thyroglobulin level greater than 20 pmol/L had a significantly increased risk of disease recurrence on univariate analysis (n = 213 [P =.0001, log rank test]), and in the Cox proportional-hazards model, both advanced tumor stage (P =.001, relative hazard, 3.4 [95% confidence interval [CI]: 2.4-4.9]) and a thyroglobulin level greater than 20 pmol/L (P =.001, relative hazard, 5.1 [95% CI: 2.0-13.1]) were significant predictors of recurrence. No other variables significantly altered the hazards model. CONCLUSIONS: Advanced tumor stage at diagnosis and a stimulated thyroglobulin level greater than 20 pmol/L taken 3 months after total thyroidectomy were independent predictors of disease recurrence. Patients with a thyroglobulin level greater than 20 pmol/L are at increased risk of recurrence and may be candidates for more intensive follow-up or additional treatment.

Impact of nodal metastases on prognosis in patients with well-differentiated thyroid cancer.

OBJECTIVES: To study the clinical and pathological variables predicting lymph node metastases in patients with well-differentiated thyroid carcinoma and to examine the impact of these metastases on recurrence and survival. DESIGN: Cohort study. Median follow-up, 56 months. SETTING: Tertiary referral university teaching hospital. PATIENTS: The study included 522 consecutive patients with well-differentiated thyroid carcinoma treated between 1964 and 1999. Data were collected on age, sex, family history of thyroid disease, prior radiation exposure, stage of disease, pathological diagnosis, size of tumor, multifocality of disease, recurrence, and survival. INTERVENTION: Total thyroidectomy and postoperative iodine 131 ablation. MAIN OUTCOME MEASURES: Disease-free and overall survival. RESULTS: A total of 347 patients with stage I disease and 118 with stage II disease were identified. The median age of patients with neck disease was 3 years younger than those without neck disease and most had papillary carcinoma. Patients with multifocal disease were more likely to have neck disease (P =.02). On univariate analysis, disease-free and overall survival rates were significantly lower in patients who presented with neck node metastases (P<.001 and P =.005); this difference in survival remained highly significant on multivariate analysis for disease-free survival (P =.001), with a relative hazard of 6.27. CONCLUSIONS: When treated with total thyroidectomy and routine postoperative iodine 131 ablation, patients with well-differentiated thyroid carcinoma who present with neck node metastases outside the central compartment of the neck have an approximately 6-fold risk of developing recurrences, most of which occur in the neck.

Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients.

Hypoxia within head and neck squamous cell carcinoma (HNSCC) predicts a poor response to radiotherapy and poor prognosis. Hypoxia-inducible factor (HIF)-1 and HIF-2 are nuclear transcription factors that regulate the cellular response to hypoxia and are important for solid tumor growth and survival. Overexpression of HIF-1alpha and HIF-2alpha was demonstrated in three HNSCC cell lines under hypoxia and tumor tissue versus normal tissue (n = 20, HIF-1alpha, P = 0.023; HIF-2alpha, P = 0.013). On immunostaining, HIF-1alpha and HIF-2alpha expression were localized to tumor nuclei; HIF-2alpha expression was also seen in tumor-associated macrophages. Expression of HIF-1alpha in surgically treated patients with HNSCC (n = 79) was associated with improved disease-free survival (P = 0.016) and overall survival (P = 0.027).

Overexpression of cyclin D1 and underexpression of p27 predict lymph node metastases in papillary thyroid carcinoma.

Lymph node metastasis in papillary thyroid carcinoma increases the morbidity of treatment and the risk of local regional relapse and may also affect cure rates and survival. Factors that predict lymph node metastasis are, however, unclear. We analyzed 125 patients with papillary thyroid carcinoma for factors that predict lymph node metastasis. On univariate analysis, age, extrathyroidal extension, tumor focality, overexpression of cyclin D1, and underexpression of p27 predicted lymph node metastasis, whereas patient gender and tumor size did not. On multivariate analysis, extrathyroidal extension, overexpression of cyclin D1, and underexpression of p27 proved to be strong independent predictors of lymph node metastasis. We suggest that immunohistochemistry for cyclin D1 and p27 will prove valuable in identifying papillary thyroid carcinomas with metastatic potential.

Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer.

How tumors access and spread via the lymphatics is not understood. Although it is clear that dissemination via the blood system involves hemangiogenesis, it is uncertain whether tumors also induce lymphangiogenesis or simply invade existing peritumoral vessels. To address the issue we quantitated tumor lymph vessels in archival specimens of head and neck cancer by immunostaining for the recently described lymphatic endothelial marker LYVE-1, the vascular endothelial marker CD34, and the pKi67 proliferation marker, correlating lymph vessel density and proliferation index with clinical and pathological variables. Discrete "hotspots" of intratumoral small proliferating lymphatics were observed in all carcinomas, and a high intratumoral lymph vessel density was associated with neck node metastases (n = 23; P = 0.027) and an infiltrating margin of tumor invasion (P = 0.046) in the oropharyngeal subgroup. Quantitation of the lymphangiogenic growth factor vascular endothelial growth factor C by real-time PCR and immunohistochemistry revealed higher levels of mRNA in tumor tissue than in normal samples (n = 8; P = 0.017), but no obvious correlation with intratumoral lymphatics. Our results provide new evidence that proliferating lymphatics can occur in human cancers and may in some cases contribute to lymph node metastasis.