Squamous cell carcinoma

Squamous cell carcinoma of the skin is common skin malignancy arising from malignant proliferation of the keratinocytes of the epidermis. Chronic exposure to ultraviolet radiation in sunlight is the most important risk factor for squamous cell carcinoma. Early diagnosis and appropriate treatment provide the best opportunity to cure cutaneous squamous cell carcinomas. Although it is locally invasive, squamous cell carcinomas usually remain localized and can be cured by a variety of techniques. Surgical excision is the most broadly used treatment for high-risk squamous cell carcinoma. It is well-tolerated, extremely effective, and the completeness of the procedure can be evaluated through histologic assessment of the specimen's margins. About 10 percent of squamous cell carcinomas in Japan spread to regional lymph nodes or more distant sites with a relatively poor outcome. Five-year cure rates are reported to be 85 to 80 percent for Japanese patients with squamous cell carcinomas, respectively. Recommendations for surgical margins vary depending upon the risk of local recurrence, especially; squamous cell carcinomas with perineural extension also need more extensive procedures. Patients with clinically enlarged lymph nodes may require radiographic imaging, fine needle aspiration, or lymph node biopsy. Depending upon the results of these tests, regional lymph node dissection may be done. Recently the sentinel lymph node biopsy technique is being evaluated for its ability to detect microscopic involvement in patients with high-risk patients who have no clinical evidence of lymph node metastasis. The occurrence of regional lymph node metastases places the patient at increased risk for the subsequent development of distant metastases. Distant metastases are associated with a markedly increased risk of disease-related mortality. Systemic chemotherapy has been to limited benefit in patients with disseminated squamous cell carcinoma patients. In Japanese patients with distant metastases, the five-year survival rate is about 10 percent. The ability of current chemotherapy protocols to increase the cure ratio in squamous cell carcinoma is still controversial.     

Lymph node metastases and prognosis in penile cancer

Lymph node status is a key prognostic factor in penile squamous cell carcinoma. Recently, growing evidence indicates a multimodality approach consisting of neoadjuvant chemotherapy followed by consolidation surgery improves the outcome of locally advanced penile cancer. Thus, accurate estimation of survival probability in node‐positive penile cancer is critical for treatment decision making, counseling of patients and follow‐up scheduling. This article reviewed evolving developments in assessing the risk for cancer progression based on lymph node related variables, such as the number of metastatic lymph nodes, bilateral lymph node metastases, the ratio of positive lymph nodes, extracapsular extension of metastatic lymph nodes, pelvic lymph node metastases, metastatic deposit in sentinel lymph nodes and N stage in TNM classification. Controversial issues surrounding the prognostic value of these nodal related predictors were also discussed.     

Immunohistologic detection of the epidermal growth factor receptor in human esophageal squamous cell carcinoma.

Epidermal growth factor receptor (EGF-R) expression was studied immunohistologically in 38 patients with esophageal squamous cell carcinoma. The EGF-R was faintly expressed in basal and parabasal layers of normal esophageal epithelia and in cancer nests of 20 patients; it was strongly expressed in all areas of dysplastic epithelia and in cancer nests of 18 patients. The patients with strongly expressed EGF-R had lymph node metastases more frequently, and their prognosis was poorer than those with faintly expressed EGF-R. The EGF-R expression showed a mosaic pattern in 17 patients and a diffuse pattern in 21 patients. The patients with a mosaic pattern had lymph node metastases more frequently and a worse prognosis than those with a diffuse pattern. Expression of EGF-R in metastatic lymph nodes was similar to that in strongly expressing areas of primary cancers with a mosaic pattern. Thus EGF-R expression may be an important indicator for malignancies of esophageal squamous cell carcinomas because primary cancer cells with strongly expressed EGF-R metastasize to lymph nodes more frequently.     

An orthotopic nude mouse model of oral tongue squamous cell carcinoma.

