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10.1245/ASO.2004.12.922
Annals of Surgical Oncology 11:192S-197 (2004)
© 2004 Society of Surgical Oncology
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SUPPLEMENT

Paradigm of Metastasis for Melanoma and Breast Cancer Based on the Sentinel Lymph Node Experience

Stanley P. L. Leong, MD, FACS

From the Department of Surgery, University of California, San Francisco, UCSF Comprehensive Cancer Center, and UCSF Medical Center at Mount Zion, San Francisco, California.

Correspondence: Address correspondence and reprint requests to: Stanley P. L. Leong, MD, Department of Surgery, University of California, San Francisco, Medical Center at Mount Zion, 1600 Divisadero Street, Room C333, San Francisco, CA 94143–1674; Fax: 415-353-7721; E-mail: leongs{at}surgery.ucsf.edu

ABSTRACT

Lymph node status is the most reliable prognostic indicator for patients with melanoma and breast cancer. Because it is the first node draining the primary cancer, the sentinel lymph node (SLN) is most likely to harbor metastatic cancer cells. The Breslow thickness of the primary melanoma and the size of primary breast cancer are highly correlated with SLN metastasis. If the SLN is negative, its negative predictive value for the remaining nodal basin exceeds 95%; thus, survival rates for melanoma and breast cancer increase when the SLN is negative. The rate of SLN identification is more than 95%, and the false-negative rate is about 5%. SLN data from melanoma and breast cancer are so convincing that they have been incorporated into the new American Joint Committee on Cancer classification of these cancers. The therapeutic value of additional lymph node dissection after a positive SLN for melanoma or breast cancer is still controversial. In melanoma, a 3-year follow-up may confirm better survival when the SLN is negative. However, about 25% of histologically negative SLNs may be upstaged by molecular techniques, and patients whose SLNs are positive by polymerase chain reaction (PCR) assay may develop recurrence. In most cases, melanoma and breast cancer follow an orderly progression of metastasis to the SLN; however, a small subgroup may develop systemic dissemination without SLN involvement. Current SLN experience has confirmed that the earlier the cancer, the less its potential for metastasis. Since treatments for metastatic cancer are still limited, early detection and resection are imperative. Better understanding of the molecular and genetic mechanisms of metastasis will be critical to select high-risk patients for adjuvant therapy.

Key Words: Breast cancer • Melanoma • Metastasis • Sentinel nodes

Although the incidence of malignant melanoma is still increasing rapidly, with one in 75 Americans diagnosed each year, the overall mortality rate has risen only slightly. This indicates that most of the melanomas being diagnosed are thin primary lesions that can be treated effectively by surgical resection.1 Various clinical and histological features have been utilized to predict the prognosis of primary melanoma.2 The Clark model is about 89% accurate in predicting survival in stage I melanoma based on tumor progression.3 Melanoma typically progresses from in situ growth to a radial growth phase and then expands into a vertical growth phase associated with increased risk of metastasis. Breslow tumor thickness as measured from the stratum granulosum of the epidermis to the deepest point of the tumor is considered the best predictor of clinical outcome and is an integral part of the pathology report.4 Regional nodal status correlates significantly with survival. The survival rate drops to single digits when metastasis is found beyond the regional lymph nodes, especially in visceral sites.5

Likewise, the recent mortality rate for breast cancer has decreased,6 while the incidence of breast cancer increased 0.5% per year between 1987 and 1998.7 In general, this is believed to be due to complete resection of early breast cancer detected by screening mammography. Cady et al.8 first documented the significant decrease of breast tumor size over the past several decades. The percentage of women 40 years of age or older who underwent mammography within the past 2 years increased from 29% in 1987 to 67% in 1998, the incidence of smaller tumors (less than 2.0 cm) more than doubled, and the incidence of tumors greater than 3.0 cm decreased by 27%.9,10

In a retrospective analysis of a large population of breast cancer patients, Nemoto et al.11 showed that nodal status was the most important predictor of outcome, as it is in melanoma. Based on the Swedish two-county trial of screening mammography, Tabar et al.12 concluded that mammographic screening resulted in earlier diagnosis of breast cancer, which corresponded to smaller tumors, fewer tumor-involved lymph nodes, and less-aggressive histology. These features were significantly correlated with survival. Thus, Tabar’s group challenged the proposal that breast cancer was a systemic disease from its inception; they asserted that the proposal was either mistaken or not relevant to the treatment of node-negative tumors that were less than 15 mm. Based on an institutional series of 778 patients, Ibarra13 confirmed a better outcome for patients with smaller tumors, relatively less nodal involvement, and less-aggressive histology.

