Melanoma cuntaneous C43.-

Author: Prof. Dr. med. Peter Altmeyer

Co-Autors: Dr. med. Norbert Buhles , Hadrian Tran

All authors of this article

Last updated on: 22.06.2021

Dieser Artikel auf Deutsch

Synonym(s)

Cutaneous melanoma; malignant melanoma; Melanoma; melanoma cutaneous; Melanomalignoma; melanoma malignes; Melanoma of the skin; Nevocarcinoma; Skin cancer black; Skin melanoma

Definition
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Malignant, invasively growing tumour of the melanocytes of the skin and/or mucous membrane that tends to metastasise early. Malignant melanoma is responsible for > 90% of all deaths from skin tumours. It is therefore the malignant skin tumour with the highest metastasis rate.

Based on clinical and histological criteria, different types of melanoma of the skin are distinguished, see table 1.

Classification
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Occurrence/Epidemiology
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Incidence (fair-skinned population in Europe and North America): 13 to 15/100,000 inhabitants/year.

A significant increase in the incidence over the last 50 years can be traced.

Lifetime risk (1960): 1:600; lifetime risk (2010) 1:75 to 1:100.

Malignant melanoma is the malignant disease with the fastest increasing incidence.

The highest increase in incidence was observed in body regions that have been increasingly exposed to the sun in recent decades due to a change in leisure habits.

In 2006, 15830 people in Germany developed malignant melanoma of the skin. In the same year 2287 Germans died from its consequences. For the year 2009, 25,570 new cases, including early forms, were reported (Krebsregister Schleswig Holstein 2012).

The frequency of malignant melanoma of the skin varies greatly from region to region. In some states it is an extremely rare disease.

African Americans have a 20-fold lower risk of developing malignant melanoma of the skin than fair-skinned people.

In the fair-skinned population of Australia, the lifetime risk is about 4 times higher compared to Europeans; it is about 4%.

As a cause of death, malignant melanoma accounts for 1.3% of all cancer deaths in Germany for both sexes.

Regarding the incidence of juvenile malignant melanoma, see Melanoma, malignes juveniles.

Etiopathogenesis
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Currently still unknown.

Growth direction: LMM, SSM and ALM primarily horizontal growth, NM primarily vertical growth direction with poorer prognosis).

Risk factors for the development of melanoma are (Vuong K et al 2016):

  • >as 4-fold risk for redheads (RR 4.20) vs blackheads.
  • >5 fold risk (RR:5.24) for high (> 100) number of melanocytic naevi versus no melanocytic naevi.
  • >5 "atypical" melanocytic naevi from families with clustered malignant melanoma (at least 2 1st degree relatives).
  • 2-fold risk (RR 1.98) of melanoma in a 1st degree relative.
  • >3 fold risk (RR 3.18) with non-melanoma skin cancer in EA versus empty history.

Other risk factors include:

UV light: UV light appears to exert an initiator function or, in predisposed individuals, a promoter function. In LMM, there is a clear cumulative carcinogenic effect of UV radiation. On the other hand, UV radiation exerts an anti-melanoma effect via activation of the vitamin D system[vitamin D hypovitaminosis]. Vitamin D receptor polymorphisms are markers of decreased vitamin D activity. In SSM and NM, the cornerstone of their development is laid by intense UV exposure during childhood and adolescence. However, studies have shown that sunburns in adulthood also result in an increased incidence of melanoma. In 10% of cases, an invasive malignant melanoma develops on the base of a lentigo maligna (lentigo maligna melanoma) after a latency period of 14.5 years on average.

The association between tanning bed use and the development of malignant melanoma cannot be proven with certainty (Burgard B et al. 2018).

Genetic disposition: About 2/3 of all malignant melanomas have a mutation in the B-RAF gene (BRAF V600 mutation), which leads to the replacement of the amino acid valine by glutamic acid and results in increased cell proliferation. This gene plays a role in the development of melanoma, as "excessive sunbathing" can lead to this "tumour-inducing" mutation. This leads to a permanent activation of the B-RAF gene. Besides B-RAF, the "melanoma genes" NRAS, KIT and GAB2 play a role in the etiopathogenesis of malignant melanoma. For uveal melanoma, a mutation in the GNAQ gene plays a role in about 50% of cases.

Development of malignant melanoma:

  • In 10-20% of cases: development of malignant melanoma on previously unchanged skin.
  • In 30% of cases: development from a melanocytic nevus that has been present for years.
  • Very rarely: development from a blue nevus.
  • M. Parkinson's disease: There are clear indications that there is an etiologically unexplained epidemiological connection with Parkinson's disease.

Manifestation
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Mainly in members of the light-skinned population (Caucasians) in middle age.

Women are more frequently affected than men (women: men = 1.5:1 to 2:1).

Age peak middle age (average age men: 56.6 years; women: 54.9 years.

Only 2% of all melanomas occur in patients under 20 years of age, and only 0.3-0.4% in children before the onset of puberty. In the 25-34 age group, melanoma is the fourth most common type of tumor in men and the second most common in women in North America.

Localization
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Possible on the whole integument; also mucous membrane, conjunctiva of the eye and in the eye. In women mainly face and lower extremities; in men mainly upper parts of the trunk. Acrolentiginous melanomas and melanomas of mucous membranes are also observed in coloured people.

Clinical features
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Mostly deep brown to blue-blackish, but more rarely also brown or brown-red, or completely pigment-free (amelanotic malignant melanoma) nodules or plaques of considerably differing clinical aspect. The subtypes given by Clark (superficial spreading, acrolentiginous, nodular and lentigo-malignant melanoma) are listed under separate headings. Rare clinical variants include amelanotic malignant melanoma, subungual malignant melanoma, verrucous and polypoid malignant melanoma, and malignant melanoma of the mucous membranes (oral mucosa, pharynx, larynx, genital and anal mucosa; increasingly detectable in people of color).

Histological variants such as desmoplastic malignant melanoma (histological diagnosis) as well as the so-called balloon cell melanoma (histological diagnosis) do not show any special clinical features that make them clinically diagnosable.

Metastasis: Both lymphogenic and hematogenic metastasis is possible. Approximately 2/3 of all initial metastases are initially confined to the regional lymphatic drainage area (lymphogenic). Regional metastasis may become manifest:

Satellite metastases: Clustered up to 2 cm around the primary tumor.

  • In-transit metastases: Skin metastases between the primary tumor and the first lymph node station.
  • Lymph node metastases: Hard, indolent, later caked, lymph nodes located in the lymphatic drainage area (regional).
  • Later usually haematogenous metastasis, especially to lungs, liver, heart, brain, skin or bone.