PURPOSE: Despite advances in our understanding, prevention, and treatment of head and neck squamous cell carcinoma (SCC), the 5-year survival rates for patients remain low. This poor prognosis for head and neck SCC and SCC of the oral tongue (SCCOT) in particular reflects a limited understanding of the mechanisms of local and regional metastasis, which accounts for a majority of deaths. To analyze the molecular and cellular mechanisms of metastasis, we have developed an orthotopic nude mouse model of SCCOT. EXPERIMENTAL DESIGN: Nude mice were injected submucosally in the tongue or subcutis with human squamous cell carcinoma of the oral cavity cell lines Tu159, Tu167, and MDA1986. The mice were necropsied and examined for the presence of primary tumors, and regional and systemic metastases. RESULTS: For all three of the squamous cell carcinoma of the oral cavity cell lines, tumors developed more readily in the orthotopic site, the tongue, than in the ectopic subcutis. MDA1986 cells were highly tumorigenic, particularly at the orthotopic site, with as few as 5 x 10(3) cells producing tumors in all of the mice. In contrast, s.c. tumor formation required at least 1 x 10(5) cells. The tumorigenicity observed between those mice given submucosal inoculation and those mice given s.c. inoculation (P < 0.0001). Regional metastases initially occurred in <10% of mice. To generate tumor lines of increased metastatic potential, regional metastases were isolated from cervical lymph nodes after the development of orthotopic tongue tumors. Serial passage of these lymph nodes resulted in a cell line more metastatic than its parental line. When injected into the tongues of mice, these cells metastasized to regional lymph nodes in 30% of mice and to the lungs in 20%. CONCLUSIONS: In this orthotopic murine model, oral tongue cancer recapitulates the behavior of human SCCOT, allowing for detailed studies of its biology and therapy.     

Fine-needle aspiration for diagnosis of intranodal squamous-cell carcinoma metastatic from the skin

Fine-needle aspiration is a useful way to determine the presence of squamous-cell carcinoma in enlarged lymph nodes of patients at high risk for metastases. Advantages include a high degree of accuracy, outpatient as well as inpatient availability, and negligible potential for seeding of malignant cells. Cutaneous oncologists should consider using this technique in patients with lymphadenopathy and a previous history of cutaneous squamous cell carcinoma.     

Cell surface antigens in squamous cell carcinoma of the oral cavity

The ABH isoantigen was investigated in 80 patients with squamous cell carcinoma of the oral cavity and in their 46 affected lymph nodes. Isoantigen deletion shows a characteristic pattern of benign to malignant transformation of oral cancer. Total loss of isoantigen was found in anaplastic tumours, in metastatic lymph nodes and in the majority of advanced stage tumours. Total loss of isoantigen in metastatic lymph nodes indicates a frequent discharge of isoantigen-negative metastatic cells from the primary tumours to the lymph nodes and the regional organs. It seems that with the recent techniques a prospective observation of ABH isoantigen added to other pathological and clinical findings could be of prognostic significance in patients with squamous cell carcinoma of the oral cavity.     

Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium

Although approximately 50% of cancers give rise to metastases via the lymphatic system, the mechanisms mediating this process have remained unknown. In this study, we have investigated the role of two lymphatic endothelial molecules, the mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 in adhesion of malignant cells to the lymphatic endothelium, and analyzed their expression in two clinical series consisting of squamous cell cancers of the head and neck (n = 17) and breast cancers (n = 72). Affinity of the tested head and neck cancer cell lines to the lymphatic endothelium varied greatly, but adhesion of all cell lines was dependent on both the MR and CLEVER-1. Almost all cancer specimens contained peritumoral vessels that expressed CLEVER-1 and MR, and also the intratumoral lymph vessels often expressed them in both tumor types. However, only intratumoral expression of these molecules seems to be essential for metastatic spread to the regional lymph nodes. Only 8 (22%) of the 36 axillary node-negative breast carcinomas expressed the MR on the intratumoral lymph vessels as compared with 16 (50%) of the 32 node-positive carcinomas (P = 0.017), and all eight head and neck carcinoma patients with regional lymph node metastases at diagnosis had tumors that expressed CLEVER-1 on the intratumoral lymph vessels. These data suggest a role for both the MR and CLEVER-1 in directing the traffic of cancer cells within the lymphatic system.     

Lymphatic mapping and sentinel lymph node biopsy in squamous cell carcinoma of the lower lip.

