Sentinel Node Biopsy

The "status" of the regional lymph nodes has always been important to oncologists. Determining whether the regional nodes do or do not contain tumor is a crucial element in the evaluation and management of most cancer patients. For years, surgeons have routinely removed the regional nodal basins in conjunction with the resection of the primary tumor. Few would argue the palliative benefit of removing isolated bulky disease that is amenable to surgery. Far more frequently, however, surgical resection is performed for nonpalpable nodes in asymptomatic groins and axillae.

Whether or not resecting clinically negative regional lymph nodes imparts any surgical advantage is controversial. For years, the pros and cons of prophylactic lymph node dissection in the management of melanoma have been debated. The early experience of the National Surgical Adjuvant Breast and Bowel Project (NSABP) challenged the concept that in patients with breast cancer, a survival benefit was achieved by axillary dissection. Despite the ongoing controversy, the value of the prognostic information that is obtained from histologically examining these nodes is indisputable. Despite the plethora of tumor markers and "prognostic factors" currently used to predict an individual's outcome nodal status remains one of the most reliable of indicators. Treatment strategies frequently hinge on the presence of nodal metastasis as well as the number of nodes involved. Unfortunately merely relying upon the clinical assessment of these basins can result in notoriously wrong information.

Lymph Mapping

Our understanding of the lymphatic system is based upon early anatomic studies dating back to the nineteenth century. These findings influenced the guidelines which evolved governing the surgical management of various malignancies; nevertheless, despite elaborate anatomical detail, there still remained considerable ambiguity particularly when predicting lymph drainage patterns on the torso and regions of the head and neck. For many tumors this uncertainty posed a considerable dilemma. Trying to determine which basin a truncal melanoma positioned along or in proximity to the midline or midtorso might drain was difficult. Because of such confusion in many clinical scenarios, more than one bed was dissected or the one chosen for dissection would prove to be free of disease while the remaining basin would ultimately prove clinically to be the site of metastasis.

With the advent of lymphoscintigraphy techniques in the 1980's¹ it became possible to better characterize lymph drainage patterns particularly within the skin and soft tissues. Lymphatic and lymph node mapping became feasible. In addition to radionuclides, various vital dyes were employed to trace and predict the pattern of lymph flow. Compared to previous anatomic studies, these newer dynamic techniques more accurately depict the pattern of lymph vessels and their drainage routes. Because they more reliably demonstrate which nodal basin(s) drain a particular region of the body, lymph node mapping has become an important tool for preoperative planning. With more refinement of these techniques it also has become apparent that considerable variability can exist among individuals. Also, these lymph mapping techniques have provided results which challenge many of our earlier concepts about the patterns of lymph drainage in certain regions of the body, particularly in the head and neck.

If the information from lymph node dissection is more prognostic than therapeutic, then identifying node negative versus node positive individuals with something less than standard nodal dissection would greatly reduce morbidity and costs. Whether it be the axilla, groin or neck, lymph node dissection is a morbid procedure which typically requires general anesthesia and frequently results in local seroma, extremity edema, chronic discomfort, and disability of the associated joint(s). Years ago surgeons backed away from total axillary dissection for breast cancer because of the high complication rates particularly when such axilla are included in radiation fields. Present lymphoscintigraphy imaging techniques coupled with hand held gamma counters have the potential of not only accurately predicting the lymph drainage pattern, but also reliably identifying the first lymph node encountered along the course of the meandering lymph vessel (Figure 1). Any tumor circulating within a particular lymph vessel should therefore encounter this node; hence, if no malignant cells are detected in these particular nodes the remaining basin should also be free of tumor. This first lymph node has been coined the "sentinel" lymph node. The ability to detect and remove for histopathological analysis this sentinel node has revolutionary implications in surgical oncology.

Figure 1. Radionuclide was injected intradermally around the site of a paraspinal melanoma. Bilateral lymphatic drainage to the axillary nodes is clearly seen. A hot marker is used to outline body landmarks. Lateral views were used to localize and mark the skin overlying the sentinel nodes (S.N.). The location was confirmed preoperatively and intraoperatively using a handheld counting probe.