Laboratory
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Serological tumour markers (S100B; MIA = Melanoma Inhibitory Activity)

Histology
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The histological staging according to the valid TNM criteria (see table) is obligatory.

The melanoma classification according to the WHO classification, which primarily takes into account the anatomical localisation and growth type (SSM, nodular malignant melanoma, lentigo-maligna melanoma) of the primary tumours, should continue to be used for the clinical description of the tumours. The histological staging includes parameters such as tumor thickness after Breslow, ulceration and mitosis rate.

In principle, the following histological criteria are considered in the diagnosis of melanoma.:

  1. Asymmetry of the tumor
  2. Atypical melanocytes
  3. Necrotic melanocytes
  4. Mitoses in melanocytes across the entire tumor parenchyma, especially at the tumor base (the mitotic index plays a role in melanoma staging)
  5. Invasive growth into local structures with their destruction (e.g. adnexal structures and/or surface epithelium with epithelial narrowing)
  6. Blurred limitation of the lateral intraepidermal melanocytic component
  7. Individual formations of melanocytes predominate focally compared to melanocyte nests
  8. Intraepidermal melanocyte nests show irregular spacing
  9. Melanocyte nests in epidermis and dermis vary in shape and size. They show confluence tendency ("sheets" of melanocytes in the dermis)
  10. Melanocytes (individually and in nests) are observed in all layers of the epidermis. ("scattering" of melanocytes)
  11. Lack of maturation of tumor cells in the deep dermis
  12. Nests at the base are often larger than at the surface
  13. Spread of melanoma nests along the epithelial adnexal structures, vascular invasion, or perineural invasion shall be recorded in the report. .

immunohistology:

  • Immunohistological markers (AK) important in routine diagnostics are S100, MART1 and IMP3.
  • The most important marker in immunohistological melanoma diagnostics is currently a monoclonal AK directed against the melanoma-specific antigen MART1 (Melan A). The AK recognizes an antigenic determinant of a melanosomal protein and is more sensitive than HMB45 and much more specific than S100. The antibody MIB1, which is directed against the Ki-67 protein, has proven to be a useful proliferation marker. Progression-associated AK with prognostic relevance are antibodies against the tumour suppressor gene p53. See below for the individual melanoma variants for details of the fine tissue characteristics.
  • To what extent CD10 overexpression(zinc-dependent metalloprotease) is an indication of a worse prognosis is still unclear.

Laser Scanning Microscopy:

  • Elimination of the normal epidermal architecture
  • lack of demarcation of the papillae
  • irregular nests of atypical melanocytes
  • ascending pagetoid cells = large, round or dendritic cells into higher epidermal layers

Diagnosis
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  • Clinical diagnostics is suitable for making a suspected diagnosis if the examiner is qualified. This includes a whole body inspection of the integument and the adjacent, visible mucous membranes, with palpation of the lymph drainage areas and the regional lymph node stations.
  • Reflected light microscopy:
    • In the differential diagnosis of pigment lesions, qualified reflected light microscopy leads to a demonstrable improvement in diagnostic certainty (recommendation level: A; evidence level: 1b).
    • Qualified, sequential digital reflected-light microscopy (also sequential digital dermatoscopy) can significantly improve the early detection of malignant melanomas (recommendation grade B, evidence level 2b).
  • primary excision:
    • If a malignant melanoma is clinically suspected, it must be excised immediately with a small safety margin in order to be able to perform a final histological examination.
  • post-excision:
    • If a histologically confirmed diagnosis of a malignant melanoma has been made, a radical post-excision of the surgical field must be carried out promptly with stage-dependent safety margins (see table Safety margin). Safety distances deviating from the guidelines (e.g. for anatomical reasons) must be agreed with the informed patient (preferably in writing).
  • Histology (see histology below):
    • For the exact classification of the primary tumor, the histological determination of the tumor thickness according to Breslow (see Breslow index) is necessary: the largest depth extension of the tumor is measured in mm. Furthermore, the invasion level according to Clark as well as an existing ulceration and an increased mitosis rate must be indicated. Tumour thickness measurement according to Breslow, ulceration and mitosis index are of the greatest prognostic importance (see table on stage classification of malignant melanoma).
    • A histological 3-D-diagnostics allows a complete evaluation of the excision areas (see below microscopically controlled surgery). It is particularly useful in special anatomical areas (face, acral localizations), if the desired safety distances cannot be maintained (see: malignant melanoma, acrolentiginous melanoma, acromiocarcinoma).
  • Sonographic and scintigraphic diagnosis of organs and lymph nodes:
    • High-resolution sonography: The sonographic measurement of the primary tumor provides important additional preoperative information for the stage-appropriate surgical procedure. The tumour tissue presents itself as a homogeneous, low-echo structure with sharp boundaries to the echo-rich dermis structures. Very good correlations result for the sonographically and histometrically determined tumor thicknesses.
    • Lymph node sonography ( 5-10 MHz sonography): A reliable differential diagnosis of pathological lymph node structures is not possible with sonography. The following sonomorphological parameters are used for evaluation: size, shape, boundary, echo pattern, perfusion pattern.
    • Peritumoral interstitial lymph drainage scintigraphy (PIL): This procedure, which has been standardized for many years, is suitable for identifying regional lymph node groups. This is particularly necessary in the case of melanoma localization at the trunk, since the regional lymph drainage cannot be predicted there. The special significance also arises in the case of melanomas within the so-called lymphatic watersheds, as these melanomas can be drained bidirectionally or multidirectionally. From a procedural point of view, the PIL can be performed together with the SNLD (Sentinel Lymph Node Dissection).
    • Sentinel Lymph Node Dissection (SLND): The presentation of the sentinel node by means of scintigraphic and vital staining identification has become established as refined lymph node staging in all major melanoma centres. SLND is performed for tumor thicknesses Breslow ≥ 1.0 mm. SLND should also be performed for tumor thicknesses Breslow < 1.0 mm (0.75-1.0 mm) and the presence of other unfavorable prognosis parameters (Clark level IV/V, ulceration of the primary tumor; mitosis rate > 1). In patients with tumor thicknesses > 4.0 mm, a positive lymph node involvement in SLND is a highly significant prognostic indicator for a shorter recurrence-free survival interval.
    • The primary draining lymph node identified by SLND is histologically and immunohistologically processed in cut series. The exact histological parameters for the determination of the nodal tumor burden still need further validation.
    • The value of a molecular biological processing of a tumour-infected sentinel lymph node is still subject of scientific discussion.
  • Detection of brain metastases: For this diagnostic indication the highest diagnostic accuracy is available for cranial MRI (GCP)
  • Sectional imaging: CT diagnostics, possibly MRT or PET-CT diagnostics.

