What is the optimal management for primary desmoplastic melanomas?

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Introduction

Initial reports of desmoplastic melanoma (DM) highlighted a very high risk of local recurrence (LR) ranging from 25% to 60%[1][2][3][4] and suggested the need for more aggressive local treatment with wider margins and use of adjuvant radiotherapy (RT) to reduce the risk of local recurrence.[5] More contemporary studies do not show such an alarming rate of local recurrence. Nevertheless, the LR rate for DM in these studies (6–15%)[6][7][8][9][10][11] is higher than for non-DM (<5%).[8] The high rate of LR does clearly relate to incomplete or close resection in a significant portion of the study groups.[7][10][12] Neurotropism has not been demonstrated to be an independent significant risk factor for LR in most studies,[5][7][10][13][2][14][3][12] including non-DM.[12][15] The reported relationship of histological sub-type of DM (pDM vs mDM) to risk of LR is variable with some studies showing pDM to carry a higher risk of LR compared with mDM[16][13] while no difference in risk has been shown in others.[7][17]

Systematic review evidence

Excision margin for desmoplastic and neurotropic melanoma

There are no clinical trials that examine the appropriate clinical or histological margin to minimise the risk of local recurrence.

Maurichi et al (2010)[16] demonstrated higher LR in pDM ≤2mm resected with a 1cm margin compared with a 2cm margin (40% vs 18.5%). This was a retrospective study of prospectively collected data with no randomisation of treatment. The varying excision margins were due to a change in management policy. The overall LR rate in this study (19%) was higher than in more recent studies,[6][8][11] the reasons for which are unclear.

Local recurrence as the initial site of recurrence is associated with a high rate of development of distant metastases. Guadagnolo et al (2014)[7] reported 19 of 130 patients (15%) with DM to develop LR as first site of recurrence. Fifteen of the 19 (60%) patients developed distant metastases. Maurichi et al (2010)[16] reported subsequent distant relapse in 22 of 37 (59%) patients with LR.

Varey et al (2017) showed no difference in LR rates between DM and non-DM when neurotropism was present. There was a significant relationship between inadequate margins (<2mm vs ≥8mm) and LR for all neurotropic melanomas.[12]

Local recurrence is strongly related to involved definitive resection margins.[6][7][10][12]

In conclusion, there is no evidence to suggest that excision margins for DM or NM should be any different to those recommended for all other cutaneous melanomas.

Adjuvant radiotherapy following excision of desmoplastic and neurotropic melanoma

There are no published randomised controlled trials addressing the potential benefit of adjuvant RT for DM or NM.

Varey et al (2017)[12] showed in a study of 671 neurotropic melanomas, of which 72% were DM, that RT (given to 82 patients) halved the risk of local recurrence if microscopic margins were less than 8mm. There was no difference between DNM and non-DNM in response to RT.

Guadagnolo et al (2014)[7] showed a significant reduction in LR with adjuvant RT in 130 patients with DM. On subset analysis of this non-randomised study, no benefit was observed with RT for patients with either; 1) definitely no evidence of neurotropism or; 2) mDM .

Oliver et al (2016)[8] showed better local control in the small subset of patients that received adjuvant RT. There was 0% LR in 10 with surgery and RT vs 12% LR in 78 with surgery only.

Strom et al (2014)[10] reported on 277 patients with median follow-up of 43 months. The overall LR rate was 13%. There was a definite benefit for RT if resection margins were involved (5-year actuarial local control 89% vs 18%, p=0.003) and improved LR rates with RT for head and neck primaries with negative margins (local control 95% vs 76%, p=0.03). It was concluded that two subsets of patients with DM and clear resection margins could safely have adjuvant RT omitted: 1) non head and neck site and ≤4mm thick; 2) no neurotropism and ≤4mm thick.

Chen et al (2008)[6] reviewed 128 patients with DNM. Twenty-seven patients received adjuvant RT, 26 with primaries in the head and neck region and often with an excision margin <5mm. Local control rates in the RT group were similar to the surgery only group. It was concluded that adjuvant RT appears to produce local control rates similar to those produced by adequate surgical excision when the latter cannot be achieved.

Evidence summary and recommendations

Evidence summary Level References
Desmoplastic melanomas have a higher rate of local recurrence than non-desmoplastic melanomas. IV [6], [7], [8], [9], [10], [11]
Neurotropism does not significantly affect the risk of LR in DM. IV [5], [7], [10], [13], [2], [14], [3], [12]
Involved or close resection margins significantly increases the risk of local recurrence of DM and NM. IV [7], [10], [12]
Evidence-based recommendationQuestion mark transparent.png
Desmoplastic melanomas and neurotropic melanomas should be excised with the same margins as would be performed on a non-desmoplastic/neurotropic melanoma of the same Breslow thickness.


Evidence summary Level References
Adjuvant radiotherapy to the primary excision site of desmoplastic and neurotropic melanoma reduces the risk of local recurrence when the resection margins are involved or deemed inadequate. IV [7], [10]
Patients with DM and disease free resection margins can safely have adjuvant RT omitted if – 1) non head and neck site and ≤ 4mm thick; 2) no neurotropism and ≤ 4mm thick. IV [10]
Evidence-based recommendationQuestion mark transparent.png
Adjuvant radiotherapy to the primary excision site should be considered for patients with desmoplastic or neurotropic melanoma for whom adequate (≥8mm) pathological resection margins cannot be achieved.



