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Journal of Clinical Oncology, Vol 18, Issue 15 (August), 2000: 2811-2816
© 2000 American Society for Clinical Oncology

Sentinel Lymph Node Procedure Is Highly Accurate in Squamous Cell Carcinoma of the Vulva

By J. A. de Hullu, H. Hollema, D. A. Piers, R. H. M. Verheijen, P. J. van Diest, M. J. E. Mourits, J. G. Aalders, A. G. J. van der Zee

From the Departments of Gynecologic Oncology, Pathology, and Nuclear Medicine, University Hospital Groningen, Groningen; and Departments of Gynecologic Oncology and Pathology, Academic Hospital Vrije Universiteit, Amsterdam, the Netherlands.

Address reprint requests to A.G.J. van der Zee, PhD, Department of Gynecologic Oncology, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands; email a.g.j.van.der.zee{at}og.azg.nl


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the diagnostic accuracy of the sentinel lymph node procedure in patients with squamous cell carcinoma of the vulva and to investigate whether step sectioning and immunohistochemistry of sentinel lymph nodes increase the sensitivity for detection of metastases.

PATIENTS AND METHODS: Between July 1996 and July 1999, 59 patients with primary vulvar cancer were entered onto a two-center prospective study. All patients underwent sentinel lymph node procedure with the combined technique (preoperative lymphoscintigraphy with technetium-99m–labeled nanocolloid and intraoperative blue dye). Radical excision of the primary tumor with uni- or bilateral inguinofemoral lymphadenectomy was performed subsequently. Sentinel lymph nodes and lymphadenectomy specimens were sent for histopathologic examination separately. Sentinel lymph nodes, negative at the time of routine pathologic examination, were re-examined with step sectioning and immunohistochemistry.

RESULTS: In 59 patients, 107 inguinofemoral lymphadenectomies were performed (11 unilateral and 48 bilateral). All sentinel lymph nodes, as observed on preoperative lymphoscintigram, were identified successfully intraoperatively. Routine histopathologic examination showed lymph node metastases in 27 groins, all of which were detected by the sentinel lymph node procedure. The negative predictive value for a negative sentinel lymph node was 100% (97.5% confidence interval [CI], 95% to 100%). Step sectioning and immunohistochemistry showed four additional metastases in 102 sentinel lymph nodes (4%; 95% CI, 1% to 9%) that were negative at the time of routine histopathologic examination.

CONCLUSION: Sentinel lymph node procedure with the combined technique is highly accurate in predicting the inguinofemoral lymph node status in patients with early-stage vulvar cancer. Future trials should focus on the safe clinical implementation of the sentinel lymph node procedure in these patients. Step sectioning and immunohistochemistry slightly increase the sensitivity of detecting metastases in sentinel lymph nodes and should be included in these trials.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE SENTINEL LYMPH node procedure has recently attracted much interest as a new diagnostic tool in common malignancies such as cutaneous melanoma and breast cancer.1,2 The sentinel lymph node is defined as the first draining lymph node, and the pathology of the sentinel lymph node would be representative for the nonsentinel lymph nodes, implying that a negative sentinel lymph node predicts the absence of tumor metastases in the other nonsentinel lymph nodes.1 Sentinel lymph node procedure has become a standard technique for determining the nodal stage of disease in patients with cutaneous melanoma.3,4 In breast cancer, the sentinel lymph node procedure has proven to be so reliable that it is more and more used as an axillary staging procedure,5 although it is not yet standard of care.6

Currently, standard treatment for early-stage squamous cell carcinoma of the vulva is wide local excision and uni- or bilateral inguinofemoral lymphadenectomy via separate incisions. There is general agreement that inguinofemoral lymphadenectomy is indicated for those patients who have lymph nodes that are clinically suggestive of metastases. In patients without clinically suggestive lymph nodes, however, only approximately 20% will have lymph node metastases. The other 80% will probably not benefit from the lymphadenectomy, but they are at risk for its significant morbidity (wound infection, leg edema, and so on).7 At present, no reliable noninvasive technique is available to discriminate between patients with and without microscopic inguinofemoral lymph node metastases, and therefore routine lymphadenectomy is performed in all patients. To obviate the negative side effects of full inguinofemoral lymphadenectomy, the application of the minimally invasive sentinel lymph node procedure is currently explored in patients with primary vulvar cancer. In pilot studies by us and others, 8-12 the sentinel lymph node procedure proved to be feasible in patients with primary vulvar cancer. Before abandoning routine inguinofemoral lymphadenectomy, however, especially the false-negative rate of the sentinel lymph node procedure must be established in larger studies.

