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01-12-2021 | Metastasis | Review

Current approaches in managing in-transit metastasis of malignant melanoma: a comprehensive review and proposal of an algorithm

Authors: Emin Kapı, Ömer Faruk Ünverdi, Ahmet Demir

Published in: European Journal of Plastic Surgery | Issue 6/2021

Abstract

The most common local and regional metastases of melanoma are skin, soft tissue, and lymph nodes. These metastases spread between the primary tumor and the regional lymph node line. The entity referred to in-transit metastasis is used to describe the lesions occurring in the superficial lymphatics at a distance of at least 2 cm from the primary tumor and in the locoregional lymph node line. In-transit metastases constitute 3.4–6.2% of malignant melanomas. This entity differs histopathologically from distant skin metastases spreading hematogenously. This feature leads to differences in the clinical course. According to the American Joint Committee on Cancer criteria, in-transit metastases are classified as stage 3b (no metastatic node involvement) and stage 3c (metastatic node involvement) disease. In this entity, 5-year survival rates have been reported as 54% in stage 3b and 24% in stage 3c. In-transit metastasis is a heterogeneous disease, and this feature leads to some differences in treatment. In order to increase the success rates in the management of this disease, a multidisciplinary approach should be applied and treatment options should be used effectively. In the treatment of in-transit metastases, a single treatment option cannot provide a complete cure and combined therapies should be applied simultaneously. Treatment options include surgical resection, radiotherapy, intralesional treatments, isolated limb perfusion and infusion, electrochemotherapy, targeted therapies, and immunotherapy. Detailed studies on combinations of these treatment options are ongoing. In this article, current approaches in the management of in-transit metastases have been evaluated.

Level of evidence: Not gradable

Hussussian CJ (2010) Surgical treatment of advanced melanoma. Clin Plast Surg 37(1):161–168PubMedCrossRef

Pointer DT Jr, Zager JS (2020) Management of locoregionally advanced melanoma. Surg Clin North Am 100(1):109–125PubMedCrossRef

Pawlik TM, Ross MI, Johnson MM, Schacherer CW, McClain DM, Mansfield PF, Lee JE, Cormier NJ, Gershenwald JE (2005) Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy. Ann Surg Oncol 12:587–596PubMedCrossRef

Knackstedt T, Knackstedt RW, Couto R, Gastman B (2018) Malignant melanoma: diagnostic and management update. Plast Reconstr Surg 142(2):202–216CrossRef

Nan Tie E, Henderson MA, Gyorki DE (2019) Management of in-transit melanoma metastases: a review. ANZ J Surg 89(6):647–652PubMedCrossRef

Moehrle M, Kraemer A, Schippert W, Garbe C, Rassner G, Breuninger H (2004) Clinical risk factors and prognostic significance of local recurrence in cutaneous melanoma. Br J Dermatol 151(2):397–406PubMedCrossRef

Read RL, Haydu L, Saw RPM, Quinn MJ, Shannon K, Spillane AJ, Stretch JR, Scolyer RA, Thompson JF (2015) In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol 22:475–481PubMedCrossRef

Meier F, Will S, Ellwanger U, Schlagenhauff B, Schittek B, Rassner G, Garbe C (2002) Metastatic pathways, and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol 147:62–70PubMedCrossRef

Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JS, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A (2016) Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 375:1845–1855PubMedPubMedCentralCrossRef

10.

Gonzalez AB, Baum CL, Brewer JD, Arpey CJ, Harmsen WS, Suman VJ, Markovic SN, Jakub JW (2018) Patterns of failure following the excision of in-transit lesions in melanoma and the influence of excisional margins. J Surg Oncol 118:606–613PubMedPubMedCentralCrossRef

11.

Racz JM, Block MS, Baum CL, Jakub JW (2019) Management of local or regional non-nodal disease. J Surg Oncol 119(2):187–199PubMedCrossRef

12.

Weide B, Neri D, Elia G (2017) Intralesional treatment of metastatic melanoma: a review of therapeutic options. Cancer Immunol Immunother 66:647–656PubMedPubMedCentralCrossRef

13.

Boyd KU, Wehrli BM, Temple CL (2011) Intra-lesional interleukin-2 for the treatment of in-transit melanoma. J Surg Oncol 104:711–717PubMedCrossRef

14.

Gassenmaier M, Eigentler TK, Keim U, Goebeler M, Fiedler E, Schuler G, Leiter U, Weide B, Grischke EM, Martus P, Garbe C (2017) Serial or parallel metastasis of cutaneous melanoma? A study of the German central malignant melanoma registry. J Invest Dermatol 137:2570–2577PubMedCrossRef

15.

Kroon HM, Coventry BJ, Giles MH, Henderson MA, Speakman D, Wall M, Barbour A, Serpell J, Paddle P, Coventry AGJ, Sullivan T, Smithers BM, Thompson JF (2016) Australian multicenter study of isolated limb infusion for melanoma. Ann Surg Oncol 23(4):1096–1103PubMedCrossRef

16.

