Primary desmoplastic and neurotropic melanomas

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Clinical practice guidelines for the diagnosis and management of melanoma > Primary desmoplastic and neurotropic melanomas


Desmoplastic melanoma

Desmoplastic melanoma (DM) is a rare sub-type of melanoma (1–4% of primary cutaneous melanoma) that may be difficult to recognise, both clinically and pathologically, and behave differently compared to non-desmoplastic melanoma (non-DM).[1][2][3][4][5] As a consequence, the guidelines for the management of non-DM may not be directly applicable to DM and special consideration of this sub-type is warranted.

Conley et al first described desmoplastic melanoma in 1971.[6] It has been characterised histologically by variably pleomorphic, spindle-shaped cells with associated collagen production/stromal desmoplasia. The cells resemble fibroblasts as would be found in scar tissue.[1]

DM usually present as a firm plaque, nodule or thickening that is often not pigmented.[7] There may be little or no change in the appearance of the overlying epidermis. The often unremarkable appearance leads to delayed diagnosis in many cases.[8][9] As a result of the later presentation, the mean and median thickness of DM is close to 4.0mm (2.0 mm- 6.5mm) in many reported series.[1][2][3][4][8][10][11][12][13][14][15][16] The vast majority of DM are Clark level IV or V.

DM are strongly associated with sun-exposure and most frequently arise in the head and neck region.[1][11][12][3][17][15][16] In a large study of scalp melanomas, 29% were desmoplastic.[18] DM have been shown in all published series to be more common in males (M:F 2:1). Patients with DM are generally older at presentation than patients with non-DM. The DM median age is 60–70 years whereas non-DM is 50 years.[1][19][11][12][2][3][4][13][15][16][14][20]

In 2005, it was proposed that DM should be further sub-classified into pure DM (pDM) and mixed DM (mDM) on the basis that the subclasses have differing clinical behaviour.[21][22][23] Pure DM have been defined as those with 90% or more desmoplastic component while mixed DM were defined as those with greater than 10% and less than 90% desmoplastic component. pDM account for close to 50% of all DM.[12][2][3][4][13][16][14] In a review of 252 DM, Murali et al showed pDM to differ significantly from mDM in location, Clark level, Breslow thickness, mitotic rate, perineural invasion and locoregional recurrence rate (4% vs 12%).[14] A lower rate of distant metastasis with pDM and better survival[21][23][12][4] has been demonstrated in some series while not in others.[11][14]

Reflecting the role of sunlight exposure in the aetiology of melanoma, cutaneous melanoma is known to have the highest number of mutations of any cancer.[24] Recent evidence indicates that desmoplastic melanoma has the highest mutation burden of any melanoma.[25] Similarly the driver mutations events associated with desmoplastic melanoma differ from those more commonly seen in other types of cutaneous melanoma. Common mutations in desmoplastic melanoma include: NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET, TERT, NFKBIE, NRAS PIK3CA PTPN11.[25]

An important histological feature of DM is a propensity for neurotropism. This subtype is referred to as desmoplastic neurotropic melanoma (DNM). Neurotropism was first described by Reed and Leonard in 1979[26] and further defined by Chen et al and Varey et al[1][27] with the following characteristics 1) tumour extension along nerves perineurally or endoneurally; 2) formation within the tumour of structures resembling nerves; 3) a change in the morphology of the tumour cells to resemble neural tissue. This is seen in 30–60% of DM[28][21][11][2][3][17][13][16][14] and may be more frequently found in pDM. Occasionally named nerves can be involved, an issue that can be particularly troublesome with cranial nerves and their branches due to extension towards the base of the skull.[11]

Neurotropic melanoma

Importantly, up to 30% of neurotropic melanomas arise in non-desmoplastic melanomas.[27] However, neurotropic melanoma has rarely been discussed in the literature outside the setting of DNM. Varey et al (2017) reported 191 such cases (28%), with the remaining 480 cases of neurotropic melanoma being DNM (72%).[27] The overall incidence of non-DM neurotropic melanoma is unknown, but likely to be less than 1% of all melanomas. There is some evidence to suggest that there may be also be a higher incidence of neurotropism in acral lentiginous melanoma (ALM), possibly up to 8% cases.[29][30] A study by Scanlon et al (2014) of 32 NM cases found that only 34% were DNM, with 22% ALM (acral lentiginous melanoma) and 41% superficial spreading or nodular.[29] A study of ALM by Nagore et al (2008) found neurotropism to be present in 2 of 25 cases (8%), compared to 8 of 549 (1.5%, p=0.014) other melanoma subtypes (superficial spreading, nodular and lentigo maligna, but excluding DNM).[30]

