Abstract
Background/Aim: Primary radiochemotherapy (RCT) is becoming increasingly important in patients with oro- and hypopharyngeal cancer. However, debate exists on the extent of salvage neck dissection (ND) in those patients. The purpose of the present study was to evaluate the regional control after salvage ND. Patients and Methods: Clinical, histological and radiological data, results of 51 patients with oro- or hypopharyngeal cancer and N2 neck who underwent selective ND in case of radiological evidence of residual neck disease, were retrospectively analyzed. Results: Altogether 52 metastases were detected in 20 (39.2%) patients by histological examination. They were localized in level II (n=23), III (n=13), IV (n=11) and V (n=5). Regional recurrence occurred in 4 patients (7.8%) in previous dissected neck levels in the follow-up. Conclusion: Selective ND of suspicious neck levels for residual disease after RCT of oro- and hypopharyngeal cancer seems to be a sufficient treatment.
- Salvage neck dissection
- oropharyngeal cancer
- hypopharyngeal cancer
- residual neck disease
- selective neck dissection
Primary radiochemotherapy (RCT) is being increasingly applied as an organ-preserving treatment in patients with advanced head and neck squamous cell carcinoma (HNSCC). Especially in the case of oro-, and hypopharyngeal cancer with lymphogenic metastasis, primary RCT is increasingly advocated. However, compared to the response rate of the primary tumor, worse results are observed for neck lymph node (LN) metastases. Previous investigations have revealed complete response rates of the primary tumor and neck metastases in up to 86% and 69% of examined cases, respectively (1). In this context the response of neck metastases depends on the size of the initial neck disease with a decrease from about 80% for N1 necks to about 40% for N3 necks (2).
Formerly a planned neck dissection (ND) was advocated for all patients with initial positive neck nodes regardless of response to RCT. However, the cervical recurrence rate of patients with a complete cervical response after primary RCT seems to be less than 5% in the follow-up (3). These results are similar to control rates reported in patients without residual disease who underwent salvage ND (4). Thus, salvage ND seems not to be required in patients without clinical evidence of residual neck lymph node metastases (5). Agreement exists on the need for salvage ND in patients with residual or recurrent tumor in the neck after organ-preserving therapy. However, due to increased morbidity of surgical therapy after RCT the extent of salvage ND is still a matter of controversial debate. Until now, there are only few studies to have evaluated the oncological results after selective ND as salvage treatment after RCT for advanced HNSCC in a relatively inhomogeneous group of patients (6-10). Most studies included patients with different clinical tumor stages including complete cervical response as well as residual neck node metastasis after RCT (6, 8, 9, 10).
Opposing this background, the aim of the present study was to evaluate the efficacy of selective ND in patients with oro- and hypopharyngeal cancer and N2 neck with clinical evidence of residual disease in the neck after primary RCT.
Patients and Methods
Clinical and inclusion criteria. The clinical and histological data of patients with advanced oro- and hypopharyngeal cancer who underwent a uni- or bilateral salvage ND because of radiological evidence of residual neck disease were retrospectively analyzed. Only patients with squamous cell carcinoma, N2 neck, as well as radiological- and histological-proven complete response of the primary tumor to RCT were included. Furthermore patients, who underwent former neck treatment, as well as patients with a metachronous second primary were excluded. Patients with a follow-up of less than 1 year, except for cases of death were excluded from the study.
In addition, all patients underwent a similar radiochemotherapy regime. Radiotherapy was carried out 5 days a week up to a total dose of 72 Gy. In the first 3 weeks radiotherapy was applied by 2-Gy fractions per day, followed by 2×1.4-Gy fractions per day in the next 3 weeks. Chemotherapy consisted of 5-fluorouracil (5-FU) as continuous infusion at 600 mg/m2/24 h during days 1–5 and mitomycin c (MMC) that was given at 10 mg/m2 on day 5 and day 36 (n=37) or 6 cycles of cisplatin (30 mg/m2) weekly (n=9). Five patients received cetuximab instead of 5-FU at 400 mg/m2 on day -7 before start of radiotherapy followed by weekly doses of 250 mg/m2 during the 6 weeks of radiotherapy.
Altogether 51 patients (10 females and 41 males, median age at diagnosis 57.4 years (range=38-77 years) fulfilled the above mentioned inclusion criteria. The clinical data of all patients, including tumor localization, tumor stage, and the development of locoregional recurrence are summarized in Table I.
Clinical staging after RCT. Prior to salvage treatment all patients were staged 10-12 weeks after the end of RCT via ultrasonography of both neck sides in combination with computed tomography (CT) with or without positron emission tomography (PET) or magnetic resonance imaging (MRI) of the neck. Sonographic examination was routinely performed by using a 7.5-MHz transducer (Sonoline G60 S, Siemens Medical Solutions, Andover, MA, USA). An endoscopy was performed for biopsy and histological determination of residual disease in the area of the primary tumor.