Various models of breast cancer metastasis have been proposed since the days of Halsted.14 According to Halsted’s model, tumor spreads first to the regional nodes. A positive lymph node is an indicator of tumor spread and the instigator of distant metastasis. Therefore, treatment involves aggressive locoregional control such as a radical mastectomy with extensive lymph node dissection.15 On the other hand, Fisher et al.16 suggests that a systemic model is more appropriate because no orderly pattern of metastasis is apparent for breast cancer. Axillary dissection does not alter the incidence of systemic recurrence or patient survival. Thus, systemic treatment is equally important at the time of treatment for local disease. Over the years, it has become obvious that patterns of metastasis do not conform strictly to either model. In the spectrum model developed by Harris and Hellman, tumor spreads via lymphatic vessels in early-stage disease and via blood vessels in late-stage disease. For this reason, the emphasis is locoregional control in the early stage of disease. Effective axillary treatment should still be considered essential for early breast cancer.17

In both melanoma5,18 and breast cancer,11,19 nodal status is the most important predictor of clinical outcome. These studies of the pre-SLN era provided strong evidence that, in general, tumor progression in a primary site resulted in metastasis first to regional nodes and then to distant sites. Thus, the premise of treatment for melanoma and breast cancer rested on the eradication of the primary tumor and the nodal disease. Oftentimes, a regional lymph node dissection was performed to ensure that all lymph nodes were harvested for staging the cancer. Furthermore, if these lymph nodes harbored microscopic disease, their removal could potentially prevent systemic metastasis.

EVOLUTION AND VALIDATION OF THE SLN CONCEPT FOR MELANOMA AND BREAST CANCER

The phenomenon of metastasis from a primary tumor to a regional lymph node through the lymphatic channels was described by Seaman and Powers.20 The term SLN was first coined by Gould et al.21 in 1960 and further studied by Cabanas22 with use of the penile carcinoma model for SLN based on radiological identification. Adopting a blue dye technique in a feline model, Wong et al.23 were able to define the SLN physiologically. The seminal work on selective sentinel lymphadenectomy (SSL) for melanoma by Morton et al.24 in 1992 established the concept of an orderly and nonrandom progression of melanoma to the SLNs.18 The 1992 report was followed by an impressive succession of SSL studies in melanoma and subsequently in breast cancer (Fig. 1). A SLN may be mapped by blue dye and radiotracer or by either alone. These publications have shown that, in general, both melanoma and breast cancer progress in an orderly fashion from the primary site to the SLN and beyond. The SLN concept has been further applied to other solid cancers.25–27



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  		FIG. 1. The number of publications on selective sentinel lymphadenectomy (SSL) for melanoma and breast cancer since the 1992 report by Morton et al.24 The number of breast cancer SSL publications exceeds that of melanoma SSL publications, and both have plateaued.

 
The validation of the SLN concept is a turning point in the management of human solid cancers, particularly melanoma and breast cancer. The rapid embracing of this technique by surgical oncologists has quickly made irrelevant the debate over elective lymph node dissection versus watchful observation for a primary invasive melanoma greater than or equal to 1 mm. Although establishment of the therapeutic role of SSL in melanoma awaits completion of the Multicenter Selective Lymphadenectomy Trial,28 SSL is being applied widely as a screening procedure. SSL selects one or a few SLNs for an extensive histopathologic examination that would not be practical for the many nodes yielded by a standard lymph node dissection. If the SLN is negative, the negative predictive value of the remaining nodal basin for melanoma and breast cancer exceeds 95%.18,28–31 Thus, most patients (about 80% with melanoma and 60% to 70% with breast cancer) can be spared the more extensive and morbid procedure of standard lymph node dissection. The need for additional lymph node dissection after a positive SLN for melanoma or breast cancer is still controversial. Thus, SSL has now become standard for primary melanoma with a Breslow thickness greater than or equal to 1 mm.32–35 For breast cancer, it is rapidly evolving into a standard approach without the maturation of results from clinical trials.36

