Cystic lymph node metastases of head and neck squamous cell carcinoma: pitfalls and controversies

Lymph node metastases of squamous cell carcinomas in the neck can appear cystic. Without a clinically apparent primary tumour they can classically be considered to originate in a branchial cleft. We report two cases of cystic squamous cell carcinoma with histopathologic criteria of branchial cleft carcinoma. After a review of the literature, diagnostic strategies, histopathologic features, and therapeutic options for this very controversial clinical situation are discussed. We conclude by suggesting that Martin's criteria, largely used to differentiate between a cystic metastasis of a squamous cell carcinoma and a very theoretical branchial cleft carcinoma should be abandoned for lack of applicability.     

p53 tumor suppressor gene as a clonal marker in head and neck squamous cell carcinoma: p53 mutations in primary tumor and matched lymph node metastases

In order to define the diagnostic value of p53 tumor suppressor gene as a clonal marker in head and neck squamous cell carcinoma (HNSCC), we investigated p53 mutations in primary tumors (PT) and matched lymph node metastases (LNM); the underlying question being whether differentiation between metastatic disease of a known PT or (a metastasis of) a synchronous or metachronous second tumor is possible by means of p53 sequencing-based mutation analysis. In 15 PT, the p53 status was analyzed, following RNA isolation, cDNA synthesis and polymerase chain reaction amplification, by direct sequencing full-length mRNA. Mutations thus found were confirmed by DNA sequencing analysis of the corresponding exon in the PT. When RNA isolation was defective, DNA sequencing analysis of exons 1 through 11 was performed. In the matched LNM, DNA analysis of the corresponding exon was performed to prove the presence of the same p53 mutation. In the event of small clones not detectable by direct sequencing, an oligo ligation assay was developed to detect a specific mutation. The presence of germline mutations was excluded by DNA sequencing analysis of the corresponding exon of peripheral blood leucocytes. In 14 PT (94%), a mutation was identified. In one PT, no p53 mutation could be identified either after full-length mRNA sequencing or after sequencing exons 1 through 11. In all cases of PT and matched LNM, the mutations proved to be identical. We conclude that p53 mutations develop in carcinogenesis before metastases occur and are maintained during metastasis. Consequently, p53 may serve as a clonal marker not susceptible to change during tumor metastasis. This merits further exploration of the application of p53 mutation analysis in differentiating between metastatic disease from a known PT versus a metastasis of another second PT.     

Radiotherapy of lymph node metastases in patients with squamous cell carcinoma of the head and neck region

The results of radiotherapy alone in 233 patients with lymph node metastases of squamous cell carcinoma in the head and neck region were examined. It appeared that the recurrence rate in the neck was mainly related to: localization of the primary tumor; the recurrence of the primary tumor; the radiation dose; and the presence of a residual palpable tumor mass in the neck 6 weeks after radiation. The optimum radiation dose was about 2000 ret. An isoeffect curve was calculated, which differed only slightly with the nominal standard dose (NSD) formula. Elective irradiation of the contralateral neck appeared to diminish the outgrowth of neck node metastases at that side. Changes in the radiation treatment in the last treatment period, such as a higher radiation dose and a larger treatment area, resulted in a lower recurrence rate for the neck node metastases, and also in a higher survival rate.     

Serum ferritin as a tumor marker in patients with squamous cell carcinoma of the head and neck

A double antibody enzyme immunoassay was used to measure serum ferritin levels in several different control and tumor-bearing populations collected from two institutions. The control groups consisted of normal volunteers, smokers, and Latter Day Saints. No statistically significant differences were noted in ferritin levels between pairs of these groups. Differences were noted among the normal groups when separated on the basis of age and sex, with higher ferritin levels in individuals older than 32 years of age and in men. By one-way analysis of variance, most control groups and subgroups were shown to have significantly lower levels (P less than 0.05) than the head and neck cancer group, with the exception of male smokers, who had levels comparable to male head and neck cancer patients. Serum ferritin levels were higher in head and neck cancer patients than in controls; however, there was no difference when compared with patients with other types of solid malignancies or when considering the anatomic site of the head and neck lesion. Ferritin levels were significantly (P less than 0.05) higher in patients with advanced (Stages III and IV) cancer than in those individuals with Stage I or II cancer. In patients with no evidence of clinical disease 5 years after treatment, the ferritin level had essentially returned to normal. In a group of head and neck cancer patients followed longitudinally, a significant decline in ferritin levels (P less than 0.05) was seen by 5 months after the completion of successful treatment. Furthermore, ferritin levels showed a tendency to increase or remain at high levels in patients with a poor prognosis and to decrease in those patients with a favorable prognosis, giving support to the contention that ferritin may prove to be a valuable tumor marker in head and neck cancer.     