Testori A, Ribero S, Bataille V (2017) Diagnosis and treatment of in-transit melanoma metastases. Eur J Surg Oncol 43(3):544–560PubMedCrossRef

17.

Veverka KK, Jakub JW, Baum CL (2018) Responses to topical diphenylcyclopropenone as an adjunct treatment for in-transit melanoma: a tertiary referral center experience. Dermatol Surg 44:1501–1508PubMedCrossRef

18.

Temple-Oberle CF, Byers BA, Hurdle V, Fyfe A, McKinnon JG (2014) Intra-lesional interleukin-2 therapy for in transit melanoma. J Surg Oncol 109:327–331PubMedCrossRef

19.

Borgstein PJ, Meijer S, van Diest PJ (1999) Are locoregional cutaneous metastases in melanoma predictable? Ann Surg Oncol 6:15–321CrossRef

20.

Estourgie SH, Nieweg OE, Kroon BB (2004) High incidence of in-transit metastases after sentinel node biopsy in melanoma. In: Estourgie SH (ed) Clinical relevance and refinement of the sentinel node procedure in breast cancer and melanoma. Drukkerij Verhaag, Amsterdam, pp 91–94

21.

Almiron CRA, Ortega S (2012) Factores de riesgo de metastasis en transito en pacientes con melanoma cutaneo. Actas Dermosifiliogr 103(3):207–213CrossRef

22.

Read RL, Stalley P, Thompson JF (2015) The contemporary role of major amputation in the management of advanced limb melanoma. Ann Surg Oncol 22(12):4067–4072PubMedCrossRef

23.

Kroon HM, Lin DY, Kam PC, Thompson JF (2009) Major amputation for irresectable extremity melanoma after failure of isolated limb infusion. Ann Surg Oncol 16:1543–1547PubMedCrossRef

24.

Overgaard J, Gonzalez Gonzalez D, Hulshof MC, Arcangeli G, Dahl O, Mella O, Bentzen SM (1995) Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. European society for hyperthermic oncology. Lancet 345:540–543PubMedCrossRef

25.

Creech O Jr, Krementz ET, Ryan RF (1958) Chemotherapy of cancer: regional 29 perfusion utilizing an extracorporeal circuit. Ann Surg 148(4):616–632PubMedPubMedCentralCrossRef

26.

Clark J, Grabs AJ, Parsons PG, Smithers BM, Addison RS, Roberts MS (1994) Melphalan uptake, hyperthermic 1 synergism and drug resistance in a human cell culture model for the isolated limb perfusion of melanoma. Melanoma Res 4(6):365–370PubMedCrossRef

27.

Wieberdink J, Benckhuysen C, Braat RP, van Slooten EA, Olthuis GA (1982) Dosimetry in isolation perfusion of the 34 limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 18(10):905–910PubMedCrossRef

28.

Benckhuijsen C, Kroon BB, van Geel AN, Wieberdink J (1988) Regional perfusion treatment 31 with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol 14(2):157–163PubMed

29.

Srivastava P (2002) Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 20:395–425PubMedCrossRef

30.

Thompson JF, Kam PC, Waugh RC, Harman CR (1998) Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol 14:238–247PubMedCrossRef

31.

Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M (2004) Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 50:722–733PubMedCrossRef

32.

Damian DL, Saw RPM, Thompson JF (2014) Topical immunotherapy with diphencyprone for in transit and cutaneously metastatic melanoma. J Surg Oncol 109:308–313PubMedCrossRef

33.

O’Day SJ, Hamid O, Urba WJ (2007) Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 110:2614–2627PubMedCrossRef

34.

Coley WB (1991) The classic: the treatment of malignant tumors by repeated inoculations of erysipelas. Clin Orthop Relat Res 262:3–11CrossRef

35.

Feeney KJ, Mastrangelo MJ (2015) Intralesional therapy for in-transit and satellite metastases in melanoma. Surg Oncol Clin N Am 24(2):299–308PubMedCrossRef

36.

Zbar B, Rapp HJ (1974) Immunotherapy of guinea pig cancer with BCG. Cancer 34(suppl):1532–1540CrossRef

37.

Zbar B, Bernstein ID, Rapp HJ (1971) Suppression of tumor growth at the site of infection with living bacillus calmette-guerin. J Natl Cancer Inst 46:831–839PubMed

38.

Karakousis CP, Douglass HOJ, Yeracaris PM, Holyoke ED (1976) BCG immunotherapy in patients with malignant melanoma. Arch Surg 111:716–718PubMedCrossRef

39.

Mujagic H, Kolaric K, Malenica B, Nola P (1979) BCG immunotherapy in previously treated malignant melanoma patients. Biomedicine 30:95–102PubMed

40.