Differential diagnosis
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Therapy
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Operational

Primary tumor (clinically and/or histologically confirmed)

  • R0 resection of the primary tumor region (clinically and histologically proven): taking into account standardized safety margins. For depth, the lesion is removed down to the muscle fascia. Defect closure either primary or by means of sliding flaps, split or full skin grafts.
  • Excision with 3-D histology:
    • Notice! In contrast to the 5 cm safety distance which was previously mandatory, today clearly smaller distances are required. (See Table 8 for recommendations of the Dermatological Oncology Working Group).
    • With difficult anatomical localisations (face, palms of hands, soles of feet) the required safety distances cannot always be observed (see below lentigo-maligna melanoma; see below acrolentiginous melanoma). In this case, a 3-D histology is recommended with the attempt to achieve the safety distance in a manner appropriate to the lymphatic flow (personal experience).
    • The surgical procedure for lentigo maligna melanoma of the face is a special case. Here, in the case of advanced age, multimorbidity or problematic localisation (eyelids, nose, cheek) in tumours with a tumour thickness of Breslow > 1.0 mm, the recommended safety distance (see Table 8) cannot usually be maintained for cosmetic or general medical reasons. The situational surgical measure will be able to adapt to acceptable safety distances using 3D histology.
  • In the case of acral localisation on the fingers and toes and corresponding deep invasion, an R0 resection of the primary tumour region should be aimed for, as with other melanoma types. Only if the R0 status cannot be achieved, an amputation of the distal phalanx and/or the beam is necessary. Especially in the case of melanomas of the hands, the surgical measure should be performed by a qualified surgeon, so that all conservative and reconstructive therapy options are optionally applicable.
  • In the case of lentigo-maligna melanoma (see there) in the facial region of older patients, radiotherapy of the primary tumour alone can be considered (see Table 9).
  • Operative procedure in R1 or R2 situation of the primary tumor region
    • In the case of microscopically or macroscopically detected residual tumour of the primary tumour region, an R0 situation should be aimed for (depending on localisation and tumour type). If this cannot be achieved, other measures for local tumour control are used (radiotherapy, hyperthermic limb perfusion, cryosurgery).

Primary tumor (clinically and histologically not secured):

  • In lesions suspected of being melanoma an excision biopsy is performed, i.e. a complete excision of the lesion with a small safety margin. After histological evaluation, in case of a melanoma diagnosis, the final therapy management can be carried out within a maximum of 4 weeks according to the usual guidelines.
  • Incisional biopsies are only performed in exceptional cases of malignant melanomas (however, there is no reliable evidence of tumour spread through incisional biopsies). Incisional biopsies are considered lege artis if large lentigo maligna melanomas are present on the face. In this case, a diagnostic incision biopsy may be necessary in order to more precisely define the extent of the final intervention.

Lymphadenectomy procedure

  • Elelective Lymph Node Dissection (ELND): Adjuvant therapeutic-diagnostic procedure for high-risk melanoma. The elective (prophylactic) lymphadenectomy is currently controversially discussed due to the lack of data and is not recommended without prior exact lymph node staging (see sentinel lymph node dissection = SLND).
  • Therapeutic Lymph Node Dissection (TLND): This is understood to be radical lymphadenectomy in case of detection of lymphogenic metastasis without evidence of distant metastasis. Results of a larger study in 5547 patients showed no advantage for recurrence-free survival or overall survival for the group with locoregional lymph node dissection compared to a follow-up group (Welch 2016). It can therefore no longer be recommended. Similar observations were made in a study on breast cancer (Giuliano 2010).
  • Therapeutic Lymph Node Dissection for micrometastases in the sentinel lymph node: The complete lymph node dissection should be offered to the patient (recommendation level B, evidence level 2b). It is important to explain the advantages and disadvantages of the procedure (e.g. sensitivity disorders of the extremity, lymphedema). Larger controlled studies must demonstrate a survival advantage of this therapeutic procedure.

Melanoma metastases

  • Melanoma metastases, regional: local recurrence, in satellite and in-transit metastases, isolated. In this case a new excision with a wide safety margin is necessary. In case of single lesions a safety margin of up to 2 cm should be aimed for.
  • Satellite or in-transit metastases, multiple: excision with short safety distance. If technically not possible (number): Destruction of the lesions by laser or cautery surgery. Alternatively for disseminated satellite or in-transit metastases of a limb: Isolated → hyperthermic limb perfusion
  • Clinically detectable lymph node metastasis, regional: radical lymphadenectomy, in case of non-curative resection radiotherapy or (immuno-) chemotherapy (see section on distant metastases)
  • Melanoma metastasis, distant metastasis, cutaneous: cutaneous/subcutaneous metastasis: excision with short safety distance, alternatively in case of inoperability: hyperthermic limb perfusion in case of localization on arms and legs; → radiotherapy, → cytokines intralesional.
  • Melanoma metastasis, supraregional lymph node metastasis: Radical lymphadenectomy, in the case of non-curative resection radiotherapy or (immuno-) chemotherapy.
  • Melanoma metastasis, visceral metastasis(s), isolated or limited: Surgery is useful if there are single or few metastases, if there is an acceptable surgical risk (monitoring of the course of the disease for about 4 weeks to rule out further progress before surgery; especially in pulmonary and cerebral filia) and if R0 resection seems possible. If necessary, follow-up radiation.
  • Melanoma metastases, visceral metastasis, disseminated: surgery not recommended. Individual procedure has to be determined by a tumor conference.

Radiation therapy
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  • Primary tumour (see also therapy) in case of R1 resection:
    • Improved success in radiation therapy is achieved with higher fractionated single doses (ED), at least 5 Gy should be given as ED (e.g. 3 times 9 Gy or 8 times 5 Gy, application 2 times/week) compared to conventional radiotherapy with 2 Gy ED.
  • Adjuvant radiotherapy after lymphadenectomy (success not proven)
    • The S3 guideline 2013 recommends postoperative radiotherapy to improve tumor control in the lymph node area under the following conditions:
      • 3 affected lymph nodes
      • Capsule breakthrough
      • Lymph node metastasis > 3cm
  • Adjuvant radiotherapy after lymph node recurrence
    • This procedure is recommended (GCP)
  • Loco-regional lymphogenic metastasis - Inoperability:
    • Adjuvant radiotherapy for inoperability is recommended. With ED of 5x 1.8-2.5 Gy/week, a total dose of 50-60 Gy should be aimed for.
  • Radiotherapy for systemic metastases:
    • Palliative use for brain metastases (in the case of solitary metastases also single-stage stereotactic convergence radiation) and skeletal metastases (pain, threat of osteolysis, risk of fracture). The dosage of palliative irradiation is analogous to the adjuvant guidelines, except for CNS metastases, which are irradiated with ED of 3.0 Gy to GD 30.0 Gy.
  • Hyperthermia/Radiotherapy: The combination of hyperthermia and radiotherapy seems to be a possible therapy option; however, there are currently no sufficient valid data available.