Cervical lymph node metastases from occult squamous cell carcinoma

Opinion statement Depending on patient and tumor characteristics, reported 5-year actuarial survival rates of patients with cervical nodal metastasis from an unknown primary carcinoma range from 18% to 63%. Prognostic factors for survival include N-stage, number of nodes, grading, extracapsular extension, and performance status. Retrospective studies suggest that neck relapse is more common than are distant metastases or emergence of mucosal primary tumors. The treatment options include neck dissection alone, radiation alone to the neck with or without the putative mucosal origin, and combination unilateral neck dissection plus limited or comprehensive radiotherapy. Combination of nodal dissection with comprehensive bilateral radiotherapy yielded most favorable results in localregional disease control. However, its impact on the quality of life should be recognized. Also, the confounding effects of patient selection for various treatment modalities on therapeutic outcome cannot be quantified. Retrospective single-institution comparisons between comprehensive and unilateral neck radiotherapy did not show apparent differences in outcome. A randomized trial to compare the therapeutic value of comprehensive versus volume-limited radiotherapy is being planned. No data were found to support the benefit of chemotherapy for the treatment of this disease.     

Macrophage colony-stimulating factor as a tumor marker for squamous cell carcinoma of the head and neck.

It has been demonstrated that in patients with epithelial ovarian cancer and malignant germ cell tumors of the ovary, macrophage colony-stimulating factor (M-CSF) is significantly elevated in the serum compared to healthy individuals. Therefore, M-CSF has been suggested as a tumor marker in these malignancies. In the present study, the tumor marker potential of the serum M-CSF concentration in patients with squamous cell carcinomas of the head and neck (SCCHN) was investigated. The serum M-CSF concentration was determined by a quantitative sandwich enzyme immunoassay in 59 patients suffering from SCCHN and 59 healthy controls. A significant difference in the mean serum concentration of M-CSF between the patients with SCCHN and the control group was found (p = 0.002). The M-CSF serum concentration correlated neither with the stage of disease nor with histopathological grading, and no correlation with serum C-reactive protein was found. The serum M-CSF concentration could be of interest as a tumor marker in SCCHN.     

Prognostic value of lymph node metastases and lymph node ratio in esophageal squamous cell carcinoma

Aims

Although the positive lymph node (LN) metastasis in patients with thoracic esophageal squamous cell carcinoma carcinoma (SCC) has been reported to be a risk factor to reduce long-term survival, only a few studies have so far evaluated the lymph node metastasis among this group of patients. The purpose of this study was to evaluate the impact of lymph node positivity and ratio on survival of esophageal SCC.

Methods

All patients undergoing esophagectomy at the Forth Hospital of Hebei Medical University between January 1986 and December 2002 were reviewed. Survival curves were estimated using the Kaplan-Meier method.

Results

Of 1325 patients with invasive cancer, had squamous cell cancer of the esophagus. Median overall survival (OS) of the entire group was 36.7 months and 5-year OS was 39.3%. The most significant prognostic factor for overall survival was the presence of positive LN (P < 0.01). Additionally, patients with zero involved LN had a 5-year survival of 49.1%, while patients with 1–3 positive LN and >3 positive LN had 5-year survival of 19.5% and 11.0%, respectively (P < 0.01). Finally, an increasing ratio of positive to examined LN was linearly associated with a worsening 5-year survival, patients with <25%, 25%–50% and >50% positive LN had 5-year survival of 47.53%, 14.6% and 8.9%, respectively (P < 0.01).

Conclusion

Increasing number of positive LN in patients with esophageal cancer and increasing ratio of metastatic to examine LN portend a poor prognosis. These factors should play an important role in predicting prognosis of patients.     

