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Sentinel Lymph Node Mapping in Breast Cancer

Sentinel Lymph Node Mapping in Breast Cancer

Sentinel node surgery for breast cancer has generated considerable interest, and the timely article by Dr. Cody provides a concise, well-written review of the topic. This commentary will add a few relatively minor points and will offer some alternative viewpoints to the author’s conclusions.

Historical Perspective

It is interesting that Ramon Cabanas verbalized the modern concept of the sentinel nodes at the Society of Surgical Oncology hosted by Memorial Sloan-Kettering Cancer Center (Dr. Cody’s institution) 22 years ago. Dr. Cabanas reported that, in penile cancer, sentinel nodes were the first nodes to receive cancer cells from a primary tumor and, importantly, that the status of these nodes (obtained through a minor surgical biopsy) would allow a decision to be made as to whether a complete lymphadenectomy should be performed.[1] Although Cabanas appears to be the first person to declare the utility of sentinel node surgery, many others throughout this century have documented and understood the concept of primary or sentinel nodes.

As early as 1915, Dr. Braithwaite of England recognized that “glands sentinel” were the initial nodal drainage basins from specific locations within the abdominal cavity.[2] Since Braithwaite’s fundamental observations, drainage to a limited set of nodes has been demonstrated for tumors of the stomach (“targeting the primary nodes”[3]), lung (“mapping of the nodes by vital staining”[4]), testicles (“primary complex of nodes”[5,6] and “the metastatic emboli from a primary testicular tumor could find their first filter in this lymph center”[7]), breast,[8] and upper gastrointestinal tract.[9]

A wide variety of tracers have been used to identify sentinel nodes. Colored dyes that vividly delineate the lymphatic channels leading to sentinel nodes and also usually stain the nodes have been used throughout this century. Since the 1930s, radiopaque contrast has also been used,[10] and has been injected interstitially (indirect lymphography) or directly into the lymphatic channels (direct lymphography).

After World War II, radioactive tracers became more readily available and were used to label lymph nodes draining cancers of the cervix,[11] breast,[12] lung,[13] head and neck ,[14] rectum,[15] and prostate.[16] Gamma camera imaging of lymph ducts and nodes (lymphoscintigraphy) was used extensively following its introduction in 1958.[17] Handheld gamma detectors have been used intraoperatively to locate radiolabeled tissues for decades[18,19] but were introduced in 1993 for the identification of sentinel nodes.[20-22]

Radiolabeling of sentinel nodes can be performed successfully with a variety of radioactive tracers. It is very encouraging that within a few short years, an otherwise challenging technique has emerged as a routinely successful procedure with a high level of accuracy.

A Recent Study

The review by Dr. Cody covers the majority of reports available. Since the paper was written, a multicenter study has been reported confirming that sentinel node surgery can be successful in a variety of clinical settings after a short period of mentored training.[23] This study also demonstrated that drainage to sentinel nodes outside of the axilla occurred in almost 1 out of 10 patients. This was clinically meaningful in that 3% of all node-positive cases occurred exclusively in nodes outside of the axilla.

Although recent modifications appear to minimize false-negative cases,[24] the rate of false-negativity will probably not reach 0%. It can be expected that, in a small percentage of patients who have pathologically negative sentinel nodes, there will be nodes left behind that contain cancer cells. This very important issue will be addressed in the National Surgical Adjuvant Breast and Bowel Project sentinel node clinical trial (NSABP-32).

Total Lymphadenectomy vs Sentinel Node Resection

There are three rationales for performing node resection in patients with breast cancer: (1) staging, (2) regional control, and (3) the possibility of improved survival. Axillary lymphadenectomy addresses all three goals. Sentinel node surgery accomplishes staging with relatively high accuracy (at least with regard to whether or not nodal metastases have occurred). However, to date there are no data on the impact of sentinel node surgery alone (without axillary lymphadenectomy) on locoregional control or survival.

The B-32 sentinel node trial is analogous to the NSABP-06 trial, which compared total mastectomy to partial mastectomy. The B-32 trial will compare total lymphadenectomy to partial lymphadenectomy (sentinel node resection). The end points of the B-32 trial are similar to those of the B-06 trial and include long-term regional (local) control and survival. Although these end points should be similar in both randomized arms, morbidity should be markedly reduced in the sentinel node resection arm.

Is Sentinel Node Surgery Ready for “Prime Time”?

A crucial question is whether sentinel node surgery is ready for “prime time.” The answer is, yes and no: yes, in that the accuracy of sentinel node resection appears to be high enough for staging purposes; and no, in that there are no data as yet comparing the ability of sentinel node surgery to provide long-term regional control. Furthermore, if we later found out that decreased morbidity were achieved at the price of decreased survival (even if that decrease were very small), how would the procedure be viewed? No single surgeon or institution can answer these critical questions.