Salvage neck treatment. Altogether 72 selective ND were performed in 51 patients 10-12 weeks after the end of RCT. Selective ND was carried out unilaterally (n=30; 58.8%) for tumors with unilateral radiological evidence of residual LN metastases, even in the case of initial bilateral neck disease. Bilateral SND (n=21; 41.2%) was performed in patients with bilateral evidence of LN metastases after primary RCT. Different types of SND were performed according to the extent of radiological proven residual neck disease and localization of the primary tumor. In most cases SND of levels II-IV (n=33) were carried out. The frequency of dissected neck levels are summarized in Figure 1. All neck levels were removed separately and marked by pins for histological consideration.
Follow-up. Follow-up examination consisted of clinical inspection and palpation of the upper aerodigestive tract as well as ultrasound imaging of the neck bilaterally. During the first two years after diagnosis, the neck was examined in 4 to 8 week intervals, during the third year post-diagnosis, every 3 months, during the fourth year every 6 months and from the fifth year onwards every 12 months. The average follow-up period was 3.4 years (range=0.8-11 years) for all patients. In patients with a suspicion for a locoregional recurrence or a secondary tumor, further diagnostic procedures including fine needle aspiration cytology (FNA) of suspicious neck nodes, panendoscopy and CT-scan of the neck were conducted.
Statistical analysis. Clinical and histological characteristics of involved patients were evaluated by descriptive analysis. Clinical characteristics included age, sex, tumor site, T-stage, N-stage, the development of local and/or regional recurrence as well as second primary or distant metastases in the follow-up period. The analyzed histological characteristics were tumor differentiation, presence of residual tumor, the number of detected lymph node metastases, extracapsular spread and the distribution pattern of residual lymph node metastases.
Patients and treatment characteristics (n=51).
Results
Histopathological examination of 936 lymph nodes revealed altogether the presence of 52 metastases in 20 patients (39.2%). In 31 patients (60.8%) histological examination revealed no evidence of vital tumor cells. Uni- and bilateral LN metastases were observed in 18 (35.3%) and 2 (3.9%) cases respectively. In 9 (17.6%) patients perinodal invasion was detected. The residual LN metastases were mostly localized in level II (n=23; 44%), level III (n=13; 25%) and level IV (n=11; 21%) (Figures 2 and 3).
Only few patients suffered from LN metastases in level V (n=4; 8%) and none in level I. In all patients with residual disease in level V, one (n=3) or two (n=1) metastases were detected unilaterally in the case of oro- (n=2) or hypopharyngeal cancer (n=2). Perinodal spread was detected in 2 of 4 cases. All metastases were preoperatively clinical and radiological apparent. None of the patients showed isolated LN metastases. In patients with level V metastases the histopathological examination of ND specimens revealed further LN metastases in at least one other neck level II, III or IV (Table II).
Number of dissected LN levels in the context of salvage ND for advanced oro- and hypopharyngeal cancer.
Regional neck recurrence, altogether occurred in 4 (7.8%) patients in the follow-up. Recurrent lymph node metastases were observed in previous dissected neck level II (n=2) and IV (n=4) without evidence for local recurrence, which was observed in 7 (13.7%) patients. Second primary tumor occurred in 8 (15.7%) patients and 19 (37.3%) patients suffered from distant metastases in the further course.
Discussion
The key point in planning salvage ND after primary treatment by RCT is detection of suspect residual cervical lymph nodes. However, conventional imaging techniques are characterized by a partly insufficient sensitivity and specificity. Thus, in patients with suspicion of regional residual or recurrent disease after chemoradiation ultrasound-guided FNAC achieves a sensitivity of 80% and a specificity of only 42% (9). Thus, radiological prediction on the dignity of residual findings may be difficult by conventional diagnostics. In this context PET-CT, which has a high negative predictive value seems to be a valuable examination method for determination of the residual tumor in the neck area. PET-CT is recommended for the identification of cervical metastases and to verify possible distant metastases (11). However, the positive predictive value and specificity of PET-CT seem to be low (12). Thus, there is a lack of agreement between clinical and histopathological findings. Furthermore, it must be mentioned, that the therapeutic effect of RCT may last over the end of treatment. Therefore, radiological staging like PET-CT for possible planning of neck dissection should be performed approximately 12 weeks after the end of radiotherapy to avoid false-positive results (13). In the present study all patients showed clinical-apparent residual metastases upon clinical and radiological examination after RCT. However, vital tumor cells were detected in less than half of patients (39.2%) by histological examination. These results are in accordance with those of former studies, that also found vital tumor cells in 40% (range=20-68%) of the patients with clinical partial response of the neck (14-16).
Number of dissected LN and LN metastases of each neck level in the context of salvage ND for advanced oro- and hypopharyngeal cancer.
Distribution pattern of residual lymph node metastases in the context of salvage ND for advanced oro- and hypopharyngeal cancer.
The frequency of detecting residual disease in the neck also depends on the histopathological methods used to detect vital tumor cells. In the present study vital tumor cells were identified morphologically without immunostaining of epithelial-associated antigens. Various immunohistochemical investigations have found micrometastases in up to 58% (mean=19.6%) of patients who had no evidence of lymph node metastases in routine pathological assessment (17-19). Thus, prevalence of vital tumor cells may be underestimated in the present study. However, half of the patients underwent ND without histological evidence of vital tumor cells.