Internal therapy
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Adjuvant therapy modalities

  • Adjuvantimmunotherapy: Patients in tumor stage III A-D (AJCC 2017) should be offered adjuvant therapy with an anti-PD1 antibody (nivolumab, pembrolizumab).
  • Adjuvanttargeted therapy: Patients with BRAF V600E or V600K mutations in stage III A-D tumours (AJCC 2017) should be offered adjuvant therapy with a BRAF and MEK inhibitor.
  • Adjuvant chemotherapy: Dacarbazine should not be used in adjuvant therapy for melanoma (recommendation grade A, evidence level 1a).
  • Other adjuvant procedures: vaccine therapy, limb perfusion, immune stimulation (Levamisole and BCG), mistletoe therapy should not be used in adjuvant therapy of melanoma (recommendation grade A, evidence level 1a/1b).
  • Adjuvant immunotherapy with interferons: R0-resected malignant melanoma
    • Adjuvant immunotherapy: Interferons and combinations: Interferons have been used for more than 2 decades in the systemic therapy of advanced malignant melanoma. Several studies have demonstrated antitumor effects using recombinant α-interferon. This therapy should be offered for clinical stage (AJCC 2009) II B/C and III A-C.
      • Malignant melanoma (stage II A: In stage II, 2 large national studies with interferon-α-2a are available (Grob and Pehamberger). Grob was able to show a survival benefit in patients with tumors > 1.5 mm (dosage: 3 times 3 million IU s.c. per week for 18 months). Pehamberger confirmed this result with a slightly modified protocol (dosage: 3 million IU s.c. daily for 3 weeks, then 3 times 3 million IU s.c. per week for 12 months). This therapy is approved for clinical stage II.
  • Malignant melanoma (stage IIb, IIIb, pT4 (Breslow > 4.0 mm), and any pT; N1,2, M0:
    • Interferon alpha: Valid results of adjuvant studies with interferon α are available (see also Table 10). With a high dosage of α-IFN (20 million IU/m2KO/day), Kirkwood succeeded for the first time in significantly prolonging both disease-free time and overall survival in patients after excision of melanoma > 4 mm and/or after removal of regional lymph node metastases (Kirkwood 1996). This therapy is approved. It belongs in the hands of the experienced dermatologic oncologist.
    • High-dose therapy, sequential: The results of sequential high-dose therapy (3-4 times a 4-week high-dose therapy at intervals of 4 months [20 million IU/m2 KO/day i.v.]) in comparison to conventional high-dose therapy are not yet conclusive. Interim results indicate better tolerability of the sequential form of therapy with similar terapy results.
    • Pegylated interferons have to be given only 1 time/week (6 or 3 µg/kg bw/week). This improves the quality of life. They prolong relapse-free survival compared to an untreated control group (evidence level 2b).

Treatment modalities for distant metastases (stage IV)

  • Metastatic melanoma (few distant metastases):
    • Interdisciplinary decision on the question of operability. Resection should be performed when an R0 situation appears to be technically feasible and
      • no acceptable functional deficit is to be expected
      • positive predictive factors for local treatment are present (long duration of metastasis-free intervals, low number of metastases)
      • no more favourable alternatives are available.
  • Metastatic melanoma (multiple or inoperable distant metastases):
    • Chemotherapy and chemoimmunotherapy. Principle indications for systemic chemotherapy/chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases, and distant metastases (stage IV). Here, the palliative approach and the quality of life factor must be critically evaluated. In stage IV, a limited metastatic pattern is distinguished from an extensive metastatic pattern. Patients with limited metastatic pattern with metastases in skin, soft tissue, lymph nodes or lung show higher response rates and better prognosis. Patients with extensive metastatic pattern with metastases to liver, brain or generalized visceral metastasis have poorer prognoses.
    • Numerous therapeutic modalities are being investigated: active immunotherapy with tumor vaccines, adaptive immunotherapy with LAK cells and tumor-infiltrating lymphocytes, gene therapy, and others. The wide range of different therapeutic agents shows that, so far, none of the current treatment regimens has convincing effects in the majority of patients.
    • Chemotherapy for metastatic melanoma: The following cytostatic drugs are used: dacarbazine, nitrosurea derivatives(fotemustine is liquid), vinca alkaloids ( vinblastine, vincristine), cisplatin and taxanes(paclitaxel). The only recent new development in chemotherapeutics is liposomal encapsulation of paclitaxel (approved as Abraxane). Dacarbazine: Dacarbazine (Deltimedac) is still considered the standard of care with a response rate of 5.3-23% (depending on dosage). A disadvantage is that dacarbazine is not compatible with liquids. Fotemustine (Muphoran - approved for metastatic malignant melanoma): A response of brain metastases was observed with → fotemustine (Muphoran). Temozolomide (Temodal): alkylane with comparable response rate to dacarbazine but lower toxicity than fotemustine. Temozolomide is a liquid-available monochemotherapeutic agent that can be administered orally due to excellent bioavailability. Response rates are comparable to those with dacarbazine. Cutaneous, subcutaneous, nodular and pulmonary metastases respond better than metastases in other organs. Complete responders in 2-5%, median duration of response 5-7 months.
    • Biochemotherapeutics: Although the use of current treatment regimens with biochemotherapeutics or polychemotherapeutics has demonstrated a prolonged relapse-free interval and/or increased response rates (at the price of significantly increased toxicity) compared with monochemotherapy with dacarbazine in some protocols, none of these studies has yet demonstrated significantly prolonged survival. In view of the low therapeutic success (long-term survival or even cure seems possible in about 10% of all remotely metastasized melanoma patients), the quality of life and the very limited lifespan of patients must be given special consideration in therapy interventions. Therefore, according to the current data, patients with metastatic malignant melanoma should only be treated with monotherapeutic approaches (e.g. dacarbazine/temozolomide) outside of trials; if necessary in combination with alfa-interferon. Biochemotherapeutics or polychemotherapeutics should only be used in controlled trials by specialized oncological-dermatological centers.
  • Alternative: "Targeted" therapeutic approaches:
    • Imatinib (use in C -kit mutated malignant melanoma): In mucosal malignant melanoma (see below melanoma , malignant, mucosal melanoma) and acrolentiginous malignant melanoma up to about 15% C-kit mutations are detected. In the meantime, several case reports have been published showing that C-kit mutants can be successfully treated with C-kit blockers (imatinib -approved as Gleevec-, sunitinib, dastinib). If an activating c-kit mutation is present, there is a high probability of a therapeutic response. Several studies with different tyrosine kinase Tyrosine kinase inhibitors are initiated for this relatively narrow patient segment with high-risk melanomas.
    • B-Raf inhibitors (see below B-RAF and Raf kinases: Spectacular study results have been achieved in individual cases with inhibitors of mutagenic B-Raf (e.g. vemurafenib). → Vemurafenib is a selective inhibitor of mutagenic B-Raf, which is found in about 60% of all primary melanoma tumors and metastases (melanomas in sunlight-exposed localization). In studies, 70% of treated patients (V600E mutation of the B-Raf gene) showed partial or complete remissions. Vemurafenib is now approved as Zelboraf and is available for appropriately mutated melanomas.
    • Dabrafenib (oral BRAF inhibitor): Dabrafenib was approved EU-wide by the European Commission in August 2013. In the pivotal phase III study (BREAK-3), monotherapy with the oral BRAF inhibitor dabrafenib was associated with a significant prolongation of progression-free survival (6.9 months vs. 2.7 months) in distant metastatic melanoma patients (n=187) compared to monochemotherapy with DTIC.