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References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 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.
  2. 2.0 2.1 2.2 2.3 2.4 Mohebati A, Ganly I, Busam KJ, Coit D, Kraus DH, Shah JP, et al. The role of sentinel lymph node biopsy in the management of head and neck desmoplastic melanoma. Ann Surg Oncol 2012 Dec;19(13):4307-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22766985.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 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.
  4. 4.0 4.1 4.2 4.3 4.4 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.
  5. Broer PN, Walker ME, Goldberg C, Buonocore S, Braddock DT, Lazova R, et al. Desmoplastic melanoma: a 12-year experience with sentinel lymph node biopsy. Eur J Surg Oncol 2013 Jul;39(7):681-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23522951.
  6. Conley J, Lattes R, Orr W. Desmoplastic malignant melanoma (a rare variant of spindle cell melanoma). Cancer 1971 Oct;28(4):914-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/5286448.
  7. Jaimes N, Chen L, Dusza SW, Carrera C, Puig S, Thomas L, et al. Clinical and dermoscopic characteristics of desmoplastic melanomas. JAMA Dermatol 2013 Apr;149(4):413-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23325288.
  8. 8.0 8.1 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.
  9. McCarthy SW, Scolyer RA, Palmer AA. Desmoplastic melanoma: a diagnostic trap for the unwary. Pathology 2004 Oct;36(5):445-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15370114.
  10. 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.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 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.
  12. 12.0 12.1 12.2 12.3 12.4 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.
  13. 13.0 13.1 13.2 13.3 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.
  14. 14.0 14.1 14.2 14.3 14.4 14.5 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.
  15. 15.0 15.1 15.2 Wasif N, Gray RJ, Pockaj BA. Desmoplastic melanoma - the step-child in the melanoma family? J Surg Oncol 2011 Feb;103(2):158-62 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21259250.
  16. 16.0 16.1 16.2 16.3 16.4 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.
  17. 17.0 17.1 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.
  18. Xie C, Pan Y, McLean C, Mar V, Wolfe R, Kelly JW. Scalp melanoma: Distinctive high risk clinical and histological features. Australas J Dermatol 2017 Aug;58(3):181-188 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26768190.
  19. Carlson JA, Dickersin GR, Sober AJ, Barnhill RL. Desmoplastic neurotropic melanoma. A clinicopathologic analysis of 28 cases. Cancer 1995 Jan 15;75(2):478-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7812919.
  20. Sims JR, Wieland CN, Kasperbauer JL, Moore EJ, Price DL. Head and neck desmoplastic melanoma: Utility of sentinel node biopsy. Am J Otolaryngol 2017 May 9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28662971.
  21. 21.0 21.1 21.2 Busam KJ, Mujumdar U, Hummer AJ, Nobrega J, Hawkins WG, Coit DG, et al. Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol 2004 Nov;28(11):1518-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15489657.
  22. Scolyer RA, Thompson JF. Desmoplastic melanoma: a heterogeneous entity in which subclassification as "pure" or "mixed" may have important prognostic significance. Ann Surg Oncol 2005 Mar;12(3):197-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15827808.
  23. 23.0 23.1 Hawkins WG, Busam KJ, Ben-Porat L, Panageas KS, Coit DG, Gyorki DE, et al. Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma. Ann Surg Oncol 2005 Mar;12(3):207-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15827812.
  24. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature 2013 Aug 22;500(7463):415-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23945592.
  25. 25.0 25.1 Shain AH, Garrido M, Botton T, Talevich E, Yeh I, Sanborn JZ, et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat Genet 2015 Oct;47(10):1194-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26343386.
  26. Reed RJ, Leonard DD. Neurotropic melanoma A variant of desmoplastic melanoma. Am J Surg Pathol 1979 Aug;3(4):301-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/539614.
  27. 27.0 27.1 27.2 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.
  28. Quinn MJ, Crotty KA, Thompson JF, Coates AS, O'Brien CJ, McCarthy WH. Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer 1998 Sep 15;83(6):1128-35 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9740077.
  29. 29.0 29.1 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.
  30. 30.0 30.1 Nagore E, Pereda C, Botella-Estrada R, Requena C, Guillén C. Acral lentiginous melanoma presents distinct clinical profile with high cancer susceptibility. Cancer Causes Control 2009 Feb;20(1):115-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18758972.

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