Another issue in the sentinel lymph node procedure is the accuracy of histopathologic examination of the sentinel lymph nodes. Recent studies in cutaneous melanomas13 and breast cancer14 show that detection of metastases in sentinel lymph nodes in these tumors is improved by additional step sectioning and immunohistochemical staining. Comparable data for sentinel lymph nodes of vulvar cancer are not yet available.

In the present study, a very high diagnostic accuracy of the sentinel lymph node procedure in patients with early-stage vulvar cancer is reported. Furthermore, the feasibility of performing step sectioning and immunohistochemistry for detection of metastatic disease in sentinel lymph nodes is evaluated.


    PATIENTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Patients with primary squamous cell cancer of the vulva were referred to the Groningen University Hospital, Groningen, and Academic Hospital Vrije Universiteit, Amsterdam, the Netherlands, for treatment. Patients with T1 (<= 2 cm) or T2 (> 2 cm) tumors that did not encroach in the urethra, vagina, or anus and whose inguinofemoral lymph nodes were not clinically suggestive of metastasis were eligible for the study. Approval for the study was given by the medical ethics committee in both hospitals, and written informed consent was obtained from each patient.

Sentinel Lymph Node Procedure
Sentinel lymph node procedure was performed as previously described.10 In short, the day before operation 0.2 to 0.6 mL of 60-MBq technetium-99m–labeled nanocolloid (Solco Nuclear, Birfelden, Switzerland) was injected circumferentially intradermally around the tumor and lymphoscintigraphy was performed. One half of an hour before the injections, lidocaine-prilocaine 5% cream (EMLA, Astra Pharmaceuticals, LP, Westborough, MA) was applied on the vulva for pain relief. The sites of the sentinel lymph nodes were marked on the skin with a pencil. On the following day after general anesthesia, 2.0 mL of patent blue V dye (2.5% in aqueous solution containing 0.6% sodium chloride and 0.05% disodium hydrogen phosphate; Laboratoire Guerbet, Aulney-Sous-Bois, France) was injected at the same localizations. Sentinel lymph nodes were identified using a handheld probe (Neoprobe; Neoprobe Corp, Dublin, Ireland) and dissection of blue-stained lymph vessels and were removed separately. After removal of the first sentinel lymph node, the groin was re-examined for radioactivity, and if radioactivity was detected at a level greater than 10% of the first excised sentinel lymph node, the dissection was continued in search of additional sentinel lymph nodes. Subsequently, routine inguinofemoral lymphadenectomy was performed. The removed sentinel lymph nodes and the lymphadenectomy specimens were sent to the pathologist separately.

Operation
Treatment consisted of radical excision of the primary tumor in combination with uni- or bilateral inguinofemoral lymphadenectomy via separate incisions. In general, bilateral lymphadenectomy was performed, except in patients with small unilateral lesions. A unilateral tumor was defined as a lesion that did not cross the midline, with the medial margin of the tumor more than 1 cm from the midline structures.15 The primary tumor was excised with a margin of at least 1 cm of normal skin.

Histopathologic Examination
For routine histopathologic examination of all of the lymph nodes, one section per 0.5 cm of the node was cut and stained with hematoxylin/eosin (H/E). Of all sentinel lymph nodes that were negative on routine histopathologic examination, additional pairs of sections were subsequently cut with three sections/mm. One section of each pair was stained with H/E and the other section was immunostained with cytokeratin 1% AE1:AE3 antikeratin solution (Boehringer Mannheim, Mannheim, Germany). The additional sections were scrutinized by the pathologists (H.H./P.J.v.D.), who were unaware of the clinical results.