    • Combination therapy (dabrafenib+trametinib): the combined use of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib (COMB-d/COMB-v - trials) demonstrated a clear survival benefit (overall and progression-free survival) (side effects: fever, chills, fatique, rash, nausea, headache, arthralgias, diarrhea).

    • CTLA-4 antibodies (see also CD152): The use of CTLA-4 antibodies (antibodies against cytotoxic T-lymphocyte antigen 4 = ipilimumab - approved as Yervoy®-, Tremelimumab®) has been evaluated in several larger studies (phase II) in metastatic malignant melanoma. Previous study results showed a survival benefit in chemotherapy-pretreated patients with advanced disease. Response rates ranged from 7-15%. Sometimes severe immune-mediated, substance-specific side effects (diarrhea with colitis, inflammatory hepatotoxicity, hypophysitis, uveitis, episcleritis, etc.) are observed in a dose-dependent manner and limit their use.
    • PD-1 antibodies (Nivolumab see below Anti-PD-1 antibodies) block the interaction between programmed cell death and its ligand PDL1. Programmed death (PD-1) is an important receptor protein expressed by activated T cells. These PD-1 ligands (PD-L1 and PD-L2) are produced by tumor cells themselves as well as by cells of the tumor stroma. If the interactions between PD-1 and its ligands are inhibited, their immunosuppressive effect is attenuated. The T-cell response (e.g. against tumor tissue) is enhanced, while an immunosuppressive response is suppressed. Nivolumab is approved as Opdivo® in metastatic malignant melanoma. The effect of nivolumab can be increased by combination therapy with ipilimumab (results of the Checkmate-067 study).
    • Combination therapy (ipilimumab/nivolumab): For stage IV melanoma, a large three-arm phase r study in non-pretreated patients showed a clear advantage in median progression-free survival (PFS) (PFS ipilimumab group: 2.9 months; PFS nivolumab group: 6.9 months, PFS combination group: 11.5 months).
  • Other monotherapeutic and combination therapies:
  • Experimental:
    • Rituximab: In a smaller study, the CD20 antibody Rituximab (MabThera - was tested in patients with advanced malignant melanoma with good success. The results should be reviewed in a larger multicenter study.
    • Pembrolizumab: Success is expected from the monoclonal "check-point blocker", an antibody against PD-1. FDA approval is available for patients with metastatic melanoma after pre-treatment with ipilimumab and a BRAF inhibitor.
    • Immunization therapies with MAGE-A3 protein (ASCI) have not yet been approved in metastatic melanoma.
    • T-VEC (Talimogene Iaherparepvec): This is a genetically modified herpes simplex virus (HSV-1) that is injected intralesionally into the metastasis. After intralesional application, the virus infects tumor cells

      , induces the production of granulocyte-monocyte colony-stimulating factor (GM-CSF), an immunostimulatory protein, and lyses them. The released tumor antigens along with GM-CSF ultimately lead to a tumor-specific immune response. The therapy can be considered as an alternative in the treatment of locally metastasized melanoma (Kleemann J 2017).

    • Hyperthermia: The limited success of conventional therapies for metastatic melanoma led to the investigation of increasingly complementary treatment options. In unresectable melanoma metastases, local response with surface hyperthermia and deep regional hyperthermia with or without combination of radiotherapy and/or chemotherapy has been published. Hyperthermia is a form of treatment for malignant neoplasms with few side effects. The affected area is heated externally by an applicator using ultrasound (radio or microwaves). If larger areas of the body are treated, this is often done with a ring applicator. Cytotoxic properties of chemotherapy and radiotherapy are enhanced additively and sometimes supraadditively by controlled hyperthermia.
  • Metastatic melanoma (locoregional metastases):
    • Patients with satellite or intransit metastases should be placed in clinical trials when possible.
    • Intratumoral electrochemotherapy: Local procedures such as: intratumoral electrochemotherapy with bleomycin or cisplatin, intratumoral injection with Il-2 are used.
    • Hyperthermic limb perfusion: Hyperthermic limb perfusion may be performed in patients with rapidly growing multiple skin and subcutaneous metastases confined to one limb (careful consideration of pros and cons).
  • Supportive therapies: see below. Cytostatic drugs, supportive therapy; see below. Common toxicity criteria.

Operative therapie
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see above under diagnosis, see table.

Radical excision of the tumor with the indicated safety distances to the tumor margin (recommendation level A, evidence level 1a). The excision of the tumor should be performed up to the fascia (recommendation grade B, evidence level 2b).

Amputations for subungual or acrolentiginous malignant melanoma should only be performed in advanced clinical cases with bone or joint involvement.

Experimental:

  • Electrochemotherapy (exclusively in palliative therapy): Alternative, non-thermal tumor ablation procedure. Electrochemotherapy is reserved for palliative therapy, especially in the case of inoperable, bleeding and severely painful metastases, inoperable recurrent tumors, inoperable regional metastases or if tumors/metastases are no longer accessible to any other therapy option!

Progression/forecast
This section has been translated automatically.