CLINICAL SIGNIFICANCE OF SLN MICROMETASTASIS

Outcome studies of melanoma patients undergoing SSL have shown that micrometastasis in SLNs is associated with a poorer prognosis. Cherpelis et al.37 have found that SLN status is predictive of disease-free survival in patients with primary melanomas greater than 3 mm. Based on databases of patients with thin and thick melanomas, Gershenwald et al.38 have found that SLN status is the most important prognostic factor for disease-free and disease-specific survival. Statius Muller et al.39 have found that SLN status along with Breslow thickness, ulceration, lymphatic invasion, and age appear to have additional value in predicting a minimal 3-year disease-free period after SSL. Patients with positive SLNs have a poorer prognosis than patients with negative SLNs.25,40–42 Starz et al.43,44 have further defined and classified micrometastasis in melanoma SLNs. In a recent report by Morton et al.45 of 1599 melanoma patients undergoing SSL, the overall survival rates at 5, 10, and 15 years were 70%, 65%, and 65%, respectively, for 322 patients with immunohistochemistry (IHC)-positive SLNs. In comparison, for 1277 patients with IHC-negative SLNs, the overall survival rates were 89%, 83%, and 81%, respectively (P <= .0001).

For breast cancer, micrometastasis was defined as a focus of tumor less than or equal to 2 mm in the draining lymph node.46 In general, micrometastasis to regional nodes had a poorer prognosis.47–50 Some studies have shown a worse outcome for patients with an IHC-positive metastasis.51–55 However, these studies were performed on routine axillary lymph node dissections rather than SLNs. Since the clinical outcome associated with IHC-positive SLNs is not known, Ibarra13 cautioned against the use of IHC as a standard on which to base treatment decisions.

Braun et al.56 used immunocytochemical staining with monoclonal anticytokeratin (CK) antibodies to analyze micrometastasis in bone marrow aspirates and level I axillary lymph nodes (n = 1590) from 150 node-negative patients with stage I or II breast cancer. CK-positive cells were present in the bone marrow aspirates of 44 patients (29%) and in the lymph nodes of only 13 (9%). Only two patients had simultaneous microdissemination to bone marrow and lymph nodes. Reduced 4-year distant disease-free and overall survival were each associated with a positive bone marrow finding (P = .032 and P = .014, respectively) but not with lymph node micrometastasis. It should be noted that SLNs were not harvested and compared with bone marrow status. Because the incidence of metastasis is reportedly higher in SLNs than non-SLNs obtained by routine axillary dissection (42% versus 29%),57 further studies should be done to compare the clinical significance of micrometastasis in SLNs versus bone marrow. A prospective study under the ACOSOG Z0010 protocol (http://www.acosog.org) will address the clinical relevance of micrometastasis to SLN and bone marrow in early breast cancer.

CLINICAL SIGNIFICANCE OF MOLECULAR FINDINGS

Molecular markers based on polymerase chain reaction (PCR) assay58,59 are now available to further assess SLNs that are negative by hematoxylin and eosin and/or IHC. Among patients whose SLNs are negative by histological and molecular assessments, survival is nearly 100%, indicating that melanoma with no metastasis to the SLN(s) can potentially be cured. Patients whose SLNs are histologically negative but PCR positive have a significantly higher recurrence rate than patients whose SLNs are negative by both assays. In the study by Morton et al.,60 SLNs from 215 patients were studied by multimarker molecular assays. Of 162 patients with IHC-negative SLNs, 49 (30%) had SLNs that expressed at least 1 of the 4 PCR markers. These patients had significantly higher risk of disease recurrence and death than did patients with negative IHC and PCR results (P < .0001). This difference suggests that IHC fails to detect 30% of SLN micrometastases. Thus, PCR not only is more sensitive than IHC for detection of micrometastases in SLNs but also may be clinically significant for recurrence. It is possible that early dissemination of microscopic cells via the circulatory system may occur. Prospective clinical follow-up of patients will further define the validity of molecular staging.61,62