Statistics
Data were entered in a computerized database and analyzed using SPSS software (Version 9.0 for Windows, SPSS, Inc, Chicago, IL). Sensitivity and negative predictive values with 95% confidence intervals (CI) were calculated.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Between July 1996 and July 1999, 66 consecutive eligible patients were asked to participate. Seven patients refused because of fear of pain. Median patient age was 69 years (range, 33 to 92 years). Twenty-five patients had T1 tumors and 34 patients had T2 tumors. In 11 patients with lateralized tumors, a unilateral inguinofemoral lymphadenectomy was performed. In the other 48 patients, bilateral inguinofemoral lymphadenectomy was performed; therefore, 59 patients underwent a total of 107 inguinofemoral lymphadenectomies (data of 10 patients were previously described).10

Sentinel Lymph Node Procedure
Sentinel lymph node procedure was uneventful in all 59 patients. In 12 patients, the primary tumor was primarily located either on the right or left labium, but with an extension of the medial margin of the tumor less than 1 cm of the midline. According to the previously mentioned definition,15 these patients were treated as having a midline tumor and therefore a bilateral inguinofemoral lymphadenectomy was performed. However, in all of these 12 patients and in another 11 patients with "true" lateral tumors, preoperative lymphoscintigram showed sentinel lymph nodes only on the ipsilateral sides of the tumors. In 59 patients, 107 inguinofemoral lymphadenectomies were performed, and sentinel lymph nodes were identified in 95 groins. In these 95 groins, a total of 139 sentinel lymph nodes were identified: one sentinel lymph node was identified in 59 groins, two sentinel lymph nodes were identified in 29 groins, three sentinel lymph nodes were identified in six groins, and four sentinel lymph nodes were identified in one groin. All sentinel lymph nodes were identified in the region above the cribriform fascia over the fossa ovalis. Identification mainly relied on the handheld probe, because only 60% of the sentinel lymph nodes were visible with the blue stain.

Histopathologic Examination
On routine H/E examination, 37 sentinel lymph nodes in 20 patients (27 groins) showed metastatic disease (Tables 1 and 2). Unilateral-positive lymph nodes were found in 13 patients, and bilateral positive sentinel lymph nodes were found in seven patients. In 95 lymphadenectomy specimens, 1,077 lymph nodes were examined (median of 12 lymph nodes per groin; range, four to 19 nodes). The sentinel lymph nodes were negative in 68 groins, and the nonsentinel lymph nodes were also without metastatic disease in those groins (ie, no false-negative sentinel lymph nodes were found). The negative predictive value of a negative (68 groins) or absent sentinel lymph node (12 groins) was 80/80, or 100% (97.5% CI, 95% to 100%). Regarding patients, no false-negative sentinel lymph nodes were found in 39 patients (negative predictive value of 39/39, or 100% (97.5% CI, 91% to 100%). In 15 of the 27 groins with positive sentinel lymph nodes, all of the other nonsentinel lymph nodes were negative, whereas in 12 groins, nonsentinel lymph nodes also showed metastases. On step sectioning and immunohistochemistry of the 102 sentinel lymph nodes that were negative on routine examination, four additional metastases were found (4%; 95% CI, 1% to 9%). Figure 1 shows one of the additional metastases after step sectioning, confirmed by immunohistochemistry in Fig 2. Three of the four metastases were observed in patients whose lymph nodes were negative on routine examination. One additional metastasis was found in a patient who already had another sentinel lymph node with metastatic disease. The modified negative predictive value is 77/77, or 100% (97.5% CI, 95% to 100%). Because step sectioning and immunohistochemistry were not performed on nonsentinel lymph nodes, no information is available on the incidence of false-negative sentinel lymph nodes regarding step sectioning and immunohistochemistry. The sensitivity of routine examination versus step sectioning and immunohistochemistry of sentinel lymph nodes is 37/40, or 93% (95% CI, 80% to 98%), in terms of nodes or 20/23, or 87% (95% CI, 66% to 97%), in terms of patients.