  • The most important prognostic factor in malignant melanoma is the tumor volume and tumor spread. This includes the volume of the primary tumor and, if applicable, the metastases. In clinical stages I and II, the prognosis can be considered favorable. Metastasis causes an unfavourable prognosis. Remarkably, a tendency towards thin melanomas can be observed in recent years.
  • The most important prognostic factors in non-metastatic malignant melanoma are:
    • Vertical tumor thickness according to Breslow(Breslow index)
    • Presence of a (clinically and/or histologically recognizable) ulceration
    • Tumor mitosis rate
    • Gender (significantly worse for men)
    • Tumor location (unfavorable prognosis for capillitium, neck, upper trunk, upper arms, acras)
    • invasion level according to Clark is not further recommended as prognostic factor
    • Status of sentinel lymph node based on immunohistological detection methods (HMB-45, Melan-A, MART-1).
  • The recurrence rates determined in a Swedish collective (n=1437) were 12.5% in clinical stage I and 18.8% in clinical stage II (Lyth J et al. 2017). On average, it takes 1.3 years (0.1-10.7 years) for recurrence to occur.
  • With lymph node involvement, micrometastasis and macrometastasis are prognostically significant. Prognosis worsens dramatically with the presence of metastases. Patients with macrometastases (> 2 mm) have a significantly shortened survival. Even "in-transit metastasis" reduces the 10-year survival rate to 28%. Distant metastasis only 3% survive for ten years. The median survival time in these patients without therapy is only about 4-6 months. Recent evidence has shown that in addition to tumor thickness, young age, increased mitotic rate (especially in young patients), angiolymphatic invasion, and localization of the primary tumor to the trunk or lower extremities increase the likelihood of a positive sentinel lymph node.
  • Regression phenomena: The regression rate is reported in the literature to be 10-35%. Views on the prognostic significance of regressive changes in malignant melanoma are controversial. Views documented in the literature and our own experience that extensive regression signs correlate with poor prognosis contrast with statistical results. Due to the increasing awareness of the population regarding the risk factors for the development of malignant melanoma, the incidence of thin (< 1 mm) tumors has increased worldwide. In Europe, the average tumor thickness decreased from 1.8 mm (1976) to 0.5 mm (2000). At the same time, the percentage of thin tumors increased from 39% (1976) to 65.5% (2000). Based on this, the relevance of prognostic factors to this subpopulation should be evaluated in detail. According to common opinion, so-called early regression signs (histologically characterized by early lymphocytic infiltration) do not correlate with a worse prognosis.
  • A positive sentinel lymph node status ( SLND) proved (independent of tumor thickness) to be a robust prognostic factor in multivariable analyses (death rate after 42 months 8% with neg. SLNA vs. 44% with pos. SLND).
  • The influence of pregnancy on the prognosis of women with melanoma was clearly negated in 10 case-control studies. In several large studies, no difference could be demonstrated with regard to overall survival or disease-free survival with adequate therapy. There is no need to refuse pregnancy in women with prior melanoma disease. Women with a later stage of melanoma disease should be informed about the increased risk that their child may grow up motherless.
  • Metallothionein overexpression in the primary tumor appears to be a prognostic factor for progression and survival of melanoma patients.

Prophylaxis
This section has been translated automatically.

Consistent public relations work can significantly improve the prognosis of malignant melanoma. For example, the incidence of melanoma in Australia is significantly higher than in the UK, but mortality is significantly lower due to earlier diagnosis.

Naturopathy
This section has been translated automatically.

Mistletoe therapy (e.g. Iscador M): In Germany very popular additional therapy for malignant melanomas in different stages of the disease. Reliable study results are rare. The results of a larger multicentre study (204 patients) showed no significant differences between the group treated with Iscador M and the placebo in terms of both recurrence-free interval and overall survival.

Tables
This section has been translated automatically.

Subtypes of malignant melanoma

Type

Distribution/ proportion of all melanomas [%].

Median age of manifestation [years]

Superficial spreading melanoma

~ 55-60

51

Nodular melanoma

~ 20

56

Lentigo-maligna melanoma

~ 5-10

68

Acrolentiginous melanoma

~ 5

63

Unclassifiable melanoma

~ 5

54

Other

~ 5

54

Safety distances OP

Tumor thickness (TD) according to Breslow

Safety distance

MM in situ

0.5 cm

TD 1.0 - 2.0 mm

1.0 cm

TD > 2.0 -4.0 mm

2.0 cm

sentinel lymph node biopsy (WLKB); sentinel lymph node biopsy (SLNB)

Tumor thickness (TD) according to Breslow Sentinel lymphnode biopsy
TD < 0.75 mm not recommended
TD 0,75 - 1 mm

recommended in case of risk factors:

- ulceration and/or

- increased mitosis rate and/or

- younger age (< 40 years).

TD > 1.0 mm recommended

Irradiation

Boundary rays

Soft rays

Tumor thickness

< 1 mm

> 1 mm

kV

12

20, 30, 40, 50

Filter, mm

1.0 Cellon

0.4/0.5/1.0/2.0 Al

FDH, cm

12/20/28,3

12/20/28,3

GHWT, mm

0,25/1,0/1,0

2,5-22,5

Single dose, Gy

10/20

5

Fractionation

10-12/5-6

7-9

Interval, days

3-4

2-3

Recombinant IFN alfa-2a

Low-dose regimen

3 million IU s.c.

3 times/week for 18 months

Recombinant IFN alfa-2b

High-dose regimen (initial)

20 million IU/m2 KO i.v.

5 times/week for 4 weeks

High-dose regimen (maintenance)

10 million IU/m2 KO s.c.

3 times/week for 48 weeks

Therapy of metastatic malignant melanoma (excerpts from the ADO guideline, 2005)

Active substances/schemes

Dosages/therapy cycles

Response rate (according to clinical studies)

Monochemotherapies

Dacarbazine

250 mg/m2 KO i.v., days 1-5; repeat every 3-4 weeks

12,1%?17,6%

Alternatively

800-1200 mg/m2 KO i.v., day 1; repeat every 3-4 weeks

Temozolomide (currently not approved for malignant melanoma)

150-200 mg/m2 KO p.o., day 1-5; repeat every 4 weeks

ongoing studies: response rate of 13.5-21% comparable to dacarbazine

Fotemustine

100 mg/m2 KO i.v. on treatment days 1, 8, 15 then 5 weeks rest; repeat every 3 weeks

approx. 7.4-24.2%

Vindesine

3 mg/m2 KO i.v., repeat every 14 days

12-26%

Interferon-alfa

9-18 million IU/m2 KO s.c., 3-weekly, continuous administration

13-25%

Interleukin-2

6 million U/kg bw i.v. (as short infusion over 15 minutes) every 8 hrs, days 1-5 (max. 14 ED); repeat cycle day 14

16-21,6%

Polychemotherapies and chemoimmunotherapies

DTIC (temozolomide) + IFN-α.