AIMS: The risk of metastases to the submandibular and submental lymph nodes in squamous cell carcinoma (SCC) of the lower lip is closely related to the primary tumour size and the differentiation of the tumour. In order to determine the feasibility of the technique and the possible metastatic lymph nodes in SCC of the lower lip, intraoperative lymphatic mapping and sentinel lymph node biopsy was performed in patients with tumour size greater than 2 cm (T2) and clinically non-palpable regional lymph nodes (N0). METHODS: Intraoperative lymphatic mapping with patent blue dye was performed in 20 patients with SCC of the lower lip. The stained lymph node (sentinel) was identified in each patient and sent for frozen section analysis in order to verify tumour metastasis. All patients had undergone bilateral suprahyoid neck dissection at the same stage. RESULTS: Three of the patients were female and 17 were male. The median age was 66. Sentinel lymph nodes were identified in 18 of the patients (90%). Intraoperative or post-operative histopathologic examination of the sentinel lymph node showed tumour metastasis in three of the patients (16.6%). The histopathologic examination of the remaining 15 patients whose sentinel lymph nodes were free of metastasis, showed no metastasis in the non-sentinel lymph nodes. In two of the three patients with metastatic sentinel lymph nodes, non-sentinel lymph nodes were free of metastases. There were no false negative results and no local or systemic complications of the technique were seen among the patients. CONCLUSIONS: Intraoperative lymphatic mapping and sentinel lymph node biopsy is feasible in patients with SCC of the lower lip who have large tumour size and non-palpable regional lymph nodes. The technique may help to avoid neck dissection when the patient has negative sentinel lymph node and when positive provides useful information for more effective radical treatment.     

Squamous cell carcinoma of the umbilicus: management of an unusual localization

We describe the case of a squamous cell carcinoma spreading to the skin and regional lymph nodes from the umbilicus. Bilateral inguinal lymphadenectomy and a session of electrochemotherapy with bleomycin 15 mg/m2 were performed. However, because of the development of new cutaneous nodules in the abdominopelvic region, we performed targeted palliative therapy with erlotinib 150 mg/day. Targeted adjuvant therapy was preferred to the use of a major cytotoxic agent because of the high risk of superinfection and heart failure. Erlotinib produced a partial clinical response with reduction of the number and size of the skin nodules. CT scan performed after 60 days of treatment did not show any new lesions. To our knowledge, this is the first report of an umbilical metastatic squamous cell carcinoma treated with modern targeted therapy. This therapeutic strategy can be considered a valid palliative option in the management of metastatic cutaneous nodules of this rare primary site.     

Sensitivity of squamous cell carcinoma lymph node metastases to herpes oncolytic therapy.

PURPOSE: Cancer metastases may have phenotypic and genetic differences from their primary cancers of origin. Engineered, replication-competent, attenuated viruses based on herpes simplex virus-1 (HSV-1) have shown potent oncolytic effects in treating primary tumors in animal tumor models, but their efficacy in treating lymph node metastases is poorly understood. We compared the efficacy of an attenuated oncolytic HSV-1 (NV1023) in treating a series of murine squamous carcinoma cell lines derived from serial implantation and harvest from metastatic lymph nodes. EXPERIMENTAL DESIGN and RESULTS: The auricles of C3H/HeJ mice were implanted with SCCVII. Cervical nodal metastases were isolated, expanded in vitro, and reimplanted into new mice. A series of cell lines (LN1-LN7) were generated through seven serial passages. Cells from higher LN passages showed consistent trends toward increased migratory and invasive ability, increased cell surface nectin-1 (an HSV-1 receptor) expression, and increased glycoprotein D binding. Exposure to NV1023 showed increased viral entry, replication, and cytotoxicity with higher LN passages. Intratumoral injection of NV1023 in a murine flank tumor model caused significantly greater tumor regression and increased viral infection of LN7 compared with SCCVII. CONCLUSIONS: These results show that lymph node metastases may undergo selection for characteristics, including increased nectin-1 expression, that make them more sensitive targets for herpes oncolytic therapy. These findings support the clinical application of these agents for the treatment of lymph node metastases.     

Expression of thymidylate synthase and dihydropyrimidine dehydrogenase in primary oral squamous cell carcinoma and corresponding metastases in cervical lymph nodes: association with the metastasis suppressor CD82

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are 5-fluorouracil (5-FU) metabolizing enzymes and are involved in the sensitivity of carcinoma patients to 5-FU. Although 5-FU is often used for the treatment of oral carcinoma, there has not been any investigation into the expression of these enzymes in metastatic lymph nodes or of their roles in the effectiveness of 5-FU in treating lymph node-metastatic cancer. Oral squamous cell carcinoma (OSCC) often metastasizes to the lymph nodes, and these enzymes may be significant in the survival of patients with this disease. This study investigated the expression of TS and DPD in cervical lymph node metastases and its relationship with primary OSCC, as well as the interaction between these enzymes and Kangai 1(KAI1/CD82) which is a metastasis suppressor protein. Surgical specimens from 20 cases of OSCC with lymph node metastasis, 20 cases of OSCC without lymph node metastasis, and 10 cases of normal mucosa were examined by immunohistochemistry. The relationship between TS and DPD expression and clinicopathological data was analyzed. TS and DPD proteins were overexpressed in primary OSCC compared to that in normal mucosa. TS expression of the primary oral cancer cells in the group with lymph node metastasis was higher than that of those without. DPD expression did not significantly correlate with the occurrence of lymph node metastasis, nor was it different between primary oral cancer cells and cervical metastases. CD82 expression was significantly reduced in lymph node metastases. These findings indicate that TS and CD82 may be of great value in assessing lymph node metastasis of OSCC, and could be taken as new targets for therapy of metastatic OSCC.     