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Table 1. Overview of 95 Groins With SLNs in 59 Patients: Number of SLNs and Metastases*
 


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Fig 1. Additional lymph node metastasis (diameter of 0.3 mm) after step sectioning.

 


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Fig 2. Confirmation of the lymph node metastasis by immunohistochemistry.

 

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Table 2. Overview of 107 Dissected Groins in 59 Patients: Number of Groins With or Without SLNs and Histopathology of SLNs and Non-SLNs
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The technique of the sentinel lymph node procedure has gained increasing attention since its introduction in melanomas by Morton et al.1 In patients with vulvar cancer, sentinel lymph node identification with the combined technique (preoperative lymphoscintigraphy with technetium-99m–labeled nanocolloid and intraoperative blue dye) seemed to be feasible in four small (n = 5 to 10) series of patients.9-12 The present study shows that the sentinel lymph node procedure with the combined technique is a highly accurate diagnostic procedure in patients with vulvar cancer. In our series of 59 patients, no false-negative sentinel lymph nodes were found on routine examination, yielding a negative predictive value of the sentinel lymph node procedure of 100% (97.5% CI, 95% to 100% for groins, 91% to 100% for patients). Recently, a multicenter study was reported on the negative predictive value of the sentinel lymph node procedure with blue dye only in vulvar cancer.16 In contrast to our present study, sentinel lymph node detection was only possible in 56% of patients, and a false-negative sentinel lymph node was found in two of 51 patients. Our superior results compared with those of Ansink et al16 confirm observations from earlier reports in melanoma17 and breast cancer,6 which already showed that the combined technique is superior to blue dye for sentinel lymph node identification. The 100% identification rate of sentinel lymph nodes in our present study is quite high also when compared with many studies in melanoma3 and breast cancer6 in which identification rates of sentinel lymph nodes of 91% to 100% and 87% to 98%, respectively, were reported. One possible explanation for our high identification rate may be that in vulvar cancer, the anatomy of lymph channels to the inguinofemoral lymph nodes seems to vary only minimally (compared with the sometimes unpredictable lymph flow of cutaneous melanoma). This minimal variation in anatomy of the lymph channels in vulvar cancer is also illustrated by the fact that in all of our patients, the sentinel lymph nodes were located above the cribriform fascia over the fossa ovalis. Lack of any false-negative sentinel lymph nodes in our study is probably also due to this clear anatomy. In 12 patients with a tumor on either the right or left labium (but a midline tumor according to definition), only ipsilateral sentinel lymph nodes were visible on the lymphoscintigraphy. We have used the following clinical definition of a lateralized tumor: a lesion that does not cross the midline, with the medial margin of the tumor more than 1 cm from the midline. These 12 patients, however, had a "midline tumor" because of extension of the medial margin less than 1 cm from the midline and should undergo bilateral lymphadenectomy. Apparently, there was no lymph flow to the contralateral side, which excludes the risk on contralateral lymph node metastases.

It is generally accepted that there is a learning curve in performing the sentinel lymph node procedure. Morton et al18 suggested a learning phase of at least 30 consecutive cases per center for cutaneous melanoma. Because of the minimal variations in anatomy of lymph channels from the vulva to the inguinofemoral lymph nodes, the learning curve in vulvar cancer will probably be steeper. In our opinion at least the first 10 patients (with sentinel lymph node procedures in 15 to 20 groins) should be regarded as comprising the learning phase for the sentinel lymph node procedure.

It is remarkable that we found a high overall percentage of patients with lymph nodes metastases (20 of 59 patients, or 34%). This may be explained by more than 50% of patients having T2 lesions. Another reason for the observed overall high percentage of patients with lymph node metastases may be that nodes that are normally missed in routine examination of lymphadenectomies are now detected, because more attention is paid to the examination of the sentinel nodes.

