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From the National Cancer Institute (NM, CC, GB, SL, FL, FI), Naples, and the European Institute of Oncology (FC), Milan, Italy.
Correspondence: Address correspondence and reprint requests to: Corrado Caracò, MD, Via Orazio 31, 80122 Naples, Italy; Fax: 39-0815903239; E-mail: corracara{at}inwind.it
ABSTRACT
The most powerful prognostic factor in patients with oral cancer is the presence of lymph node metastases. The management of the neck at diagnosis in the absence of adenopathy is still controversial, but sentinel lymph node biopsy (SLB) may help resolve this issue. At the National Cancer Institute in Naples, we performed SLB in 41 patients with T1 to T2 oral cancer. All patients underwent lymphoscintigraphy. Intraoperative blue dye and gamma probe examination identified a sentinel node (SN) in 39 patients. Four patients (10%) had double drainage, and 7 (18%) had drainage beyond the expected anatomical site. Complete concordance between the pathology of the SN and nodes obtained from radical dissection confirmed SLB as a reliable staging procedure. Since January 2001, seven patients with T1 to T2 oral cancers have been staged with SLB only; modified radical neck dissection was carried out only in cases with a positive SN. The rate of SN identification was 100%, and all five cases with negative SNs were free of disease after a median follow-up of 10 months. Lymphoscintigraphy plus SLB seems to be a good staging system for guiding neck management in patients with oral cancer. A larger number of patients and a longer follow-up in a randomized trial will confirm the potential staging value of this procedure and determine which patients might benefit from a conservative approach that avoids radical neck dissection.
Key Words: Lymphadenectomy • Lymphoscintigraphy • Oral cancer • Sentinel biopsy
Metastasis to the cervical lymph nodes represents the most important prognostic factor and a crucial step in the surgical planning for patients with oral cancer. The role of a prophylactic neck dissection in patients with clinically negative nodes is still controversial because the incidence of occult metastases ranges from 15% to 60%, depending on several prognostic factors.1,2 The promising results of our previous experience with sentinel lymph node biopsy (SLB) and modified radical neck dissection in T1 to T2 oral cancer encouraged us to examine SLB as a staging system for guiding decisions about neck treatment.3 Lymphoscintigraphy in conjunction with SLB seems to resolve unclear issues regarding the lymphatic pathway, explaining ipsilateral and contralateral relapses described in the literature.
METHODS
From 1997 to 1999, 41 consecutive patients with T1 to T2 carcinoma of the tongue and floor of the mouth were studied (group 1).3 None had clinical or radiological evidence of nodal metastases, and none had undergone any prior surgical procedure in the oral cavity or the neck area. Pregnant and lactating women were excluded.
Lymphoscintigraphy with human albumin labeled with 99mTc was performed 2 to 4 hours before surgery by peritumoral injection; serial planar images were acquired within 60 minutes. The hot spot was marked on the overlying skin with India ink and checked just before skin incision with an intraoperative hand-held gamma probe. After general anesthesia prior to commencement of surgery, 0.5 cc of Patent Blue V dye (Jacopo Monico, Mestre, Italy) was injected submucosally around the tumor (Fig. 1). After a few minutes, a 2- to 3-cm incision was made on the neck at the site marked by a nuclear physician, and the sentinel node (SN) was located by both blue dye and radioactivity (Fig. 2). The SN was removed and the operative field checked for residual radioactivity. Modified neck dissection (type III) was performed in all cases. All lymph nodes were studied by standard technique with hematoxylin and eosin. Each SN was divided in many sections and accurately examined. Frozen sections were not used.
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In January 2001, we began a trial of SLB, followed by modified radical neck dissection (MRND) only when the SLB specimen was positive for tumor. The trial was approved by our institutional review board, and all patients signed an informed consent form.
In seven consecutive patients (group 2), SLB was used to stage T1 to T2 carcinoma of the tongue or floor of the mouth. All patients underwent SLB in conjunction with excision of the primary tumor. Patients with tumor-positive SNs underwent neck dissection of five levels. All negative cases were followed every 3 months for the first 2 years and every 6 months thereafter by clinical and ultrasound evaluation.
RESULTS
In group 1, SLB was successful in 39 (95%) of 41 cases. In four patients (10%), double drainage was shown on lymphoscintigraphy; in two of these cases, drainage was contralateral to the tumor. In seven cases (18%), SNs were beyond the expected drainage site and located at levels IV and V. Thirty-nine SNs in 35 patients were negative for micrometastases and correctly predicted the pathological status of the specimen from neck dissection. Four patients had micrometastases, and the SN was the only site of disease after neck dissection. At a follow-up of 42 to 66 months, all patients were free of disease; only one patient developed contralateral metastases in the neck (10 months after surgery).
In group 2, an SN was identified in all cases. In one patient, lymphoscintigraphy revealed double omolateral drainage at levels II and IV. Five patients were negative; the remaining two patients had SN micrometastases and underwent MRND. All cases were free of disease after a follow-up ranging from 12 to 30 months.