Practice pointQuestion mark transparent.png

It is important for all clinicians performing skin checks to be aware of DM and its often subtle clinical presentation.


Practice pointQuestion mark transparent.png

MRI and nerve biopsy should be considered for patients with facial DM located close to named nerves.

Issues requiring more clinical research study

A higher level of evidence on the role of adjuvant RT to the primary site after complete excision of desmoplastic and neurotropic melanoma is needed. There is an ongoing randomised controlled trial on the role of RT in neurotropic melanoma in the head and neck region.

References

  1. Rule WG, Allred JB, Pockaj BA, Markovic SN, DiCaudo DJ, Erickson LA, et al. Results of NCCTG N0275 (Alliance) - a phase II trial evaluating resection followed by adjuvant radiation therapy for patients with desmoplastic melanoma. Cancer Med 2016 Jul 1 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27368067.
  2. 2.0 2.1 2.2 Vongtama R, Safa A, Gallardo D, Calcaterra T, Juillard G. Efficacy of radiation therapy in the local control of desmoplastic malignant melanoma. Head Neck 2003 Jun;25(6):423-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12784232.
  3. 3.0 3.1 3.2 Lens MB, Newton-Bishop JA, Boon AP. Desmoplastic malignant melanoma: a systematic review. Br J Dermatol 2005 Apr;152(4):673-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15840097.
  4. Jaroszewski DE, Pockaj BA, DiCaudo DJ, Bite U. The clinical behavior of desmoplastic melanoma. Am J Surg 2001 Dec;182(6):590-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11839322.
  5. 5.0 5.1 5.2 Foote MC, Burmeister B, Burmeister E, Bayley G, Smithers BM. Desmoplastic melanoma: the role of radiotherapy in improving local control. ANZ J Surg 2008 Apr;78(4):273-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18366400.
  6. 6.0 6.1 6.2 6.3 6.4 Chen JY, Hruby G, Scolyer RA, Murali R, Hong A, Fitzgerald P, et al. Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 128 cases. Cancer 2008 Nov 15;113(10):2770-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18823042.
  7. 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 Guadagnolo BA, Prieto V, Weber R, Ross MI, Zagars GK. The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. Cancer 2014 May 1;120(9):1361-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24142803.
  8. 8.0 8.1 8.2 8.3 8.4 Oliver DE, Patel KR, Switchenko J, Parker D, Lawson DH, Delman KA, et al. Roles of adjuvant and salvage radiotherapy for desmoplastic melanoma. Melanoma Res 2016 Feb;26(1):35-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26397051.
  9. 9.0 9.1 Posther KE, Selim MA, Mosca PJ, Stanley WE, Johnson JL, Tyler DS, et al. Histopathologic characteristics, recurrence patterns, and survival of 129 patients with desmoplastic melanoma. Ann Surg Oncol 2006 May;13(5):728-39 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16538415.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 Strom T, Caudell JJ, Han D, Zager JS, Yu D, Cruse CW, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer 2014 May 1;120(9):1369-78 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24142775.
  11. 11.0 11.1 11.2 Han D, Han G, Zhao X, Rao NG, Messina JL, Marzban SS, et al. Clinicopathologic predictors of survival in patients with desmoplastic melanoma. PLoS One 2015;10(3):e0119716 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25811671.
  12. 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 Varey AHR, Goumas C, Hong AM, Mann GJ, Fogarty GB, Stretch JR, et al. Neurotropic melanoma: an analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center. Mod Pathol 2017 Jul 21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28731051.
  13. 13.0 13.1 13.2 Murali R, Shaw HM, Lai K, McCarthy SW, Quinn MJ, Stretch JR, et al. Prognostic factors in cutaneous desmoplastic melanoma: a study of 252 patients. Cancer 2010 Sep 1;116(17):4130-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20564101.
  14. 14.0 14.1 Livestro DP, Muzikansky A, Kaine EM, Flotte TJ, Sober AJ, Mihm MC Jr, et al. Biology of desmoplastic melanoma: a case-control comparison with other melanomas. J Clin Oncol 2005 Sep 20;23(27):6739-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16170181.
  15. Scanlon P, Tian J, Zhong J, Silva I, Shapiro R, Pavlick A, et al. Enhanced immunohistochemical detection of neural infiltration in primary melanoma: is there a clinical value? Hum Pathol 2014 Aug;45(8):1656-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24890944.
  16. 16.0 16.1 16.2 Maurichi A, Miceli R, Camerini T, Contiero P, Patuzzo R, Tragni G, et al. Pure desmoplastic melanoma: a melanoma with distinctive clinical behavior. Ann Surg 2010 Dec;252(6):1052-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21107116.
  17. Pawlik TM, Ross MI, Prieto VG, Ballo MT, Johnson MM, Mansfield PF, et al. Assessment of the role of sentinel lymph node biopsy for primary cutaneous desmoplastic melanoma. Cancer 2006 Feb 15;106(4):900-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16411225.

Appendices