Extent of extracapsular spread: a critical prognosticator in oral tongue cancer

BACKGROUND: Extracapsular spread (ECS) of metastatic squamous cell carcinoma of the head and neck to regional lymph nodes is the most reliable predictor of poor treatment outcomes. Recently, the authors have shown that ECS is significantly associated with higher rates of locoregional recurrence, distant metastasis, and decreased survival in patients with squamous cell carcinoma of the oral tongue (SCCOT). The purpose of this review was to determine if the degree of ECS impacts distant metastasis rates and survival. METHODS: Two hundred sixty-six patients treated for SCCOT with surgery +/- adjuvant radiotherapy from 1980-1995 were reviewed. The setting was a tertiary referral center. The extent of ECS on histopathologic review of involved lymph nodes was measured from the capsular margin to the farthest perinodal extension in mm. Extent of ECS and the number of pathologic lymph nodes with or without ECS were analyzed for disease-free interval, survival rates, and distant metastases. RESULTS: No differences in the survival of patients with ECS of 2 mm was found (P = 0.92). Patients with both ECS and multiple positive lymph nodes had decreased overall survival (P = 0.0003), disease-specific survival (P = 0.0005), and a shorter disease-free interval (P = 0.019) when compared with those with a single positive lymph node with ECS. Those with multiple ECS+ lymph nodes had the worst prognosis (P = 0.001). CONCLUSIONS: Based on these findings, the authors recommended that all patients with SCCOT with ECS or multiple positive lymph nodes with or without ECS on pathologic review be considered for clinical trials that intensify regional and systemic adjuvant therapy.     

The role of lymph node dissection in renal cell carcinoma: the pendulum swings back

The incidence of regional lymph node metastases in patients with renal cell carcinoma ranges from 13% to over 30%, and portends a poor prognosis in both locally advanced and metastatic settings. Patients with small, organ confined tumors are at low risk for regional lymph node metastases and lymph node dissection can be omitted in these patients. In contrast, patients with clinical evidence of regional lymph node metastases may derive therapeutic benefit from aggressive removal of all affected lymph nodes within the retroperitoneum. Patients with locally advanced primary tumors but no clinical evidence of lymphadenopathy can be selectively targeted for aggressive lymph node dissection as an adjunct to radical nephrectomy, based on their individual risk of harboring micrometastatic lymph node disease. Several predictive tools have been developed for prediction of occult retroperitoneal nodal metastases. Although early identification of micrometastatic nodal disease in this group of patients has not conclusively been shown to improve survival, accurate pathologic nodal staging allows for early implementation of adjuvant systemic therapies in these high-risk patients. No formal guidelines exist regarding the extent and boundaries of lymph node dissection at the time of radical nephrectomy; however, overwhelming evidence suggests that the staging accuracy of lymph node dissection can be markedly improved if extended template dissections, rather than limited node sampling, is implemented.     

Site‐specific cancer deaths in cancer of unknown primary diagnosed with lymph node metastasis may reveal hidden primaries

Cancer of unknown primary site (CUP) is a fatal cancer ranking among the five most common cancer deaths. CUP is diagnosed through metastases, which are limited to lymph nodes in some patients. Cause‐specific survival data could guide the search for hidden primary tumors and help with therapeutic choices. The CUP patients were identified from the Swedish Cancer Registry between 1987 and 2008; 1,444 patients had only lymph node metastasis of defined histology (adenocarcinoma, squamous cell or undifferentiated). Site‐specific cancer deaths were analyzed by lymph node location and histology. Kaplan‐Meier survival curves were compared with metastatic primary cancer at related sites. Among the patients with metastasis to head and neck lymph nodes, 117 (59.1% of the specific cancer deaths) died of lung tumors. Patients with axillary lymph node metastasis died of lung and breast tumors in equal proportions (40.2% each). Also, squamous cell CUP in head and neck lymph nodes was mainly associated with lung tumor deaths (53.1%). With a few exceptions, survival of CUP patients with lymph node metastasis was indistinguishable from survival of patients with metastatic primary cancer originating from the organs drained by those nodes. The association between lymph node CUP metastases with cancer deaths in the drained organ and the superimposable survival kinetics suggests that drained organs host hidden primaries. Importantly, half of all site‐specific cancer deaths (266/530) were due to lung tumors. Thus, an intense search should be mounted to find lung cancer in CUP patients with lymph node metastases.     

