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Asia-Pacific Journal of Clinical Oncology 2014; 10: 376–377
doi: 10.1111/ajco.12169
CASE REPORT
Positive sentinel lymph node metastasis from a metastasis in Melanoma Samantha BOWYER,1 Kynan FEENEY1 and Michael MILLWARD1,2 1 Department of Medical Oncology, Cancer Centre, Sir Charles Gairdner Hospital, and 2School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
Abstract The rationale for certain patterns of metastatic spread seen in melanoma is not well understood. Currently, there is no clear experimental evidence to support the potential for metastases to form metastases in this disease. We report a case of a 31-year-old woman, with metastatic melanoma, who developed axillary lymph node metastases hypothesized to originate from a breast metastasis rather than the primary disease. Improved understanding of the underlying molecular processes involved in systemic spread would facilitate development of improved adjuvant therapies and prognostic markers.
CASE REPORT We report a case of a 31-year-old woman, with metastatic melanoma, who developed axillary lymph node metastases presumed from a breast metastasis on a background of stage III melanoma. She had a history of a Breslow thickness 9.5 mm and Clark level V cutaneous melanoma completely excised from her left calf in January 2012. A staging positron emission tomography (PET) scan did not show any evidence of metastatic disease. Six months later, she underwent a left groin dissection for recurrent disease in the left femoral triangle. Four lymph nodes out of nine resected were involved with metastatic melanoma with no extranodal extension. Serine-threonine protein kinase B-BRAF gene mutational analysis did not demonstrate a mutation in exon 15. A subsequent PET scan demonstrated asymmetrical parenchymal uptake in the left breast. No additional disease was seen elsewhere. A 16 mm breast mass was located on ultrasound and a core biopsy confirmed metastatic melanoma. In January 2013, the breast lesion was completely excised by wide local excision. A sentiCorrespondence: Dr Samantha Bowyer MBBCh, Department of Medical Oncology, Cancer Centre, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, WA 6009, Australia. Email: [email protected]; [email protected] Conflict of interest: none Accepted for publication 19 November 2013.
© 2014 Wiley Publishing Asia Pty Ltd
nel node biopsy demonstrated two micrometastases measuring less than 1 mm in size. The sentinel lymph node is hypothetically the first lymph node to be encountered by lymphatic fluid draining from a primary cancer site. We hypothesize, because of the pattern of distant metastatic spread in this patient, that the sentinel axillary nodal involvement was a result of lymphatic spread from the breast metastasis rather than spread from the primary tumor or inguinal lymph nodes. To the best of our knowledge, the potential for metastases to metastasis in melanoma has not been reported in a clinical case.
DISCUSSION The reasons behind certain patterns of metastatic spread in melanoma are still not well understood. The most widely accepted theory is that development of distant disease is an early event originating from the primary tumor; however, it is unclear if lymph node and distant metastases have the potential to further metastasize.1 Cancers are formed of a heterogeneous group of cells with certain gene expression allowing some cells to complete the metastatic process. This gene expression signature may be similar to the primary or be altered in the metastatic cells. This process has been postulated to occur in a stepwise fashion with the initial event being a detachment of the migratory cell from the primary tumor followed by intravasation into the blood or lymphatic system. However, gaining accesses to the
377
Metastasis from metastasis in Melanoma
vasculature is only part of the process, with less than 0.01% of circulating tumor cells forming metastases.2 The mechanism to allow metastases to form metastases is unknown but it has been postulated that cells at metastatic sites retain their phenotypic plasticity and can undergo secondary epithelial to mesechymal transition to allow further seeding to alternative distant metastatic sites.3 Chemokine receptors and adhesion molecules are proposed to be involved in the process of favoring spread via the lymphatics versus adhesion to tissues at distant sites via the vasculature.4 It has been shown that tumors can influence the lymph node microenvironment to facilitate metastatic seeding and growth. In vitro and mouse models have demonstrated lymphangiogenesis to occur as a result of local growth factors, particularly vascular endothelial growth factor (VEGF)-C and its receptor VEGF receptor 3, around the site of the primary tumor and in the draining lymph node basin leading to increased lymphatic flow even prior to involvement with tumor. Blockade of lymphangiogenesis pathways are being explored as a potential therapeutic target to reduce distant metastases. Preclinical models have looked at targeting VEGF receptor 3 and have shown some promise, however, not demonstrated complete blockade of metastases.5 The ability for sites of metastatic disease to form further metastases has been proposed from murine models where systemic metastases were found not to be dependent on the continuing presence of implanted subcutaneous tumors or involved lymph node metastases.3 In addition, a large proportion of single melanoma cells isolated from primary tumors or distant metastases have been demonstrated to have the capacity to form tumors in immune deficient mice.6 Early evidence of metastases metastasizing has been hypothesized in colorectal cancer from a case series of seven patients undergoing hepatic resection of liver metastases. At the time of surgery, disease was also found in the lymphatics draining the liver in the absence of other extrahepatic tumor.7,8 We report a case, which due to the pattern of metastatic spread, is hypothesized to be lymphatic spread
Asia-Pac J Clin Oncol 2014; 10: 376–377
to a local lymph node from a metastatic lesion of the breast. There is currently not conclusive experimental evidence to support the potential of metastases to form metastases. To prove or disprove this theory, a greater appreciation is required of the underlying molecular mechanisms involved in the processes leading to systemic spread. A better understanding would also assist in the development of improved adjuvant treatments and identification of accurate prognostic markers.