PARADIGM OF METASTASIS IN THE SENTINEL NODE ERA

Breslow thickness of a primary melanoma is linearly correlated with the SLN tumor status.25 Likewise, there is a linear relationship between size of a primary breast cancer and tumor status of the SLN.63–65 Because of the accuracy of SSL as a staging method, the 6th edition of the American Joint Committee on Cancer’s staging manual incorporates SLN status for both melanoma and breast cancer.66 Melanoma progression can be further defined in terms of primary melanoma proliferation, metastasis to the SLNs or distant sites, progression from SLNs to non-SLNs, and progression from SLNs or non-SLNs to systemic sites (Fig. 2). Early metastasis occurs mostly in the regional SLNs, and SLN metastasis is a poor prognostic factor with respect to disease-free and overall survival. Likewise, for breast cancer, metastatic cells are generated as a result of proliferation, and early metastasis may occur in the SLN (Fig. 3).67 Clinical follow-up is needed for survival correlation. In general, the paradigm of metastasis for melanoma and breast cancer is a sequential progression from the primary tumor to SLNs, non-SLNs, and distant sites. Occasionally, tumor cells spread via systemic circulation to distant sites from the primary site, SLN(s) or non-SLN(s) (Fig. 4). At what point in this progression can the cancer be arrested? If only the SLNs are involved, can the removal of these nodes be curative? In the future, molecular markers may be used to identify patients whose disease can be cured by SSL without further lymph node dissection.



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  		FIG. 2. Specific pattern of metastasis, with corresponding survival rates for melanoma.5

 


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  		FIG. 3. Specific pattern of metastasis, with corresponding survival rates for breast cancer.67 In both melanoma and breast cancer models, cells from the primary site may spread through the lymphatic channels to SLNs or through the vascular as well as the lymphovenular channels to systemic sites.

 


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  		FIG. 4. The paradigm of metastasis for melanoma and breast cancer is similar: initial local growth and proliferation result in more aggressive clones that metastasize to SLNs and subsequently to non-SLNs and then to distant sites. Occasionally, tumor cells from the primary site, SLNs, or non-SLNs may spread via systemic circulation to distant sites.

 
FUTURE PERSPECTIVES

Early diagnosis of melanoma through education and surveillance should be encouraged.68 Similarly, screening mammography should be continued to detect early breast lesions. Multifaceted aspects of micrometastatsis including proliferation and differentiation of various clones from the primary tumor, the acquisition of adhesion molecules, the process of angiogenesis and host interaction with the mocroscopic tumor may shed new lights on the biology and mechanism of early metastasis. Molecular and genetic tools may be used to dissect the mechanisms of lymphatic and hemotogenous routes of metastasis. Understanding such mechanisms may help us to develop therapeutic strategies to prevent the process of micrometastasis.

CONCLUSION

In conclusion, a cancer’s metastatic potential increases with its stage; the process is progressive. Most cases of melanoma and breast cancer follow an orderly progression of metastasis to the SLN. A small subgroup of patients may develop systemic dissemination without SLN involvement. Since treatments for metastatic cancer are still limited, it is imperative for oncologists to detect and resect an early cancer as soon as possible.

ACKNOWLEDGMENTS

This work was supported in part by a grant from the Eva B. Buck Charitable Trust.

The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.

FOOTNOTES

Presented as a special lecture at the 3rd International Sentinel Node Congress in Yokohama, Japan, November 16–18, 2002.

Presented at the Third International Sentinel Node Congress, Yokohama, Japan, November 16–18, 2002.