The significance of Tenascin-C serum level as tumor marker in squamous cell carcinoma of the head and neck

BACKGROUND: Tenascin, an extracellular matrix glycoprotein, is transiently present in embryonic tissue, in benign granulation tissue, but also in several highly anaplastic tumors like fibrosarcoma, melanoma and squamous cell carcinoma of the skin. This study was performed to validate elevated Tenascin serum levels as a possible marker for head and neck squamous cell carcinomas (HNSCC). PATIENTS AND METHODS: Tenascin serum levels were evaluated in patients with primary (n = 92) and with recurrent (n = 28) HNSCC. Patients with benign, non inflammatory ear, nose and throat diseases (n = 16) served as the control. The Tenascin serum levels were measured by ELISA (Aventis). RESULTS: Serum Tenascin concentrations of patients with benign ENT diseases ranged between 0.37 and 2.19 micrograms/ml (n = 16, mean +/- SD: 1.23 +/- 0.59 micrograms/ml), of patients with HNSCC (primary diagnosis) between 0.05 and 8.75 micrograms/ml (n = 92, mean +/- SD: 1.81 (1.36 micrograms/ml) and of patients with recurrent HNSCC between 0.53 and 10.0 micrograms/ml (n = 28, mean +/- SD: 2.78 +/- 2.2 micrograms/ml). CONCLUSION: We found a significant elevation of Tenascin serum levels only in patients with higher tumor stages (T4/UICC4) (p < 0.01/p < 0.1) or recurrent disease compared to Tenascin serum levels in healthy controls. Thereby Tenascin serum levels cannot be used clinically as a routine serum marker for the control of head and neck cancer. Further investigations are necessary to evaluate whether the measurement of Tenascin levels as tumor markers could offer additional information to the clinical outcome of patients with HNSCC.     

Serum hepatocyte growth factor as a marker of tumor activity in head and neck squamous cell carcinoma

Hepatocyte growth factor (HGF) has previously been reported to be elevated in the serum of patients with malignancy, including breast, colorectal and gastric cancers. Here, we evaluated the correlation between serum HGF and the progression of head and neck squamous cell carcinoma (HNSCC). The mean serum HGF levels in 71 healthy control subjects, 78 patients with primary HNSCC, and eight patients with recurrent HNSCC were 0.538 ± 0.163, 0.701 ± 0.252, and 0.925 ± 0.349 ng/ml, respectively. The increase in the HGF level was significantly correlated with tumor stage progression. The HGF level had decreased to normal at 1 month after curative resection of the tumors. During follow-up for several months, the HGF level significantly increased in recurrent HNSCC patients, whereas there was no increase in nonrecurrent patients. Our data suggest that serum HGF is significantly corrected with tumor progression and may be a strong predictor of recurrence in HNSCC.     

CD44 as a stem cell marker in head and neck squamous cell carcinoma

In the recent past, evidence is increasing indicating the existence of a subpopulation of resistant tumor cells in head and neck squamous cell carcinoma (HNSCC) that cannot be eradicated by established antineoplastic treatments. These cancer stem cells (CSCs) have features of somatic stem cells such as selfrenewal, proliferation and differentiation. CD44+ cells in tumors of the head and neck are referred to as CSCs of HNSCC. Expression profiling of CD44 in 29 HNSCC tumors was performed by fluorescence microscopy. ELISA analysis was performed to detect concentration of soluble CD44 in the peripheral blood of 29 HNSCC patients and 11 healthy controls. Expression of CD44 was determined in all HNSCC tissue samples (n=29). In all samples a surface staining pattern was found. The concentration of CD44 in the peripheral blood of HNSCC patients was significantly higher compared to a healthy control group (mHNSCC =13.5 ± 0.5 ng/ ml; mCont = 9.3 ± 0.6 ng/ml; P=0.6 x 10(-12)). The role of CD44 as a marker for CSCs in HNSCC remains to be ascertained. Further experiments might reveal its role as a diagnostic and prognostic factor, and possibly as a therapeutic target.     

RhoC GTPase expression as a potential marker of lymph node metastasis in squamous cell carcinomas of the head and neck.