ACKNOWLEDGMENTS There were no study sponsors or funding sources for this publication. We did not seek informed consent or ethical committee approval for this case report. The paper does not report primary research. All data collected was part of routine diagnosis and treatment. This paper does not report the use of any experimental treatments.
REFERENCES 1 Leiter U, Meier F, Schittek B, Garbe C. The natural course of cutaneous melanoma. J Surg Oncol 2004; 86 (4): 172–8. 2 Wong SY, Hynes RO. Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle 2006; 5 (8): 812–7. 3 Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenvironment 2012; 5 (1): 19–28. 4 Zbytek B, Carlson JA, Granese J, Ross J, Mihm MC, Slominski A. Current concepts in metastasis in melanoma. Expert Rev Dermatol 2008; 3 (5): 569–85. 5 Alitalo A, Detmar M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 2012; 31 (42): 4499–508. 6 Swoboda A, Schanab O, Tauber S et al. MET expression in melanoma correlates with a lymphangiogenic phenotype. Hum Mol Genet 2012; 21 (15): 3387–96. 7 August D, Sugarbarker P, Schneider P. Lymphatic dissemination of hepatic metastases. Cancer 1985; 55: 1490–4. 8 Tait CR, Dodwell D, Horgan K. Do metastases metastasize. J Pathol 2004; 203 (1): 515–8.
© 2014 Wiley Publishing Asia Pty Ltd
Copyright of Asia Pacific Journal of Clinical Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Asia-Pacific Journal of Clinical Oncology 2014; 10: 376–377
doi: 10.1111/ajco.12169
CASE REPORT
Positive sentinel lymph node metastasis from a metastasis in Melanoma Samantha BOWYER,1 Kynan FEENEY1 and Michael MILLWARD1,2 1 Department of Medical Oncology, Cancer Centre, Sir Charles Gairdner Hospital, and 2School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia
Abstract The rationale for certain patterns of metastatic spread seen in melanoma is not well understood. Currently, there is no clear experimental evidence to support the potential for metastases to form metastases in this disease. We report a case of a 31-year-old woman, with metastatic melanoma, who developed axillary lymph node metastases hypothesized to originate from a breast metastasis rather than the primary disease. Improved understanding of the underlying molecular processes involved in systemic spread would facilitate development of improved adjuvant therapies and prognostic markers.
CASE REPORT We report a case of a 31-year-old woman, with metastatic melanoma, who developed axillary lymph node metastases presumed from a breast metastasis on a background of stage III melanoma. She had a history of a Breslow thickness 9.5 mm and Clark level V cutaneous melanoma completely excised from her left calf in January 2012. A staging positron emission tomography (PET) scan did not show any evidence of metastatic disease. Six months later, she underwent a left groin dissection for recurrent disease in the left femoral triangle. Four lymph nodes out of nine resected were involved with metastatic melanoma with no extranodal extension. Serine-threonine protein kinase B-BRAF gene mutational analysis did not demonstrate a mutation in exon 15. A subsequent PET scan demonstrated asymmetrical parenchymal uptake in the left breast. No additional disease was seen elsewhere. A 16 mm breast mass was located on ultrasound and a core biopsy confirmed metastatic melanoma. In January 2013, the breast lesion was completely excised by wide local excision. A sentiCorrespondence: Dr Samantha Bowyer MBBCh, Department of Medical Oncology, Cancer Centre, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, WA 6009, Australia. Email: [email protected]; [email protected] Conflict of interest: none Accepted for publication 19 November 2013.