Agarwala SS, Neuberg D, Park Y, Kirkwood M (2004) Mature results of a phase III randomized trial of bacillus calmette-guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer 100:1692–1698PubMedCrossRef

41.

Morton DL, Eilber FR, Holmes EC, Hunt JS, Ketcham AS, Silverstein MJ, Sparks FC (1974) BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann Surg 180:635–641PubMedPubMedCentralCrossRef

42.

Heinzerling L, Burg G, Dummer R, Maier T, Oberholzer A, Schultz J, Elzaouk L, Pavlovic J, Moelling K (2005) Intratumoral injection of DNA encoding human interleukin 12 into patients with metastatic melanoma: clinical efficacy. Hum Gene Ther 16(15):35–48PubMedCrossRef

43.

Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, spesific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A 90:3539–3543PubMedPubMedCentralCrossRef

44.

Thompson JF, Agarwala SS, Smithers BM, Ross MI, Scoggins CR, Coventry BJ, Neuhaus SJ, Minor DR, Singer JM, Wachter EA (2015) Phase 2 study of intralesional PV-10 in refractory metastatic melanoma. Ann Surg Oncol 22(7):2135–2142PubMedCrossRef

45.

Andtbacka RHI, Ross M, Puzanov I, Milhem M, Collichio F, Delman KA, Amatruda T, Zager JS, Cranmer L, Hsueh E, Chen L, Shilkrut M, Kaufman HL (2016) Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol 23:4169–4177PubMedPubMedCentralCrossRef

46.

Bedikian AY, Richards J, Kharkevitch D, Atkins MB, Whitman E, Gonzalez R (2010) A phase 2 study of high-dose allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res 20:218–226PubMedCrossRef

47.

Doukas J, Rolland A (2012) Mechanisms of action underlying the immunotherapeutic activity of Allovectin in advanced melanoma. Cancer Gene Ther 19:811–817PubMedPubMedCentralCrossRef

48.

Stopeck AT, Hersh EM, Akporiaye ET, Harris DT, Grogan T, Unger E, Warneke J, Schluter SF, Stahl S (1997) Phase I study of direct gene transfer of an allogeneic histocompatibility antigen. HLA-B27, in patients with metastatic melanoma. J Clin Oncol 15:341–349PubMedCrossRef

49.

Mali B, Jarm T, Snoj M, Sersa G, Miklavcic D (2013) Antitumor effectiveness of electrochemotherapy: a systematic review and meta-analysis. Eur J Surg Oncol 39:4–16PubMedCrossRef

50.

Ricotti F, Giuliodori K, Cataldi I, Campanati A, Ganzetti G, Ricotti G, Offidani A (2014) Electrochemotherapy: an effective local treatment of cutaneous and subcutaneous melanoma metastases. Dermatol Ther 27:148–152PubMedCrossRef

51.

Von Wussow P, Block B, Hartmann F, Deicher H (1988) Intralesional interferon-alpha therapy in advanced malignant melanoma. Cancer 61(6):1071–1074CrossRef

52.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferruci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbe C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356PubMedPubMedCentralCrossRef

53.

Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694–1703PubMedPubMedCentralCrossRef

54.

Day CL Jr, Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, Pasternack BS, Kopf AW, Fitzpatrick TB, Mihm MC Jr (1981) Malignant melanoma. Prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg 194:108–112PubMedPubMedCentralCrossRef

55.

Leon P, Daly JM, Synnestvedt M, Schultz DJ, Elder DE, Clark WH Jr (1991) The prognostic implications of microscopic satellites in patients with clinical stage 1 melanoma. Arch Surg 126:1461–1468PubMedCrossRef

56.

Roses DF, Harris MN, Rigel D, Carrey Z, Friedman R, Kopf AW (1983) Local and in-transit metastases following definitive excision for primary cutaneous malignant melanoma. Ann Surg 198:65–69PubMedPubMedCentralCrossRef

57.

Singletary SE, Tucker SL, Boddie AW Jr (1988) Multivariate analysis of prognostic factors in regional cutaneous metastases of extremity melanoma. Cancer 61:1437–1440PubMedCrossRef

58.

Zogakis TG, Bartlett DL, Libutti SK, Liewehr DJ, Steinberg SM, Fraker DL, Alexander HR (2001) Factors affecting survival after complete response to isolated limb perfusion in patients with in-transit melanoma. Ann Surg Oncol 8:771–778PubMedCrossRef

Title: Current approaches in managing in-transit metastasis of malignant melanoma: a comprehensive review and proposal of an algorithm
Authors: Emin Kapı
Ömer Faruk Ünverdi
Ahmet Demir
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keywords: Metastasis
Melanoma
Melanoma
Published in: European Journal of Plastic Surgery / Issue 6/2021
Print ISSN: 0930-343X
Electronic ISSN: 1435-0130
DOI: https://doi.org/10.1007/s00238-021-01875-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Current approaches in managing in-transit metastasis of malignant melanoma: a comprehensive review and proposal of an algorithm

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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