Working with melanoma patients, Morton's group was one of the initial pioneers to demonstrate that sentinel modes could be reliably identified in humans. His work and others have substantiated the accuracy of predicting the presence of absence of nodal metastasis upon sentinel node analysis^2-7.

Clinical Impact

Identifying these sentinel nodes soon had a significant impact upon the clinical management of melanoma. For years, patients with intermediate depth melanomas were submitted to the rigors of prophylactic lymph node dissection. The value of such was questioned in many clinical studies with the consensus gradually evolving that routine prophylactic lymph node dissection offered little survival advantage for the majority of patients and should therefore be abandoned as a routine procedure; nevertheless, there are data to suggest that certain subsets of patients might benefit⁸. Traditionally, patients with clinically and pathologically positive lymph nodes at the time of diagnosis of their primary melanoma appear to experience poorer survival than patients who were clinically negative yet histologically positive at the time of initial diagnosis; these individuals in turn appear to do worse than those who are both clinically and histologically negative. Proponents of nodal dissection have argued that identifying the middle group justified nodal dissection and that such a dissection can improve overall survival for individuals with clinically occult metastatic disease, a thesis never fully substantiated in prospectively randomized clinical trials.

Until the advent of sentinel node biopsy the only way to stratify these individuals meant subjecting each and every patient with an intermediate depth lesion and clinically negative nodal basins to formal nodal dissection. It is noteworthy that over the years as the pattern of spread for melanoma was better understood. Total radical lymph node dissection gave way to a more limited superficial dissection with the former being applied only to those who ultimately proved to histopathologically harbor metastasis. Identifying and removing only the sentinel node further refines this approach. Various clinical studies^3-7 have now shown that in patients with melanoma, the sentinel node results can be used to accurately predict the pathologic stage of the nodal basin. Therefore patients with clinically negative nodal basin(s) whose sentinel node(s) proves to be histopathologically negative can be spared formal nodal dissection.

Recently, alpha interferon employed as adjuvant therapy in high risk patients has been shown to improve survival in patients with melanoma⁹. High risk patients were defined as those with deeply invasive primary lesions or those who have node positive disease. In subset analysis it became apparent that those individuals with nodal metastasis particularly benefited from this therapy. These results have provided an even greater impetus for identifying those patients who harbor occult malignant disease. In part, the intent of the Sunbelt Melanoma Trial is to prospectively study these patients and ascertain the significance of occult metastatic nodal disease and what, if any, impact interferon may have on these particular patients' outcome. These developments mirror those experienced in the evolution of adjuvant chemotherapy for breast cancer patients.

The successful application of lymph node mapping and sentinel node biopsy in melanoma patients has generated interest in applying these same principles to breast cancer. Unlike melanoma, standard practice dictates that women presenting with locally advanced breast cancer require systemic therapy regardless of nodal status; however, such is not so well established for women with small (<2 cm) tumors. In the latter category there is little published data to substantiate the routine use of adjuvant chemotherapy in these node negative women. With the widespread application of breast self examination and screening mammography, more women are being diagnosed with early stage breast cancer. Hence, a large proportion of women newly diagnosed with breast cancer will predictably have node negative disease and may not require systemic therapy. It is these women who would benefit most from sentinel node biopsy. The reliability of identifying specifically the sentinel node within the axilla of breast cancer patients is not as well established as with melanoma; nonetheless, reports are appearing attesting to the validity of the technique^10-12. As surgeons and nuclear medicine physicians become more familiar with the technique more widespread application can be expected.