DISCUSSION
Lymph node status is the most powerful prognostic factor in the majority of cancers, but in the absence of clinical disease, no radiological modalities or biological marker can accurately reveal micrometastatic disease. Byers et al.4 stated that computed tomography and ultrasonography were no better than clinical examination to correctly stage the disease at diagnosis. Braams et al.5 reported a better result with FDG-PET (positron emission tomography with 18-fluorodeoxyglucose) in identification of nodal metastases larger than 5 mm, but further investigations are necessary to validate these results. SLB has resolved this issue in cutaneous melanoma and breast cancer and is being widely studied in other neoplasms.6 A few investigators have evaluated the role of SLB in oral cavity cancer and reported promising results.3,6–11 Fewer than one-third of patients with clinically negative nodes have lymph node micrometastases, and SLB seems to accurately identify the group requiring a neck dissection. Some important issues remain to be clarified: the timing of biopsy, whether MRND is necessary when the SLB specimen is negative, and the extent of neck dissection when an SLB specimen is positive.
Our results confirm that the analysis of the SN correctly reflects the status of neck nodes: in the four metastatic cases, the SN was the only metastatic site. As previously reported, only one patient developed contralateral metastases 10 months after surgery. Both groups of patients underwent SLB at the time of primary tumor excision, which probably is the best choice because of the lymphatic changes related to a complete excision of the primary site. Chiesa et al.7 used lymphoscintigraphy to evaluate changes in lymphatic drainage before and after surgery of the primary site. Five of six cases had a different scintigraphic pattern postoperatively, which the authors attributed to surgical disruption of lymphatic channels and distant postoperative injection of radiotracer.
The correct timing of neck staging is controversial. Previous studies found that 1.72% of cases recurred in the operated neck in pathologically node-negative patients.12 Some authors identified the biological aspect of tumor cells and how long they take to travel from the primary tumor to the SN as a cause of nodal relapse. Leemans et al.13 explained this finding as an inadequate removal of the lymphatic network when transoral excision was not in continuity with neck dissection. SLB as the only staging procedure, as undertaken in group 2 patients of our study, will clarify the correct timing and indicate whether primary excision and SLB is the ideal policy.
Complete correspondence between pathology of SLB and MRND specimens indicates that SN status can be used to guide decisions regarding neck dissection. The 97% overall accuracy reported by Shoaib et al.8 confirms SLB as an accurate reflector of the status of regional lymph nodes in T1 to T2 tumors. The association of blue dye and radiotracer is the best way to maximize SN identification rate, as is the case for melanoma and breast cancer. More patients and longer follow-up in a randomized trial will clarify the potential staging value of SLB and identify which group of patients might benefit from a conservative approach that avoids unnecessary neck dissections.
In group 1, the seven cases (18%) that had SNs outside the expected drainage area (levels IV and V) explain the failure of a conservative neck dissection (supra-omohyoid or jugular-carotid lymphadenectomy), advocated in the past as possible treatment. Our results correlate very closely with the data of Byers et al.,4 who found that 15.8% of 277 cases had "skip metastases" as the only manifestation of disease in the neck after conservative surgery. This can explain relapses after dissections that do not include all five levels. Other series reported contralateral SN localization at lymphoscintigraphy, confirming a possible nonsequential progression from levels I to V,14 which could be explained by functional rather than anatomical lymphatic drainage. In our group 1, the only recurring case had a contralateral nodal metastasis not identified at the time of lymphoscintigraphy.
The term "skip metastases" becomes incorrect when referring to an anatomical but not functional lymphoscintigraphic evaluation of tumor drainage. As in melanoma and breast cancer,15–17 the closest basin is not the only possible location of metastatic diffusion. Lymphoscintigraphy is essential for staging disease in patients without evidence of clinical metastases. It can indicate patterns of lymphatic diffusion and eliminate the problem of a contralateral dissection in 5% of cases, as proposed by the Brazilian Study Group18 and by Carvalho et al.19
In our group 2, all cases with a positive SLB were treated with MRND, and the specimen revealed no other nodal metastases. This means that the SLB procedure can reflect the neck nodal status. If an SN is positive, all five levels must be dissected because recurrence carries a poor prognosis. Future evaluation with the SLB technique will provide more information regarding intraindividual variations in the distribution of metastatic nodes draining a primary site and indicate when a more conservative approach might be appropriate for patients with SN metastases. Lymphoscintigraphy plus SLB seems to be a good staging system that can clarify the controversial issues in neck management of all patients with oral cancer and clinically normal lymph nodes.
FOOTNOTES
Lymphoscintigraphy plus SLN biopsy seems to be a good staging system for guiding neck management in patients with oral cancer. A larger number of patients and a longer follow-up in a randomized trial will confirm the potential staging value of this procedure and determine which patients might benefit from a conservative approach that avoids radical neck dissection.
Received for publication November 12, 2003. Accepted for publication December 12, 2003.
REFERENCES
This article has been cited by other articles:
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  C. Caraco, U. Marone, E. Celentano, G. Botti, and N. Mozzillo Impact of False-Negative Sentinel Lymph Node Biopsy on Survival in Patients with Cutaneous Melanoma Ann. Surg. Oncol., September 1, 2007; 14(9): 2662 - 2667. [Abstract] [Full Text] [PDF]
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