Patients and physicians have had to contend with so much uncontrolled data for so long that it is hardly tenable in this modern era to consider substantial changes in management without adequate, easily understandable evidence. Accrual to large clinical trials to address these important issues is in the best interests of breast cancer patients and can be accomplished very rapidly with appropriate input. Surgeons in this country will benefit by providing leadership in the rational management of breast cancer and should consider this an open invitation to participate in these trials and to urge patients to do the same.

References

1. Cabanas RM: An approach for the treatment of penile carcinoma. Cancer 39:456-466, 1977.

2. Braithwaite LR: The flow of lymph from the ileocaecal angle, and its possible bearing on the cause of duodenal and gastric ulcer. Br J Surg 7:7-26, 1923.

3. Weinberg J, Greaney EM: Identification of regional lymph nodes by means of a vital staining dye during surgery of gastric cancer. Surg Gynecol Obstet 90:561-567, 1950.

 4. Weinberg JA: Identification of regional lymph nodes in the treatment of bronchiogenic carcinoma. J Thorac Surg 22:517-526, 1951.

5. Busch RM, Sayegh ES: Roentgenographic visualization of human testicular lymphatics: A preliminary report. J Urol 89:106-110, 1963.

6. Busch FM, Sayegh ES, Chenault OW: Some uses of lymphangiography in the management of testicular tumors. J Urol 490-493, 1964.

7. Chiappa S, Uslenghi C, Bonadonna, et al: Combined testicular and foot lymphangiography in testicular carcinoma. Surg Gynecol Obstet 123:10-14, 1966.

8. Halsell JT, Smith JR, Bentlage CR, et al: Lymphatic drainage of the breast demonstrated by vital dye staining and radiography. Ann Surg 162:221-226, 1965.

9. Drinkwater DC Jr, Whittnigh C, Bethune DC, et al: Endoscopic gastrointestinal lymphoscintigraphy. Curr Surg, pp 67-71, January-February 1981.

10. Gray JH: The relation of lymphatic vessels to the spread of cancer. Br J Surg 26:462-495, 1938.

11. Gitsch E, Philipp K: Radionuclide-guided radical surgery for cervical cancer. Baillieres Clin Obstet Gynaecol 2:867:875, 1988

12. Gabelle PH, Comet M, Bodin JP, et al: Mammary lymphatic scintiscans by intratumoral injection in the assessment of breast cancer 105 examinations in 100 patients. Nouv Presse Med 10:3067-3070, 1981.

13. Drew CG, Bethune, Mulder DS, et al: Endobronchial lymphoscintigraphy (EBLS). J Thorac Cardiovasc Surg 76:446-452, 1978.

14. Welsh LW, Welsh JJ: Cervical lymphatics: Pathologic conditions. Ann Otol Rhinol Laryngol 75:176-191, 1966.

15. Arnaud JP, Bergamaschi R, Schloegel M, et al: Progress in the assessment of lymphatic spread in rectal cancer: Rectal endoscopic lymphoscintigraphy. Dis Colon Rectum 33:398-401, 1990.

16. Gardiner RA, Fitzpatrick JM, Constable AR, et al: Improved techniques in radionuclide imaging of prostatic lymph nodes. Br J Urol 51:561-564, 1979.

17. Sage H, Gozun BV: Lymphatic scintigrams: A method for studying the functional pattern of lymphatics and lymph nodes. Cancer 11:200-203, 1958.

18. Krag DN, Ford PV, Patel M, et al: Gamma probe-guided bone biopsies: A simplified technique to biopsy abnormal bony radiolocalizations. Surg Oncol 1:371-377, 1992.

19. Harvey WC, Lancaster JL: Technical and clinical characteristics of a surgical biopsy probe. J Nucl Med 22:184-186, 1981.

20. Alex JC, Krag DN: Gamma-probe guided localization of lymph nodes. Surg Oncol 2:137-143, 1993.

21. Alex JC, Weaver DL, Fairbank JT, et al: Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 2:303-308, 1993.

22. Krag DN, Weaver DL, Alex JC, et al: Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335-340, 1993.

23. Krag DN, Weaver DL, Ashikaga T, et al: The sentinel node in breast cancer: a multicenter validation study. N Engl J Med 339:941-946, 1998.

24. Krag DN, Ashikaga T, Harlow SP, et al: Development of sentinel node targeting technique in breast cancer patients. Breast J 4:67-74, 1998.

 
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