DTIC 850 mg/m2 KO i.v., day 1 (or temozolomide 150 mg/m2 KO p.o., days 1-5)

14-27,7%

IFN-a2a/b 3 million IU/m2 KO s.c., day 1-5

IFN-a2a/b 3 times/week 5 million IU/m2 KO s.c. at weeks 2-4; repeat every 4 weeks.

Vindesine + IFN-α

Vindesine 3 mg/m2 KO i.v., day 1

24%

IFN-a2a/b 5 mI/m2 KO s.c. 3 times/week; repeat every 2 weeks.

BHD regimen

BCNU 150 mg/m2 KO i.v., day 1, only every 2nd cycle

12,7-30,4%

Hydroxyurea 1500 mg/m2 KO p.o., days 1-5.

DTIC 150 mg/m2 KO i.v., days 1-5; every 4 weeks

BOLD regimen

Bleomycin 15 mg i.v., day 1 + 4

22-40%

Vincristine 1 mg/m2 KO i.v., day 1 + 5

CCNU 80 mg/m2 KO i.v., day 1

DTIC 200 mg/m2 KO i.v., day 1-5, every 4-6 weeks

DVP regimen

DTIC 200 mg/m2 KO i.v., day 1-5

31,4-45%

Vindesine 3 mg/m2 KO i.v. day 1

Cisplatin 50 mg/m2 KO i.v., day 1, every 3-4 weeks

DVP regimen

DTIC 450 mg/m2 KO i.v., day 1 + 8

24%

Vindesine 3 mg/m2 KO i.v., day 1 + 8

Cisplatin 50 mg/m2 KO i.v., day 1 + 8, every 3-4 weeks

DBCT regimen

DTIC 220 mg/m2 KO i.v., day 1-3

18,5-31,9%

BCNU 150 mg/m2 KO i.v., day 1, every 2nd cycle only

Cisplatin 25 mg/m2 KO i.v., day 1-3

Tamoxifen 2 times/day 10 mg p.o., every 3-4 weeks

B = Bleomycin; B* = BCNU (Carmustine); D = DTIC = Dacarbazine; H = Hydroxyurea; L = Lomustine (CCNU); O = Oncovin (Vincristine); P = Platinex (Cisplatin); V = Vindesine; CR = Complete Remission; PR = Partial Remission; OR = Overall Response

T

Tumor thickness

Ulceration status

Tis

Not applicable

not applicable

Tx Not specified Stage not determinable

T1a

tumour thickness < 1,0 mm

without ulceration, mitosis rate <1/qmm

T1b

tumour thickness < 1.0 mm

with ulceration or mitosis rate >1/qmm

T2a

tumour thickness 1.01- 2.0 mm

without ulceration

T2b

tumour thickness 1,01- 2,0 mm

with ulceration

T3a

tumour thickness 2.01 - 4.0 mm

without ulceration

T3b

tumour thickness 2.01 - 4.0 mm

with ulceration

T4a

tumour thickness > 4.0 mm

without ulceration

T4b

tumour thickness > 4.0 mm

with ulceration

N

Number of metastasized lymph nodes

Mass of lymph node metastases

N0

0

Not applicable

N1a

1 node

micrometastasis(s)*

N1b

1 node

macrometastasis(n)**

N2a

2-3 nodes

Micrometastasis(n)*

N2b

2-3 nodes

macrometastasis(n)**

N2c

2-3 nodes

In-transit metastasis(s) / satellite metastasis(s) without regional lymph node involvement

N3

4 or more lymph nodes involved. or caked lymph nodes, or in-transit/satellite metastases with lymph node involvement

or in-transit metastasis(s)/satellite metastasis(es) with regional lymph node involvement

* evidence of micrometastasis is already in the new AJCC classification when a single cell is found that is immunohistologically positive. These cases should be labeled separately.

M

Localization

Serum LDH

M0

No distant metastases

not applicable

M1a

Distant metastases of the skin, subcutis or lymph nodes, beyond the regional lymph nodes*

normal

M1b

Lung metastasis(s)

normal

M1c

all other visceral metastases

normal

M1c

any distant metastasis

elevated

* The classification M1a also includes the iliac Lk

Stage

T

Ulceration

T

N

T

N

M

0

Tis

-

N0

Tis

N0

M0

IA

T1a

Ø

1.0 mm

N0

T1a

N0

M0

IB

T1b

+/or mitotic rate >1/mm2

1.0 mm

N0

T1b

N0

M0

T2a

Ø

1.01-2.0 mm

N0

T2a

N0

M0

IIA

T2b

+

1,01-2,0 mm

N0

T2b

N0

M0

T3a

Ø

2.01-4.0 mm

N0

T3a

N0

M0

IIB

T3b

+

2,01-4,0 mm

N0

T3b

N0

M0

T4a

Ø

> 4.0 mm

N0

T4a

N0

M0

IIC

T4b

+

> 4.0 mm

N0

T4b

N0

M0

III

any T

N1-N3

M0

IIIA

any T (no ulceration)

Microscopic metastases (clin. occult) in up to 3 lymph nodes

M0

IIIB

any T (with ulceration)

Microscopicmetastases (clinical occult) in up to 3 lymph nodes

M0

IIIB

each T (no ulceration)

Up to 3 macroscopic Metastases.

M0

IIIB

any T (no ulceration)

None, but satellite and/or intransit metastases

M0

IIIC

any T (with ulceration)

Up to 3 macroscopic metastases Metastases/ satellites/ intransit metastases without regional lymph node met astases

N1b

M0

IIIC

any T (with/without ulceration)

4 or >4 macroscopic metastases Metastases/ satellites +/ or intransit metastases with regional lymph node metastases

T1-4b

M0

IV

each T

each N

any T

each N

M1a-c

* Clinical staging includes histopathological staging of primary melanoma and clinical/radiological diagnosis of metastases. By convention, clinical staging should be used after complete excision of the primary melanoma along with a clinical/radiological search for regional lymph node and distant metastases.

** Pathologic staging includes histopathologic staging of primary melanoma including mitotic index and pathologic findings on regional lymph nodes after partial or complete lymphadenectomy. Patients with pathologic stage 0 or 1A are an exception. They do not require pathological examination of their regional lymph nodes.

Studies and therapy regimen

Cycle duration (days)

Number of Pat.