Current SLN experience has confirmed that the earlier the cancer, the less its potential for metastasis. Since treatments for metastatic cancer are still limited, early detection and resection are imperative. Better understanding of the molecular and genetic mechanisms of metastasis will be critical to select high-risk patients for adjuvant therapy.

Received for publication December 4, 2003. Accepted for publication December 9, 2003.

REFERENCES

  1. Reintgen D, Balch CM, Kirkwood J, Ross M. Recent advances in the care of the patient with malignant melanoma. Ann Surg 1997; 225: 1–14.[CrossRef][Medline]
  2. Zettersten E, Shaikh L, Ramirez R, Kashani-Sabet M. Prognostic factors in primary cutaneous melanoma. Surg Clin North Am 2003; 83: 61–75.[CrossRef][Medline]
  3. Clark WH, Elder DE, DuPont G, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 1989; 81: 1893–904.[Abstract/Free Full Text]
  4. Liu V, Mihm MC. Pathology of malignant melanoma. Surg Clin North Am 2003; 83: 31–60.[CrossRef][Medline]
  5. Balch CM, AC B, Soong S, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19: 3535–648.
  6. Niederhuber JE. Seeking calmer waters in a sea of controversy. Oncologist 2002; 7: 172–3.[Free Full Text]
  7. Von Eschenbach AC. NCI remains committed to current mammography guidelines. Oncologist 2002; 7: 170–1.[Free Full Text]
  8. Cady B, Stone MD, Schuler JG, et al. The new era in breast cancer. Invasion, size, and nodal involvement dramatically decreasing as a result of mammographic screening. Arch Surg 1996; 131: 301–8.[Abstract]
  9. Andersen LD, Remington P, Trentham-Dietz A, Reeves M. Assessing a decade of progress in cancer control. Oncologist 2002; 7: 200–4.[Abstract/Free Full Text]
  10. Begg CB. The mammography controversy. Oncologist 2002; 7: 174–6.[Free Full Text]
  11. Nemoto T, Vana J, Bedwani RN, et al. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 1980; 45: 2917–24.[CrossRef][Medline]
  12. Tabar L, Vitak B, Chen HH, et al. The Swedish Two-County Trial twenty years later. Updated mortality results and new insights from long-term follow-up. Radiol Clin North Am 2000; 38: 625–51.[CrossRef][Medline]
  13. Ibarra JA. The pathologist in breast cancer: contemporary issues in the interdisciplinary approach. Surg Oncol Clin N Am 2000; 9: 295–317.[Medline]
  14. Chung MA, Cady B. New lessons from the sentinel node. Surg Oncol Clin N Am 2001; 10: 461–73, xi–xii.
  15. Halsted WS. The results of operations for the cure of cancer of the breast performed at The John Hopkins Hospital from June, 1889 to January, 1894. In: Operations for Cure of Cancer of the Breast. Vol. 4. Baltimore: The Johns Hopkins Press, 1894–95: 497–553.
  16. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985; 312: 674–81.[Abstract]
  17. Harris JR, Osteen RT. Patients with early breast cancer benefit from effective axillary treatment. Breast Cancer Res Treat 1985; 5: 17–21.[CrossRef][Medline]
  18. Reintgen DS, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg 1994; 220: 759–67.[Medline]
  19. Adjuvant therapy for breast cancer. NIH Consens Statement 2000; 17: 1–35.[Medline]
  20. Seaman W, Powers W. Studies on the distribution of radioactive colloidal gold in regional lymph nodes containing cancer. Cancer 1955; 8: 1044–6.[CrossRef][Medline]
  21. Gould EA, Winship T, Pholbin PH, Hyland Kerr H. Observations on a "sentinel node" in cancer of the parotid. Cancer 1960; 13: 77–8.[CrossRef][Medline]
  22. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977; 39: 456–66.[CrossRef][Medline]
  23. Wong JH, Cagle LA, Morton DL. Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg 1991; 214: 637–41.[Medline]
  24. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127: 392–9.[Abstract]