Technique

The techniques involved in performing sentinel node biopsies are relatively straight forward, albeit a degree of experience is required to obtain reliable and repeatable results. At the University of Florida Cancer Center / Jacksonville we routinely perform these on an ambulatory basis. The patient initially reports to Nuclear Medicine where the primary site is injected with radiolabeled filtered technetium sulfur colloid. Imaging is performed for two hours. During this time the sentinel node(s) is (are) identified (Figure 2). The patient is then brought to the operating room. Once surgically prepped the primary site is injected with lymphazurin blue. The approximate site of the sentinel node is confirmed using the Neoprobe handheld gamma counter. An incision is made. Using both the probe and direct visual inspection of the coursing blue dye within the lymphatics the sentinel node is located and removed. While some institutions employ one agent or the other^4-5, we have found, as others ^3,5,7, that our yield in identifying the sentinel node(s) is (are) improved using the combination of localizing agents.

Figure 2. Radionuclide was injected around the post-excisional biopsy seroma using ultrasound guidance. Anterior imaging confirms drainage into the axillary nodal basin with none seen in the internal mammary chain. Prone lateral imaging with the breast in the free dependent position helps remove the injection site from the axillary region of interest and allows skin marking over the sentinel node.

We generally perform this procedure in conjunction with the definitive surgery needed for melanoma or breast cancer treatment. As such, we employ general anesthesia. Performed alone, sentinel node biopsy could be done exclusively with local anesthesia. In those patients undergoing the additional surgery, pending their preference, they are discharged home later than evening or early the next morning.

The surgical specimen is submitted to pathology. Our policy is to routinely submit the removed node for serial sectioning. This enhances our yield in detecting the presence of micro-metastatic disease. Processing only one or two nodes allows the pathologist the luxury to more thoroughly investigate the node(s) than heretofore routinely possible with the standard tissue specimens that accompanied dissection of the nodal basin. For those individuals enrolled in the Sunbelt Melanoma Trial or participating in the Department of Defense Multi-Center Breast Lymphatic Mapping Trial, a portion of the specimen is submitted for additional studies.

Conclusion

Sentinel node biopsy has changed the surgical management of melanoma. It clearly should be offered as a definitive staging procedure to all patients diagnosed with intermediate or deeply invasive lesions. The impact of sentinel node biopsy upon the staging of breast cancer remains to be seen, but we anticipate that ultimately this less invasive procedure will replace standard axillary node dissection in a large number of women.

1. Zinsmeister MS. Lymphoscintigraphy: Current techniques and limitations. Applied Radiology. 1997. 26(7):32-39.

2. Morton DL, Wen D, Wong JH, Economou JS et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992; 27:392-399.

3. Reintgen D, Cruse CW, Wells K, Berman C, et al. The orderly progression of melanoma metastasis. Ann Surg. 1994; 220:759-767.

4. Brady MS, Cort DG. Sentinel lymph node evaluation in melanoma. Arch Dermatol. 1997; 133(8):1014-1020.

5. Wells KE, Rapaport DP, Cruse CW, Payne W, et al. Sentinel lymph node biopsy in melanoma of the head and neck. Plast Reconstr Surg. 1997; 100(3):591-594.

6. Essner R. The role of lymphoscintigraphy and sentinel node mapping in assessing patient risk in melanoma. Semin Oncol. 1997; 24(Suppl 4):S8-10.

7. Reintgen D, Rapaport D, Tanake KK, Ross M. Lymphatic mapping and sentinel node biopsy in patients with malignant melanoma. J Fla Med Assoc. 1997; 84(3):188-193.

8. Balch CM, Soong S, Bartolucci AA, Urst MM, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Aurg. 1996; 224:255-266.

9. Reintgen D. Kirkwood J. The adjuvant treatment of malignant melanoma. J Fla Med Assoc. 1997; 84(3):147-152.

10. Albertini JJ, Lyman GH, Cox C, Yeatmen T, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA. 1996; 276(22): 1818-1822.

11. Uren RF, Howman-Giles RB, Thompson JF, Malouf D, et al. Mammary lymphoscintigraphy in breast cancer. J Nucl Med. 1995; 36:1775-1780.

12. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994; 220(3): 391-398.

Sentinel Node Biopsy

Background

Lymph Mapping

Clinical Impact

Technique

Conclusion

Jacksonville Medicine / March, 1998