In view of the high diagnostic accuracy of the sentinel lymph node procedure in early-stage vulvar cancer, future trials should focus on safe clinical implementation of the sentinel lymph node procedure in these patients. Before application of the sentinel node technique in routine practice for patients with cutaneous melanoma, a randomized study was performed in which patients were randomized between elective lymph node dissection and sentinel lymph node procedure (with only lymphadenectomy if sentinel lymph node(s) showed metastatic disease).19 Survival rates seemed to be equivalent for the two groups, and similar incidences of same-basin recurrences were found. An observational study of 243 patients with cutaneous melanoma and negative sentinel nodes showed that 10 patients (4.1%) developed regional nodal failure.20 In breast cancer, observational and randomized trials on the sentinel lymph node procedure are ongoing. Until now, few randomized trials have been performed in vulvar cancer because of the low incidence of this tumor type and the excellent prognosis of early-stage vulvar cancer with current standard treatment. To further explore the application of the sentinel lymph node procedure in vulvar cancer, we are currently designing a so-called two-step randomized multicenter study: in step 1, participating centers must perform sentinel lymph node procedures with subsequent full inguinofemoral lymphadenectomy in 10 patients as part of the learning curve. When a center has successfully completed step 1, subsequent patients with negative sentinel lymph nodes will be randomized to either complete inguinofemoral lymphadenectomy or observation in step 2. Primary end points in this study will be to demonstrate (1) equivalence for groin recurrences between the two arms, and (2) improved quality of life for patients in the observational arm. A major drawback of such a study design is the large number of patients with vulvar cancer required (n = approximately 500). In the end, it may well be that the only feasible study design for application of the sentinel node technique in patients with vulvar cancer will be an observational study design with stopping rules.

The predictive value of the sentinel lymph node also depends on the accuracy of the histopathologic investigation. Our study shows that step sectioning and immunohistochemistry do have a higher sensitivity as compared with routine H/E examination, although the gain was limited to 4% of the routinely negative sentinel lymph nodes. In other types of cancer, the same techniques detected micrometastases in 10% to 20% of originally negative sentinel lymph nodes.13,14,21,22 The relatively low number of additionally detected metastases in our study might be explained by the fact that squamous cancer cells are easier to identify in lymph nodes than in melanoma or breast cancer cells because of their more distinct morphology. Owing to the improvement in the detection rate of metastatic cells, the intensive histopathologic work-up of sentinel lymph nodes by step sectioning and immunohistochemistry has become customary. An even more refined (molecular biologic) approach to detect micrometastases is by the use of reverse transcriptase polymerase chain reaction,14 which has also been described for detection of squamous cell carcinomas.23 Detection of occult metastases by reverse transcriptase polymerase chain reaction is a very sensitive method, but contamination risks are high and false-positive results in healthy individuals have been described.14 An important issue in the discussion of the application of more sensitive techniques to identify metastases is the clinical importance of the detection of these micrometastases. Giard and Coebergh24 warn of stage migration on the basis of micrometastases, although it is yet unclear whether resulting changes in treatment policy will benefit these women.

In conclusion, the sentinel lymph node procedure with the combined technique is highly accurate in predicting the inguinofemoral lymph node status in patients with early-stage vulvar cancer. Future trials should focus on the safe clinical implementation of the sentinel lymph node procedure in these patients. Step sectioning and immunohistochemistry slightly increase the sensitivity of detecting metastases in sentinel lymph nodes and should be included in these trials.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992[Abstract]

2. Giuliano AE, Kirgan DM, Geunther JM, et al: Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 220:391-398, 1994[Medline]

3. Statius Muller MG, van Leeuwen PAM, Borgstein PJ, et al: The sentinel node procedure in cutaneous melanoma: An overview of 6 years’ experience. Eur J Nucl Med 26:S20-S25, 1999 (suppl 4)[Medline]

4. Gershenwald JE, Thompson W, Mansfield PF, et al: Multi-institutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17:976-983, 1999[Abstract/Free Full Text]