PURPOSE: Survival rates for squamous cell carcinoma of the head and neck (SCCHN) have remained unchanged for several decades due to local tumor recurrences as well as regional and distant metastases. Recent evidence has shown that RhoC GTPase is overexpressed in stages III and IV regionally metastatic SCCHN compared with stages I and II localized disease. This study evaluated the expression of RhoC in head and neck carcinoma and investigated the prognostic use of this marker on a large cohort of previously untreated patients with SCCHN. EXPERIMENTAL DESIGN: Standard Western blot techniques were used to evaluate RhoC protein expression in nine established head and neck cancer cell lines and in normal oral epithelium. In vivo expression of RhoC in metastatic and nonmetastatic SCCHN was investigated using immunohistochemical analysis on a tissue microarray composed of 113 independent tumor samples. RhoC expression was analyzed as it related to clinical and pathologic variables of interest. RESULTS: Levels of RhoC protein were increased in the SCCHN cell lines compared with normal oral epithelium. The in vivo expression of RhoC correlated with advanced clinical stage and lymph node metastases for the entire patient cohort as well as in small primary tumors (T(1) and T(2)). CONCLUSIONS: This study is the first to examine the expression of RhoC GTPase protein in SCCHN and normal squamous epithelium. It is clear from the results that RhoC is a specific marker of lymph node metastases in patients with this challenging form of carcinoma. RhoC levels seem to identify a subset of patients with early tumor stage primary tumors and high metastatic potential that might benefit from more aggressive therapy. Through continued investigation, blockade of RhoC activity may be a potential target in the development of novel strategies for treating metastases of head and neck cancer.     

Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC)

Overrepresentation of chromosomal bands 3q25-q29 has been associated with shortened disease-specific survival in head and neck squamous cell carcinoma (HNSCC). To assess the prevalence of copy number gains (>4 signals per cell) and high-level amplifications (>8 signals per cell) from putative oncogenes in this chromosomal region (CCNL1, SNO, PIK3CA, TP73L), tissue microarray analysis was applied on 280 HNSCCs by fluorescence in situ hybridization. Overall frequency of additional copy numbers was 34.3% for CCNL1, 31.8% for SNO, 39.0% for PIK3CA and 38.3% for TP73L, respectively. In general, gains were more frequently detected in stage IV compared to stage I-III tumours. Performing multivariate logistic regression analysis, a significant association of CCNL1 gains and the presence of lymph node metastases was found, which was independent of anatomical site and T-stage of the primary tumour (P=0.049). Site-specific subgroup analysis further showed that copy number gains of CCNL1 and SNO occurred more frequently in oral carcinomas in advanced clinical stages as compared to N0 oral lesions (CCNL1: P=0.03; SNO: P=0.03). Finally, Kaplan-Meier analysis revealed that high-level amplifications of CCNL1 correlated with shorter overall survival of the patients. Our results indicate that CCNL1 plays a critical role in the loco-regional progression of HNSCC and may serve as an indicator for occult advanced tumour stages.     

Bone metastases from squamous cell carcinoma of the head and neck

BACKGROUND AND OBJECTIVES: Carcinoma of the head and neck is an uncommon primary source of bone metastases. The increasing duration of survival of these patients, however, increases the probability of late bone involvement. The objective was to identify the frequency, clinical presentation, and clinical course of metastatic disease to bone from head and neck primaries. METHODS: A retrospective review was accomplished of the radiographs and nuclear medicine studies for 363 cases of squamous cell carcinoma of the head and neck for whom radiologic studies had been performed. For those with identified bone involvement, a chart review was performed to identify clinical presentation, disease course, and outcome. RESULTS: Only approximately 1% of these patients had clinically demonstrable bone metastases. Eight sites of bone involvement were identified in five patients, including three pelvic, two femoral, and one each humeral, rib, and thoracic spine lesions. All lesions were purely lytic with moth-eaten or permeative borders. Time from primary tumor diagnosis to identification of metastatic disease ranged from being present at diagnosis to a maximum 3.5 years later. Time from identification of metastatic disease to patient death was no greater than 8 months. CONCLUSIONS: Despite the increasing overall survival of patients with these carcinomas, distant bone metastases are infrequent, but should be considered a possibility in any patient with a concurrent or past diagnosis of head and neck carcinoma. The very short time from discovery of bone dissemination to death in most of these patients should be taken into consideration when contemplating operative intervention.     

Does node location affect the incidence of distant metastases in head and neck squamous cell carcinoma?

An analysis of 455 patients with head and neck carcinomas and clinically positive neck nodes who were treated with radiation therapy alone to their primary tumors (with or without a neck dissection) was conducted to determine the relative role of several prognostic factors in the subsequent development of distant metastases (DM). The factors analyzed were N stage, node location (upper neck only vs. lower with or without upper neck), T stage, primary site (oral cavity, oropharynx, nasopharynx, hypopharynx, supraglottic larynx), modified AJCC stage, and neck treatment. All patients were treated between 1964 and 1985 and had a minimum follow-up of 2 years. The N stage and node location were the most significant prognostic factors in the subsequent development of distant metastases. The incidence of distant metastases increased with increasing neck stage (N1, 11%; N2, 18%; N3, 27%), and in four of five neck stages (N2B being the exception), the incidence of distant metastases was greater for those patients with metastatic adenopathy in the lower neck. The incidence of distant metastases by modified AJCC stage was 12/111 (11%) for Stage III, 34/146 (23%) for Stage IVA, and 41/198 (19%) for Stage IVB. The primary site and T stage had little influence on the subsequent development of distant metastases. A multivariate analysis of the clinical factors confirmed the importance of neck stage and node location in estimating the probability of distant metastases. Control of disease above the clavicles and the addition of a neck dissection also significantly affected the chance of developing distant metastases.     