  25. Leong SPL. Selective sentinel lymphadenectomy for malignant melanoma. Surg Clin North Am 2003; 83: 157–85.[CrossRef][Medline]
  26. Leong SPL, Wong JH. Sentinel Lymph Nodes in Human Solid Cancer. Vol. 80. Philadelphia: WB Saunders, 2000.
  27. Borgstein P, Meijer S. Historical perspective of lymphatic tumour spread and the emergence of the sentinel node concept. Eur J Surg Oncol 1998; 24: 85–9.[CrossRef][Medline]
  28. 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. Ann Surg 1999; 230: 453–65.[CrossRef][Medline]
  29. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276: 1818–22.[Abstract]
  30. Thompson JF, McCarthy WH, Bosch CM, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 1995; 5: 255–60.[Medline]
  31. Cody HS 3rd. Sentinel lymph node mapping in breast cancer. Oncology 1999; 13: 25–34.
  32. Coit D, Wallack M, Balch C. Society of Surgical Oncology practice guidelines: melanoma surgical practice guidelines. Oncology 1997; 11: 1317–23.[Medline]
  33. Emilia JCD, Lawrence W. Sentinel lymph node biopsy in malignant melanoma: the standard of care? J Surg Oncol 1997; 65: 153–4.[CrossRef][Medline]
  34. Houghton A, Coit D, Bloomer W, et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology 1998; 12: 153–77.[Medline]
  35. Reintgen DS. Changing standards of surgical care for the melanoma patient. Ann Surg Oncol 1996; 3: 327–8.[CrossRef][Medline]
  36. Carpenter R. Sentinel node biopsy should be introduced into routine practice before results of randomized trials are available. Breast 2001; 10: 281–4.[CrossRef][Medline]
  37. Cherpelis BS, Haddad F, Messina J, et al. Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 2001; 44: 762–6.[CrossRef][Medline]
  38. 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 1999; 17: 976–83.[Abstract/Free Full Text]
  39. Statius Muller MG, van Leeuwen PA, de Lange-De Klerk ES, et al. The sentinel lymph node status is an important factor for predicting clinical outcome in patients with Stage I or II cutaneous melanoma. Cancer 2001; 91: 2401–8.[CrossRef][Medline]
  40. Clary BM, Mann B, Brady MS, et al. Early recurrence after lymphatic mapping and sentinel node biopsy in patients with primary extremity melanoma: a comparison with elective lymph node dissection. Ann Surg Oncol 2001; 8: 328–37.[Abstract/Free Full Text]
  41. 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 1999; 6: 442–9.[Abstract]
  42. Gadd MA, Cosimi AB, Yu J, et al. Outcome of patients with melanoma and histologically negative sentinel lymph nodes. Arch Surg 1999; 134: 381–7.[Abstract/Free Full Text]
  43. Starz H, Balda BR, Kramer KU, et al. A micromorphometry-based concept for routine classification of sentinel lymph node metastases and its clinical relevance for patients with melanoma. Cancer 2001; 91: 2110–21.[CrossRef][Medline]
  44. Starz H, De Donno A, Balda BR. The Augsburg experience: histological aspects and patient outcomes. Ann Surg Oncol 2001; 8 (9 Suppl): 48S–51S.[Medline]
  45. Morton D, Essner R, Hoon DS, et al. Long-Term Results of Lymphatic Mapping and Sentinel Lymphadenectomy for Early-Stage Melanoma: Implications of Nodal Microanatomy and Molecular Staging on Detection of Nodal Micrometastasis. American Surgical Association 123rd Annual Meeting. Washington, DC: American Surgical Association, 2003:60.
  46. Huvos AG, Hutter RV, Berg JW. Significance of axillary macrometastases and micrometastases in mammary cancer. Ann Surg 1971; 173: 44–6.[Medline]
  47. Rosen PP, Saigo PE, Braun DW, et al. Axillary micro- and macrometastases in breast cancer: prognostic significance of tumor size. Ann Surg 1981; 194: 585–91.[Medline]
  48. Rosen PP, Saigo PE, Braun DW, et al. Prognosis in stage II (T1N1M0) breast cancer. Ann Surg 1981; 194: 576–84.[Medline]