5. Diest PJ van, Torrenga H, Borgstein PJ, et al: Reliability of intraoperative frozen section and imprint cytological investigation of sentinel lymph nodes in breast cancer. Histopathol 35:14-18, 1999[Medline]

6. Nieweg OE, Jansen L, Valdes Olmos RA, et al: Lymphatic mapping and sentinel lymph node biopsy in breast cancer. Eur J Nucl Med 26:S11-S16, 1999 (suppl 4)[Medline]

7. Hacker NF: Vulvar cancer, in Berek JS, Hacker NF(eds): Practical Gynecologic Oncology (ed 2). Baltimore, MD, Williams & Wilkins, 1994, pp 403-439

8. Levenback C, Burke TW, Gershenson DW, et al: Intraoperative lymphatic mapping for vulvar cancer. Obstet Gynecol 84:163-167, 1994[Abstract/Free Full Text]

9. Decesare SL, Fiorica JV, Roberts WS, et al: A pilot study utilizing intraoperative lymphoscintigraphy for identification of the sentinel lymph nodes in vulvar cancer. Gynecol Oncol 66:425-428, 1997[Medline]

10. De Hullu JA, Doting E, Piers DA, et al: Sentinel lymph node identification with Technetium-99m-labeled nanocolloid in squamous cell cancer of the vulva. J Nucl Med 39:1381-1385, 1998[Abstract/Free Full Text]

11. Terada KY, Coel MN, Wong JH: Combined use of intraoperative lymphatic mapping and lymphoscintigraphy in the management of squamous cell cancer of the vulva. Gynecol Oncol 70:65-69, 1998[Medline]

12. Rodier JF, Janser JC, Routiot T, et al: Sentinel node biopsy in vulvar malignancies: A preliminary feasibility study. Oncol Rep 6:1249-1252, 1999[Medline]

13. Yu LL, Flotte TH, Tababe KK, et al: Detection of microscopic melanoma metastases in sentinel lymph nodes. Cancer 86:617-627, 1999[Medline]

14. Van Diest PJ, Peterse HL, Borgstein PJ, et al: Pathological investigation of sentinel lymph nodes. Eur J Nucl Med 26:S43-S49, 1999 (suppl 4)[Medline]

15. Burger MPM, Hollema H, Bouma J: The side of groin node metastases in unilateral vulvar carcinoma. Int J Gynecol Cancer 6:318-322, 1996

16. Ansink AC, Sie-Go DMDS, van der Velden J, et al: Identification of sentinel lymph nodes in vulvar carcinoma patients with the aid of patent blue V injection. Cancer 86:652-656, 1999[Medline]

17. Kapteijn BA, Nieweg OE, Liem I, et al: Localizing the sentinel node in cutaneous melanoma: Gamma probe detection versus blue dye. Ann Surg Oncol 4:156-160, 1997[Abstract]

18. Morton DL, Thompson JF, Essner R, et al: Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: A multicenter trial—Multicenter selective lymphadenectomy trial group. Ann Surg 230:453-463, 1999[Medline]

19. Essner R, Conforti A, Kelley MC, et al: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6:442-449, 1999[Abstract]

20. Gershenwald JE, Colome MI, Lee JE, et al: Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 16:2253-2260, 1998[Abstract]

21. Turner RR, Ollila DW, Stern S, et al: Optimal histopathologic examination of the sentinel node for breast carcinoma staging. Am J Surg Pathol 23:263-267, 1999[Medline]

22. Ambrosch P, Brinck U: Detection of nodal micrometastases in head and neck cancer by serial sectioning and immunostaining. Oncology 10:1221-1226, 1996[Medline]

23. Chaubal S, Wollenberg B, Kastenbauer E, et al: Ep-CAM: A marker for the detection of disseminated tumor cells in patients suffering from SCCHN. Anticancer Res 19:2237-2242, 1999[Medline]

24. Giard RW, Coebergh JW: Increasingly sophisticated detection of lymph node metastases: The problem of stage migration. Ned Tijdschr Geneeskd 143:1766-1771, 1999[Medline]

Submitted January 5, 2000; accepted April 12, 2000.




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