Metastatic pathways and time courses in the orderly progression of cutaneous melanoma
ABSTRACT It is known that two-thirds of patients who develop clinical metastases following treatment of a primary cutaneous melanoma initially present with locoregional metastases and one-third initially present with distant metastases. However, few reports in the literature give detailed figures on different metastatic pathways in cutaneous melanoma.
The aim of the present study was to perform a detailed analysis of the different metastatic pathways, the time course of the development of metastases and the factors influencing them.
In a series of 3001 patients with primary cutaneous melanoma at first presentation, 466 subsequently developed metastasis and were followed-up over the long term at the University of Tuebingen, Germany between 1976 and 1996. Different pathways of metastatic spread were traced. Associated risk factors for the different pathways were assessed. Differences in survival probabilities were calculated by the Kaplan-Meier method and evaluated by the log-rank test.
In 50.2% of the patients the first metastasis after treatment of the primary tumour developed in the regional lymph nodes. In the remaining half of the patient sample the first metastasis developed in the lymphatic drainage area in front of the regional lymph nodes, as satellite or in-transit metastases (21.7%) or as direct distant metastases (28.1%). Anatomical location, sex and tumour thickness were significant risk factors for the development of metastasis by different pathways. The most important risk factor appeared to be the location of the primary tumour. The median intervals elapsing before the first metastasis differed significantly between the different metastatic pathways. The direct distant metastases became manifest after a median period of 25 months, thus later than the direct regional lymph node metastases (median latency period, 16 months) and the direct satellite and in-transit metastases (median latency period, 17 months). In patients who developed distant metastases the period of development was independent of the metastatic route. The time at which the distant metastases developed was roughly the same (between 24 and 30 months after the detection of the primary tumour), irrespective of whether satellite or in-transit metastases, lymph node metastases or distant metastases were the first to occur.
The time course of the development of distant metastasis was more or less the same irrespective of the metastatic pathway; this suggests that in patients with in-transit or satellite metastasis or regional lymph node metastasis, haematogenic metastatic spread had already taken place. Thus, the diagnostic value of sentinel lymph node biopsy and the therapeutic benefit of elective lymph node dissection may be limited, as satellite and in-transit metastases or direct distant metastases will not be detected and haematogenous spread may already have taken place when the intervention is performed.
SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: The oestrogen-dependent regulation of cell behaviour is realised by stimulation of specific oestrogen receptors. The classical oestrogen receptors ERα and ERβ are transcription factors, and they modulate expression of hormonally regulated genes, while the third one, GPER, is thought to be responsible for the observed rapid, non-genomic cellular response. Oestrogen dependency is attributed to a number of cancers, including breast, ovarian and endometrial cancer; however, there is still growing evidence that melanoma should also be cited as a hormonally dependent tumour. This comes from the observations of gender-related differences in melanoma progression and reports concerning the history of the malignant course of melanomas during pregnancy. Although, the observations of oestrogen regulation of melanoma progression are controversial, the effect of oestrogen should not be neglected, as the skin possesses its own hormonal microenvironment. This aspect of melanoma progression should be taken under careful consideration as it may offer new therapeutic possibilities.Contemporary Oncology / Wspólczesna Onkologia 11/2014; 18(5):302-306. DOI:10.5114/wo.2014.43938 · 0.22 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Evaluation of: Flaherty KT, Infante JR, Daud A et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 367(18), 1694–1703 (2012). The treatment of metastatic melanoma with BRAF inhibitors initially gave dramatic results compared with standard chemotherapy with significant progression-free survival times. Unfortunately, within a matter of months, the melanomas become refractory to anti-BRAF-targeted therapy and some patients experience toxicity in the form of primary cutaneous squamous cell carcinomas. While recent reports of dual therapy targeting the MAPK pathway (e.g., dabrafenib and trametinib) show increased response rates and less toxicity, it is not apparent that overall survival has been significantly impacted. While targeted therapy has significantly altered the management of melanoma, novel approaches and strategies will likely have to be employed to counter melanoma cell heterogeneity and the selection of resistant clones.Expert Review of Dermatology 01/2014; 8(2). DOI:10.1586/edm.13.3
[Show abstract] [Hide abstract]
ABSTRACT: Erratum to: Eur J Nucl Med Mol ImagingDoi 10.1007/s00259-014-2914-4Unfortunately, Fig. 1c was not published; instead, Fig. 1b was duplicated. The missing figure is reproduced here.Figure 1c shows a clearly depicted lymphatic vessel. Patients with macrometastasis were more likely to show clear depiction of an afferent lymphatic vessel. In patients with clinically nonsuspicious nodes undergoing sentinel lymph node biopsy (SLNB), the clear depiction of an afferent vessel was associated with a higher number of radioactive lymph nodes depicted and a higher number of lymph node metastases excised by SLNB plus completion lymphadenectomy.European journal of nuclear medicine and molecular imaging 10/2014; 42(2). DOI:10.1007/s00259-014-2914-4 · 5.22 Impact Factor