Complete rem ission (%)

Partial remission (%)

p (if given)

Mean survival (months)

Reference

Dacarbazine 300 mg/m2 KO; day 1-6

30

25

8

16,0

0,35

6

Moon et al. (1975)

Dacarbazine 100 mg/m2 KO/8 hr; day 1-6

30

21

4,8

23,8

6

Dacarbazine 4.5 mg/kg bw; day 1-10

30

48

6,3

10,4

0,19

8

Carter et al. (1976)

Dacarbazine 2.7 mg/kg bw; day 1-5

42

67

3

13,4

7

Lomustine 1.5 mg/kg bw; day 2

Vincristine 0.027 mg/kg bw; day 1 and 5

Dacarbazine 2.7 mg/kg bw; day 1-5

42

65

0

23,1

7

Camustine 2 mg/kg bw; day 2

Vincristine 0.027 mg/kg bw; day 1 and 5

Dacarbazine 2.7 mg/kg bw; day 1-5

42

63

4,8

7,9

6

Camustine 2 mg/kg bw; day 2

Hydroxyurea 30 mg/kg bw; days 2, 5, 9, 12, 16, 19

Dacarbazine 250 mg/m2 KO; day 1-4

21

26

0

15,4

0,18

5

Chauvergne et al. (1982)

Dacarbazine 250 mg/m2 KO; day 1-4

21

22

13,6

22,7

8

Detorubicin 120 mg/m2 KO; day 1-4

Dacarbazine 250 mg/m2 KO; day 1-5

28

51

7,8

9,8

> 0,2

4,7

Ringborg et al. (1989)

Dacarbazine 250 mg/m2 KO; day 1-5

28

59

13,6

11,9

5,8

Vindesine 3 mg/m2 KO; day 1

Dacarbazine 1000 mg/m2 KO; day 1

21

118

0

10,2

0,09

6,3

Chapman et al. (1999)

Dacarbazine 220 mg/m2 KO; day 1-3

28

108

0

18,5

7,7

Cisplatin 25 mg/m2 KO; day 1-3

Carmustine 150 mg/m2 KO; day 1/every 2nd cycle.

Tamoxifen 10 mg 2 times/day; day -7 to 0, then continuous

Dacarbazine 1200 mg/m2 KO; day 1

21

19

0

5,3

0,15

7

Chiarion-Sileni et al. (2001)

Dacarbazine 220 mg/m2 KO; day 1-3

28

41

2,4

22

9

Cisplatin 25 mg/m2 KO; day 1-3

Carmustine 150 mg/m2 KO; day 1/every 2nd cycle

Tamoxifen 160 mg; day -7 to 0

  • Confirmation of diagnosis by excision biopsy (in sano)

  • Exact diagnosis (TNM, AJCC, 2009)

  • Definitive surgical treatment with 1 and 2 cm safety margin

  • Sentinel lymph node biopsy for MM ≥ 1.0 mm tumor thickness

  • Comprehensive information (risks, follow-up, doctor's letter)

  • Adjuvant therapy with IFN alfa in MM ≥ 1.5 mm tumor thickness

  • Exact follow-up regimen

  • For disseminated metastasis: monotherapy (± IFN alfa), no poly- or biochemotherapy; inclusion in ongoing trials.

Stage

Tumor thickness

Physical examination 1st-5th year

[Intervals in months]

Physical examination 6th-10th year

[Intervals in months]

Lymph node sonography 1st-5th year

[Intervals in months]

Blood test 1st-5th year **

[Intervals in months]

Imaging examination 1st-5th year ***

[Intervals in months]

I

< 1 mm

6

12

None

None

None ****

I + II

> 1 mm

3

6-12

6

6

None

III *

3

6

3-6

3-6

6

IV

individual

* AJCC stage IIC (< 4 mm tumor thickness + ulceration) should be treated as stage III, as prognosis is comparable.

** Lactate dehydrogenase (LDH), alkaline phosphatase (AP), and protein S100ß.

*** Abdominal ultrasonography and chest x-ray, or CT or MRI or PET.

**** If adjuvant therapies are used, every 6-12 months

Examination method

Recommended examination methods for patients with V.a

locoregional metastasis (stage IIC and III)

Grade of recommendation

MRI head

yes

GCP

CT* (without head)

yes

B

X-ray thorax

no

B

Lk sonography

yes

A

abdominal sonography

no

B

Tumor marker S 100

yes

A

Tumor marker LDH

yes

0

Aftercare
This section has been translated automatically.

  • Currently, a follow-up period of 10 years is common (see table aftercare scheme); 90% of metastases occur in the first 5 postoperative years.
  • A lifelong follow-up is recommended. In the first 5 years 1/4 to 1/2 annual examination intervals, thereafter 1/2 annual.
  • In patients with melanoma in situ, an annual follow-up examination with incident light microscopy is sufficient. Caution! Increased risk of secondary melanoma!
  • Full body examination with inspection and palpation of the excision site and surrounding area and peripheral lymph node status are necessary at every follow-up examination.
  • Psychosocial care should not be neglected either.
  • The current guideline recommends that every melanoma patient should be advised of the possibility of a rehabilitation measure (general treatment or follow-up rehabilitation (AR; formerly: AHB)) according to § 15 or § 31 SGB VI.
  • Notice! About 60% of malignant melanomas are discovered by the patient himself and about 10% by his partner. Recurrences are mostly discovered by the patient himself or by a relative (> 70%) and only about 25% are discovered through routine aftercare!

  • Depending on the risk of metastasis (from 1.0 mm tumour thickness) in stages I and II AJCC 2009: Laboratory (if necessary with S100; LDH and MIA in the sense of), instrumental diagnostics 2 times/year (sonography of the peripheral lymph node stations).
  • From stage III AJCC 2009, more detailed checks and additional diagnostics every 6 months (X-ray thorax, abdominal sonography, CT if necessary, or MRI or PET-CT if appropriate clinical questions arise).

Note(s)
This section has been translated automatically.

  • For the special features of malignant melanoma in children and adolescents, see below Melanoma, malignes, juveniles.
  • For the early detection of recurrences, the anamnesis and the clinical examination are of the greatest importance. Especially in the case of thin melanomas (< 1.0 mm), instrumental diagnostics are negligible. Here the danger of false positive results with consecutive cost-intensive spreading diagnostics is high. A relatively new option in the treatment of skin metastases is the topical application of immunomodulators.
  • Imiquimod: (3 times/week occlusive overnight and 2 times/day occlusive for 6-8 hours) is said to have led to a complete remission of metastases in case studies. However, the number of therapy failures seems to be significant. The development of lentigo maligna melanomas was also observed in the treatment of lentigo maligna with imiquimod.
  • A loss of MTAP expression(methylthioadenosine phosphorylase) is detected in some malignant melanomas in vitro as well as in vivo. This loss seems to correlate with a worse response to interferon therapy.
  • Further possible therapy approaches in stage IIIB/IV are multipeptide vaccines (Melan-A, gp 100, tyrosinase), which, however, need to be verified in larger studies.

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