© 2014 Wiley Publishing Asia Pty Ltd
nel node biopsy demonstrated two micrometastases measuring less than 1 mm in size. The sentinel lymph node is hypothetically the first lymph node to be encountered by lymphatic fluid draining from a primary cancer site. We hypothesize, because of the pattern of distant metastatic spread in this patient, that the sentinel axillary nodal involvement was a result of lymphatic spread from the breast metastasis rather than spread from the primary tumor or inguinal lymph nodes. To the best of our knowledge, the potential for metastases to metastasis in melanoma has not been reported in a clinical case.
DISCUSSION The reasons behind certain patterns of metastatic spread in melanoma are still not well understood. The most widely accepted theory is that development of distant disease is an early event originating from the primary tumor; however, it is unclear if lymph node and distant metastases have the potential to further metastasize.1 Cancers are formed of a heterogeneous group of cells with certain gene expression allowing some cells to complete the metastatic process. This gene expression signature may be similar to the primary or be altered in the metastatic cells. This process has been postulated to occur in a stepwise fashion with the initial event being a detachment of the migratory cell from the primary tumor followed by intravasation into the blood or lymphatic system. However, gaining accesses to the
377
Metastasis from metastasis in Melanoma
vasculature is only part of the process, with less than 0.01% of circulating tumor cells forming metastases.2 The mechanism to allow metastases to form metastases is unknown but it has been postulated that cells at metastatic sites retain their phenotypic plasticity and can undergo secondary epithelial to mesechymal transition to allow further seeding to alternative distant metastatic sites.3 Chemokine receptors and adhesion molecules are proposed to be involved in the process of favoring spread via the lymphatics versus adhesion to tissues at distant sites via the vasculature.4 It has been shown that tumors can influence the lymph node microenvironment to facilitate metastatic seeding and growth. In vitro and mouse models have demonstrated lymphangiogenesis to occur as a result of local growth factors, particularly vascular endothelial growth factor (VEGF)-C and its receptor VEGF receptor 3, around the site of the primary tumor and in the draining lymph node basin leading to increased lymphatic flow even prior to involvement with tumor. Blockade of lymphangiogenesis pathways are being explored as a potential therapeutic target to reduce distant metastases. Preclinical models have looked at targeting VEGF receptor 3 and have shown some promise, however, not demonstrated complete blockade of metastases.5 The ability for sites of metastatic disease to form further metastases has been proposed from murine models where systemic metastases were found not to be dependent on the continuing presence of implanted subcutaneous tumors or involved lymph node metastases.3 In addition, a large proportion of single melanoma cells isolated from primary tumors or distant metastases have been demonstrated to have the capacity to form tumors in immune deficient mice.6 Early evidence of metastases metastasizing has been hypothesized in colorectal cancer from a case series of seven patients undergoing hepatic resection of liver metastases. At the time of surgery, disease was also found in the lymphatics draining the liver in the absence of other extrahepatic tumor.7,8 We report a case, which due to the pattern of metastatic spread, is hypothesized to be lymphatic spread
Asia-Pac J Clin Oncol 2014; 10: 376–377
to a local lymph node from a metastatic lesion of the breast. There is currently not conclusive experimental evidence to support the potential of metastases to form metastases. To prove or disprove this theory, a greater appreciation is required of the underlying molecular mechanisms involved in the processes leading to systemic spread. A better understanding would also assist in the development of improved adjuvant treatments and identification of accurate prognostic markers.
ACKNOWLEDGMENTS There were no study sponsors or funding sources for this publication. We did not seek informed consent or ethical committee approval for this case report. The paper does not report primary research. All data collected was part of routine diagnosis and treatment. This paper does not report the use of any experimental treatments.
REFERENCES 1 Leiter U, Meier F, Schittek B, Garbe C. The natural course of cutaneous melanoma. J Surg Oncol 2004; 86 (4): 172–8. 2 Wong SY, Hynes RO. Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle 2006; 5 (8): 812–7. 3 Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenvironment 2012; 5 (1): 19–28. 4 Zbytek B, Carlson JA, Granese J, Ross J, Mihm MC, Slominski A. Current concepts in metastasis in melanoma. Expert Rev Dermatol 2008; 3 (5): 569–85. 5 Alitalo A, Detmar M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 2012; 31 (42): 4499–508. 6 Swoboda A, Schanab O, Tauber S et al. MET expression in melanoma correlates with a lymphangiogenic phenotype. Hum Mol Genet 2012; 21 (15): 3387–96. 7 August D, Sugarbarker P, Schneider P. Lymphatic dissemination of hepatic metastases. Cancer 1985; 55: 1490–4. 8 Tait CR, Dodwell D, Horgan K. Do metastases metastasize. J Pathol 2004; 203 (1): 515–8.
© 2014 Wiley Publishing Asia Pty Ltd
Copyright of Asia Pacific Journal of Clinical Oncology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