Parotid lymph node metastases from squamous cell carcinoma of the skin

Nineteen parotid lymph node metastases from squamous cell carcinoma of the skin were treated, seven with irradiation and 12 with surgery and postoperative irradiation. In the group treated with combined therapy, size of nodal metastasis and extent were strong predictors of relapse. Further postoperative irradiation with 60 Gy is not adequate to control extensive parotid nodal disease. Finally, elective treatment of clinically negative parotid nodes is not necessary in patients who can be closely followed, since early nodal disease can be controlled readily.     

Heat-Stable Alkaline Phosphatase A putative tumor marker of head and neck squamous cell carcinoma

Serum total alkaline phosphatase (AP) activity and heat-stable AP (HSAP) were investigated in patients with uncontrolled squamous cell carcinoma of the head and neck before and after treatment. No significant differences in AP activity were seen between normal subjects and cancer patients. However, the HSAP fraction of the total AP activity was significantly elevated prior to treatment and the level declined and remained low during successful treatment, while it increased with tumor progression or recurrences. Heat-stable AP was found to be a useful tumor marker of potential usefulness in the management of patients with squamous cell carcinoma of the head and neck.     

Combined radiotherapy and surgery in the treatment of neck node metastases from squamous cell carcinoma of the head and neck.

A prospectively recorded series of 107 patients with clinical neck node metastases from head and neck squamous cell carcinomas, treated in 1983-1988, and with initial local control, is evaluated. Eighty-eight patients received preoperative, and were operated 4-6 weeks after radiotherapy, and 19 received postoperative radiotherapy. Forty-four of the neck specimens in the preoperatively treated patients showed vital tumor tissue, 7 with positive and 37 with negative resection margins. Nine of the latter 37 patients died due to regional recurrence. Twenty-three of the preoperatively treated patients had no palpable residual tumor following radiotherapy, but histological examination showed vital tumor tissue in five, of whom two had N1 neck disease. The overall regional failure rate was 19%. Eleven patients (10%) died from local recurrence and 11 from distant metastases. Forty-one patients (38%) are alive without evidence of disease and three (3%) alive with disease (mean observation time 30 months). Combined treatment is recommended for all cases of neck node metastases.     

N1S3: A revised staging system for head and neck cutaneous squamous cell carcinoma with lymph node metastases

BACKGROUND.

A staging system was designed for metastatic cutaneous squamous cell carcinoma (SCC) that would incorporate the parotid as a regional level and facilitate a better prognostic discrimination between subgroups.

METHODS.

A retrospective review of clinical and pathological information of patients treated for metastatic cutaneous SCC to the parotid and/or neck was conducted. Potential prognostic factors were analyzed using univariate and multivariate analyses. A staging system was elaborated and externally validated.

RESULTS.

Two hundred fifteen patients were included. All patients had surgery as their primary treatment; 148 had parotidectomy with neck dissection, 50 parotidectomy alone, and 18 neck dissection alone. One hundred seventy‐five patients received postoperative radiotherapy. On univariate analysis, the number of involved lymph nodes (P < .001), maximal size (P = .01), and extracapsular spread (P = .003) were found to be significant predictors of survival. On Cox regression, the number of involved lymph nodes as single or multiple (P = .006) was significant. The N1S3 staging system incorporates involved lymph nodes from parotid and neck (single or multiple) and the size (< or >3 cm). This system demonstrates significant predictive capacity for locoregional control (P < .001), disease‐specific survival (P<.0001), and overall survival (P<.0001). N1S3 was tested on a different cohort of 250 patients, and the results confirmed those obtained from our primary analyses.

CONCLUSIONS.

The N1S3 system stages patients according to the number of involved lymph nodes and size, and incorporates parotid as 1 of the regional levels. These 2 predictors are easily applied on both clinical and pathological data. Cancer 2010. © 2010 American Cancer Society.