Thus far, accurate assessment of regional response to RCT may be achieved only by histological examination in terms of salvage ND that may be associated with possible complications and an increased postoperative morbidity. In this context mortality and morbidity depend on the extent of surgical intervention as well as the specific conditions of patients such as relevant previous diseases, e.g., heart or lung diseases, or immunosuppression. Opposite to this background less invasive treatment procedures like selective ND should be beneficial. Apart from the reduced surgery time, selective ND has the advantage of a comparably lower morbidity compared to modified or radical ND (20, 21). In a retrospective evaluation of 52 patients, we analyzed the functional and aesthetic results after SND of different extent and regions (22). Although 80% of the examined patients underwent preoperative radiotherapy, acceptable functional and aesthetic results could be achieved. A comparative investigation of the quality of life of patients after exclusive RCT and ND after RCT revealed that patients with additionally performed ND had not a significant difference in the quality of life. Only in the domain of pain significant differences could be revealed (23). However, the question arises, whether such a less invasive treatment may be associated with worse oncological results.
Clinical characteristics of patients with LN metastases in level V after primary RCT for advanced oro- and hypopharyngeal cancer.
A function-preserving approach by selective ND is based on predictable patterns of lymph node metastasis in HNSCC and the assumption that uninvolved neck levels prior to treatment should have a very low risk of occult disease after RCT (24). The lymphatic drainage of the oro- and the hypopharyngeal region is effectuated via collectors mainly into the lymph nodes of levels II, III, and in case of the hypopharyngeal region also into lymph nodes of level IV. Retropharyngeal lymph nodes are affected in the lymphatic drainage of the posterior and lateral wall of the mentioned regions (11). Thus, lymph node metastases of level I or level V rarely occur in these patients, even in cases of N+ necks, and are mostly associated with lymph node metastases of other neck regions (25, 26). In former studies it could be confirmed that the lymph nodes in the levels I and V (except from cancers of the oral cavity) only rarely show tumor residues while metastatic tumor residues occur nearly exclusively in the levels II-IV (7). Histological examination in the present study also revealed lymph node metastases mainly in level II to IV that corresponds to the results of previous studies.
In contrast to the traditional philosophy of removing lymph node groups in all five neck levels, selective ND of suspicious neck levels with radiological evidence for residual disease involves the risk of missing occult lymph node metastases. Therefore selective ND might be associated with a higher risk of regional recurrence outside dissected lymph node levels. However, in patients with advanced regional disease at presentation (N2) with planned selective ND after RCT subsequent neck failure seems to be less than 5% (9, 27, 28) which compares favorably with the performance of more extensive forms of ND in the same setting (29). Thus, some authors advocate the suitability of SND after RCT even in the case of initial advanced regional disease (6, 9, 30, 31) as well as partial regional response after RCT (7, 32). The feasibility of performing a super-selective ND for patients after RCT has also been addressed (33). Robbins et al. showed that even a super-selective ND of two contiguous neck levels may be an adequate treatment for patients with clinical evidence for a single neck node metastases limited to one neck level (8, 34). In a further series of 35 patients with super-selective ND and a median follow-up of 33 months (range=8-72 months), there were 8 recurrences, all of which occurred either at the primary or distant sites, without isolated recurrences in the neck (24). Recently, Cannady et al. (14) reported their experience with different types of ND in a group of 241 patients with stage IV HNSCC. No differences in regional failure were found based on the type of ND and selective ND would have removed residual disease in most cases, if the dissection had encompassed the next distal level. However, the specific study lacks important information about the indications for neck dissection and the criteria to determine the extent of ND. In the present study, regional recurrence was observed in about 8% of all patients. All regional recurrences occurred in previous dissected neck levels. Thus, even by a more radical approach these recurrences would not have been prevented. However, it should be considered, that in some reports in about 20% of the patients undergoing selective or super-selective ND, for adequate resection of residual disease, it is necessary to remove either the internal jugular vein, a part of sternocleidomastiod muscle or the spinal accessory nerve, which may be associated with further morbidity (8).
To date, the oncological value of the residual lymph node disease is not clarified in detail. An extensive review article analyzed the significance of lymphadenectomy in solid tumors and revealed that lymph node dissection does not lead to a significant improvement in the total survival (35). Thus, the value of ND in N0 or N+ necks and salvage neck treatment cannot be exactly defined at the moment.
Conclusion
SND of residual disease in radiological examination is an adequate salvage treatment for patients with radiological evidence of neck metastases after primary RCT for advanced oro- and hypopharyngeal cancer. Residual disease is almost localized in the high-risk levels II, III and IV.
Footnotes
Conflicts of Interest
None.
Financial Disclosure
Nothing to disclose.
- Received December 14, 2015.
- Revision received January 24, 2016.
- Accepted February 2, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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