P53 expression in squamous cell carcinomas of the supraglottic larynx and its lymph node metastases: new results for an old question

BACKGROUND: Although p53 overexpression is frequent in head and neck squamous cell carcinomas (HNSCCs), controversy remains regarding the prognostic significance of that overexpression. The objective of this study was to investigate the expression pattern and prognostic significance of p53 expression in HNSCC of the same location, treated in the same way, and with long-term follow-up. METHODS: P53 expression was determined by immunohistochemistry in paraffin-embedded tissue specimens from 107 consecutive patients (107 primary squamous cell carcinomas of the supraglottic larynx and 46 matched lymph node metastases). All patients underwent surgical resection and bilateral neck dissection. RESULTS: A strong correlation was observed between p53 expression in the primary tumor and in the matched lymph node metastases (P=.0001). P53 overexpression in the lymph nodes was an independent predictor of regional recurrence (P=.027). Likewise, expression of p53 in the lymph nodes correlated significantly with disease-specific survival (P=.018). Five years after treatment, 70% of patients with p53-negative, metastatic lymph nodes remained alive, whereas only 30% of patients with p53-positive lymph nodes remained alive. In multivariate analysis, lymph node status and p53 expression in the lymph nodes remained associated with survival. CONCLUSIONS: The current data suggested that, although p53 overexpression is common in supraglottic carcinomas, its expression in the primary tumor is of limited clinical significance. However, the results supported the role of p53 in the lymph node metastases as an independent predictor of regional failure and a poor prognosis in patients with HNSCC. A prospective trial is indicated to validate these findings.     

Prognostic influence of retropharyngeal lymph node metastasis in squamous cell carcinoma of the oropharynx

PURPOSE: To investigate the impact of involvement of retropharyngeal lymph nodes on the prognosis of squamous cell carcinoma of the oropharynx. METHODS AND MATERIALS: The pretreatment computed tomographic scans of 208 patients with squamous cell carcinoma of the oropharynx were reviewed for the presence of metastatic retropharyngeal lymph nodes. All patients were treated at the Leuven department between 1984 and 2003: by radiotherapy alone in 84.1% of patients, by surgery with postoperative radiotherapy in 11.5%, and by concomitant chemoradiotherapy in 4.4%. Retropharyngeal node involvement was present in 34 (16%) patients. The influence on recurrence (local and regional), distant metastasis, and survival was retrospectively analyzed. Median follow-up was 47 months (3.9 years), and results were analyzed for 201 patients. RESULTS: At 5 years, patients with retropharyngeal adenopathy had significantly more regional recurrences (45% vs. 10%, p = 0.004). Involvement of retropharyngeal lymph nodes significantly (relative risk 4.29 [95% confidence interval 3.33-5.25], p = 0.01) and independently predicted regional recurrence in multivariate analysis. Disease-specific survival was significantly lower in the retropharyngeal node positive group (38% vs. 58%, p = 0.03). CONCLUSIONS: Retropharyngeal node involvement has a negative impact on the prognosis of squamous cell cancer of the oropharynx. Patients are particularly at risk for regional recurrence, resulting in worse disease-specific survival. Retropharyngeal node involvement should be taken into account in designing the treatment plan for these patients.     

Sentinel-node guided lymph-node dissection for merkel cell carcinoma.

Merkel cell carcinoma is an aggressive neuroendocrine skin tumour. Treatment is still debatable. Merkel cell carcinoma resembles malignant melanoma in its cutaneous presentation and its embryonic origin; both have unpredictable biological behaviour, early regional lymph node involvement, early distant metastases and a high recurrence rate. In light of these common features, we used pre-operative lymphoscintigraphy, intraoperative lymph-node mapping and sentinel-node biopsy-a well-described technique for the treatment of melanoma-in a 60-year-old man with Merkel cell carcinoma in the right buttock. Following frozen section identification of a metastatic first-order sentinel node, radical right groin dissection was performed. All the other lymph nodes in this basin proved to be disease-free, including the second-order sentinel node and Cloquet node. The patient is now being treated with adjuvant chemotherapy and radiotherapy. This case shows that sentinel-node guided dissection is applicable to Merkel cell carcinoma.     

