Prognostic S ignificance o f O ccult M etastases D etected b y Sentinel L ymphadenectomy a nd R everse Transcriptase-Polymerase C hain R eaction i n E arly-Stage Melanoma P atients

Purpose: Detection of micrometastases in the regional tumor-draining lymph nodes is critical for accurate staging and prognosis in melanoma patients. We hypothesized that a multiple-mRNA marker (MM) reverse transcriptase‐polymerase chain reaction (RT-PCR) assay would improve the detection of occult metastases in the sentinel node (SN), compared with hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC), and that MM expression is predictive of disease relapse. Patients and Methods: Seventy-two consecutive patients with clinical early-stage melanoma underwent sentinel lymphadenectomy (SLND). Their SNs were serially sectioned and assessed for MAGE-3, MART-1, and tyrosinase mRNA expression by RT-PCR, in parallel with H&E staining and IHC, for melanoma metastases. MM expression in the SNs was correlated with H&E and IHC assay results, standard prognostic factors, and diseasefree survival. Results: In 17 patients with H&E- and/or IHC-positive SNs, 16 (94%) expressed two or more mRNA markers. Twenty (36%) of 55 patients with histopathologically negative SNs expressed two or more mRNA markers. By multivariate analysis, patients at increased risk of metastases to the SN had thicker lesions (P 5 .03), were 60 years of age or younger (P F .05), and/or were MM-positive (P F .001). Patients with histopathologically melanoma-free SNs who were MM-positive, compared with those who were positive for one or fewer mRNA markers, were at increased risk of recurrence (P 5 .02). Patients who were MM-positive with histopathologically proven metastases in the SN were at greatest risk of disease relapse (P 5 .01). Conclusion: H&E staining and IHC underestimate the true incidence of melanoma metastases. MM expression in the SN more accurately reflects melanoma micrometastases and is also a more powerful predictor of disease relapse than are H&E staining and IHC alone. J Clin Oncol 17:3238-3244. r 1999 by American Society of Clinical Oncology.

[1]  P. Livingston Ganglioside vaccines with emphasis on GM2. , 1998, Seminars in oncology.

[2]  G. Lyman,et al.  Molecular staging of malignant melanoma: correlation with clinical outcome. , 1998, JAMA.

[3]  A. Giuliano,et al.  Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  R. Elashoff,et al.  Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine linked to the human leukocyte antigen phenotype of patients? , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  D. Morton,et al.  Assessment of messenger RNA of beta 1-->4-N-acetylgalactosaminyl-transferase as a molecular marker for metastatic melanoma. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  M. Ross,et al.  Evaluation of tyrosinase mRNA as a tumor marker in the blood of melanoma patients. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  D L Morton,et al.  Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. , 1997, The American journal of pathology.

[8]  M. Kashani-Sabet,et al.  Optimal selective sentinel lymph node dissection in primary malignant melanoma. , 1997, Archives of surgery.

[9]  J. Klein,et al.  Survival Analysis: Techniques for Censored and Truncated Data , 1997 .

[10]  D. Garrison,et al.  Melanoma-associated antigens as messenger RNA detection markers for melanoma. , 1997, Cancer research.

[11]  A. Cochran,et al.  Nodal nevi and cutaneous melanomas. , 1996, The American journal of surgical pathology.

[12]  D. Colomer,et al.  Detection of circulating neoplastic cells by reverse-transcriptase polymerase chain reaction in malignant melanoma: association with clinical stage and prognosis. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  D. Morton,et al.  Vaccine therapy for malignant melanoma , 1996, CA: a cancer journal for clinicians.

[14]  C. Karakousis,et al.  The technique of sentinel node biopsy. , 1996, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[15]  A. Ganser,et al.  Peripheral blood tyrosinase messenger RNA detection and survival in malignant melanoma. , 1996, Journal of the National Cancer Institute.

[16]  D. Morton,et al.  Detection of β‐human chorionic gonadotropin mRNA as a marker for cutaneous malignant melanoma , 1996 .

[17]  M. Ross,et al.  Prognostic value of size of lymph node metastases in patients with cutaneous melanoma. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  D. Garrison,et al.  Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  A. Cochran,et al.  Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  A. Cochran,et al.  Management of Early-Stage Melanoma by Intraoperative Lymphatic Mapping and Selective Lymphadenectomy: An Alternative to Routine Elective Lymphadenectomy or “Watch and Wait” , 1992 .

[21]  D L Morton,et al.  Technical details of intraoperative lymphatic mapping for early stage melanoma. , 1992, Archives of surgery.

[22]  K. Pittman,et al.  Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction , 1991, The Lancet.

[23]  R. Elashoff,et al.  Improved Long-term Survival After Lymphadenectomy of Melanoma Metastatic to Regional Nodes , 1991 .

[24]  Internationalludwigbreastcanc Prognostic importance of occult axillary lymph node micrometastases from breast cancers , 1990 .

[25]  A. Cochran,et al.  Occult melanoma in lymph nodes detected by antiserum to S‐100 protein , 1984, International journal of cancer.

[26]  D. Morton,et al.  Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins. , 1999, Archives of surgery.