  49. Clayton F, Hopkins CL. Pathologic correlates of prognosis in lymph node-positive breast carcinomas. Cancer 1993; 71: 1780–90.[CrossRef][Medline]
  50. Fisher ER, Costantino J, Fisher B, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). The National Surgical Adjuvant Breast and Bowel Project Collaborating Investigators. Cancer 1995; 75: 1310–9.[CrossRef][Medline]
  51. Byrne J, Horgan PG, England S, et al. A preliminary report on the usefulness of monoclonal antibodies to CA 15–3 and MCA in the detection of micrometastases in axillary lymph nodes draining primary breast carcinoma. Eur J Cancer 1992; 28: 658–60.[Medline]
  52. Chen ZL, Wen DR, Coulson WF, et al. Occult metastases in the axillary lymph nodes of patients with breast cancer node negative by clinical and histologic examination and conventional histology. Dis Markers 1991; 9: 239–48.[Medline]
  53. Cote R, Peterson HF, Chaiwun B, et al. Role of immunohistochemical detection of lymph node metastases in management of breast cancer. International Breast Cancer Study Group. Lancet 1999; 354: 896–900.[CrossRef][Medline]
  54. Sedmak DD, Meineke TA, Knechtges DS, Anderson J. Prognostic significance of cytokeratin-positive breast cancer metastases. Mod Pathol 1989; 2: 516–20.[Medline]
  55. Trojani M, de Mascarel I, Bonichon F, et al. Micrometastases to axillary lymph nodes from carcinoma of breast: detection by immunohistochemistry and prognostic significance. Br J Cancer 1987; 55: 303–6.[Medline]
  56. Braun S, Cevatli BS, Assemi C, et al. Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy. J Clin Oncol 2001; 19: 1468–75.[Abstract/Free Full Text]
  57. Giuliano AE, Dale PS, Turner RR, et al. Improved axillary staging of breast cancer with sentinel lymphadenectomy. Ann Surg 1995; 222: 394–9.[Medline]
  58. Wang X, Heller R, VanVoorheis N, et al. Detection of submicroscopic lymph node metastases with polymerase chain reaction in patients with malignant melanoma. Ann Surg 1994; 220: 768–74.[Medline]
  59. Bostick P, Morton DL, Turner RR, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999; 17: 3238–44.[Abstract/Free Full Text]
  60. Morton DL, Hoon DS, Cochran AJ, et al. Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases. Ann Surg 2003; 238: 538–49.[Medline]
  61. Davis EG, Chao C, McMasters KM. Polymerase chain reaction in the staging of solid tumors. Cancer J 2002; 8: 135–43.[Medline]
  62. McMasters K, Reintgen D, Ross M, et al. Sunbelt Melanoma Trials: sensitivity and specificity of reverse transcriptase polymerase chain reaction (RT-PCR) markers for sentinel lymph nodes (SLN). Proc Am Soc Clin Oncol 1999; 18: 537a.
  63. Cox CE, Salud CJ, Harrinton MA. The role of selective sentinel lymph node dissection in breast cancer. Surg Clin North Am 2000; 80: 1759–77.[CrossRef][Medline]
  64. Chen M, Palleschi S, Khoynezhad A, et al. Role of primary breast cancer characteristics in predicting positive sentinel lymph node biopsy results: a multivariate analysis. Arch Surg 2002; 137: 606–9.[Abstract/Free Full Text]
  65. Giuliano AE, Jones RC, Brennan M, Statman R. Sentinel lymphadenectomy in breast cancer. J Clin Oncol 1997; 15: 2345–50.[Abstract/Free Full Text]
  66. Greene FL, Page DL, Fleming ID, et al., eds. AJCC Cancer Staging Manual. 6th ed. New York: Springer, 2003.
  67. Harris JR, Henderson CI. Natural history and staging of breast cancer. In: Harris JR, Henderson CI, Hellman S, Kinne DW, eds. Breast Diseases. Philadelphia: Lippincott, 1987: 233–58.
  68. Leong SPL. Future perspectives on malignant melanoma. Surg Clin North Am 2003; 83: 453–6.[CrossRef][Medline]



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