胸段食管癌根治术后复发规律的临床研究

食管癌恶性度高, 手术治疗仍是其治疗主要手段, 即使行广泛三野淋巴引流区域清扫仍有较高复发比例。对于局部晚期、淋巴结转移或伴有其他不良预后因素者术后放疗可以降低胸腔内复发, 提高部分患者生存率。然而, 多组关于术后预防性放射治疗的前瞻性研究均显示放疗范围不统一。胸段食管癌根治术后主要的复发部位为上纵隔淋巴结区和锁上淋巴结区, 影响其复发的因素主要包括手术术式、肿瘤部位、肿瘤侵犯深度、术后淋巴结是否转移以及转移数量等。根据食管癌根治术后的复发规律合理进行术后放射治疗的靶区设计, 对提高食管癌根治术后患者的局控率, 进而改善生存率具有重要的临床意义。      

Cancer‐associated fibroblasts and epithelial‐mesenchymal transition in metastatic oral tongue squamous cell carcinoma

We examined cancer‐associated fibroblasts (CAFs) and a panel of immunohistochemical markers of epithelial‐mesenchymal transition (EMT) in 19 pair‐matched oral tongue squamous cell carcinoma (SCC) and metastatic tumors to regional lymph nodes (RLNs). α‐Smooth muscle actin (α‐SMA) was studied to identify CAFs. EMT was studied with syndecan‐1, Cadherin‐11, fibroblast‐specific protein (FSP)‐1, s ecreted p rotein a cidic and r ich in c ysteine (SPARC) and Twist. Triple immunostaining in RLNs was used to highlight the carcinoma cells (E‐cadherin and Ki‐67) and their relationship to the CAFs (α‐SMA). We found that metastatic RLNs hosted CAFs similarly as in pair‐matched primary tumors. Expression of EMT markers is common in both primary and metastatic tumors. We demonstrate that metastatic carcinoma cells (Ki‐67 positive) downregulate E‐cadherin expression at the periphery of cancer islands, where they are in direct contact with CAFs. The supporting connective tissue microenvironment also commonly expresses syndecan‐1, Cadherin‐11, FSP‐1, and SPARC. In conclusion, CAFs are common to both primary and metastatic SCC. We hypothesize that CAFs not only promote tumor invasion but also facilitate metastases, either by cometastasizing and/or being recruited to lymph nodes. Evidence of EMT is common within primary tumors and metastatic SCC and may be further modulated by CAFs.     

Pattern of lymph node metastases in squamous cell carcinoma of the tonsil: implication for selective neck dissection

The aim of this study was to prospectively analyze the distribution of neck metastases and the outcome in patients surgically treated for tonsillar carcinoma in order to deduce implications for selective neck dissection. The criteria for inclusion in the study were (1) previously untreated, histologically proven, resectable squamous cell carcinoma of the tonsil, (2) curative surgical intent on the primary tumor and neck, (3) no history of prior head and neck cancer, (4) absence of synchronous second primary in the upper aerodigestive tract, lung and esophagus, (5) absence of distant metastases. Fifty-eight previously untreated consecutive patients with tonsillar squamous cell carcinoma were included in this prospective study. Among 22 patients with clinically negative cervical lymph nodes, 4 patients (18.2%) had metastatic lymph nodes on pathologic examination. Occult node metastases were mainly located in ipsilateral II level. No occult metastases occurred at levels I and V. Among 36 patients with clinically positive cervical lymph nodes, 3 patients (8.3%) had an occult pathologic metastatic involvement of cervical lymph nodes of ipsilateral level V. Level I was free of lymph node metastases. Clinical N category >N2a (p=0.003), nodal metastases to levels III (p=0.026) and IV (p=0.009) were significantly related to level V nodal metastases. The 2 and 5 years actuarial disease-free survival was 82.7% (95% CI 71.2-93.5%) and 58.3% (95% CI 36.7-79.9%), respectively. The actuarial recurrence-free survival was 87.9% (95% CI 78.9-96.8%) and 72.2% (95% CI 53.9-90.5%) at 2 and 5 years, respectively. Our findings support the role of a selective lateral neck dissection in the management of clinically N0 necks and in selected N+ necks (N1 and N2a disease located at level II) in patients with tonsillar carcinoma without oral involvement.