Melanoma cutaneous C43.-

Malignant, invasively growing tumour of the melanocytes of the skin and/or mucous membrane that tends to metastasise at an early stage. 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.

Malignant melanomas of the skin/mucosa are classified clinically/histologically as follows:

• Superficial spreading malignant melanoma (SSM)
• Nodular malignant melanoma (NM)
• Acrolentiginous malignant melanoma (ALM)
• Lentigo-maligna melanoma (LMM)
• Primary dermal malignant melanoma
• Unclassifiable malignant melanoma
• Melanoma with unknown primary tumor.
• Clinical melanoma variants:
• Amelanotic malignant melanoma
• Mucinous melanoma.

Histologic melanoma variants:

• Nevoid malignant melanoma
• Spitzoid malignant melanoma
• Genuine spitzoid malignant melanoma
• Uniform spitzoid malignant melanoma
• "Packed spitzoid malignant melanoma
• Polypoid spitzoid malignant melanoma
• Pigmented spitzoid malignant melanoma
• Small cells melanoma
• Desmoplastic (neurotropic) malignant melanoma
• Animal-type melanoma
• Bladder cell melanoma
• Malignant nevus bleu
• Primary dermal malignant melanoma
• MELTUMP (acronym for "melanocytic tumors of uncertain malignant potential"; currently unable to be definitively assessed).

Classifications/staging (see respective tables):

• According to EORTC
• TNM according to UICC
• pTNM according to UICC
• According to the German Dermatological Society
• TNM classification according to AJCC (2009)
• Stage classification according to AJCC (2009).

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.

Currently unknown.

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

Risk factors for melanoma development 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 nevi 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:

• Sun sensitivity
• significant, cumulative sun exposure
• numerous sunburns in childhood, adolescence, and adulthood
• Dysplastic nevus syndrome (>5 atypical melanocytic nevi and > 50 "common" melanocytic nevi).
• Bap1 tumor predisposition syndrome (increased risk associated with the following tumor types (in descending order of frequency): uveal melanoma (UM), malignant mesothelioma (MMe), melanoma (of the skin) (CM), renal cell carcinoma (RCC),basal cell carcinoma (BCC).
• MDM2-SNP309 polymorphism in women < 50 years of age.
• Permanent immunosuppression
• BK mole syndrome
• Li-Fraumeni syndrome (LFS), a rare tumor predisposition syndrome is associated with an increased risk of melanoma already in childhood and young adulthood. It is caused by mutations in the Tp53 gene (Nieuwenburg SA et al. 2020).
• Xeroderma pigmentosum
• Ingestion of versch. Drugs, including thiazides (Drucker AM et al. 2021).

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 increased melanoma incidence. In 10% of cases, invasive malignant melanoma develops on the base of lentigo mal igna (lentigo maligna melanoma) after a latency 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 melanoma development, as "excessive sunbathing" can lead to this "tumor-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: There is strong evidence that there is an etiologically unexplained epidemiological association with Parkinson's disease.

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.

Possible on the entire integument; also mucosa, conjunctiva of the eye and in the eye. In women, mainly face and lower extremities; in men, mainly upper trunk areas. Acrolentiginous melanomas and mucosal melanomas are also observed in dark-skinned people.

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.

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

Histological staging according to the valid TNM criteria is obligatory (see table).

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

Basically, the following histological criteria are considered in melanoma diagnosis:

1. Asymmetry of the tumor
2. Atypical melanocytes
3. Necrotic melanocytes
4. Mitoses in melanocytes over the entire tumor parenchyma, especially also at the tumor base (the mitotic index plays a role in melanoma staging)
5. Invasive growth into resident structures with their destruction (e.g., adnexal structures and/or surface epithelium with epithelial narrowing)
6. Blurred boundary of the lateral intraepidermal melanocytic component
7. Single formations of melanocytes predominate focally compared to melanocyte nests
8. Intraepidermal melanocyte nests show irregular spacing from each other
9. Melanocyte nests in epidermis and dermis vary in shape and size. They show confluence tendency ("sheets" of melanocytes in the dermis).
10. Melanocytes (single 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 epithelial adnexal structures, vascular invasion, or perineural invasion should be noted in the report of findings.

Immunohistology:

Immunohistological markers (AK) important in routine diagnostics are S100, MART1 and IMP3.

Currently, the most important marker in immunohistological melanoma diagnostics is considered to be 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 far more specific than S100. The antibody MIB1, directed against the Ki-67 protein, has been shown to be a proliferation marker. Progression-associated AK with prognostic relevance are antibodies against the tumor suppressor gene p53. For fine-tissue specificities, see below the individual melanoma variants.

The extent to which CD10 overexpression(zinc-dependent metalloprotease) is indicative of a poorer prognosis is still unclear.

Laser Scanning Microscopy:

Abrogation of normal epidermal architecture.

lack of delineation of papillae

irregular nests of atypical melanocytes

ascending pagetoid cells = large, round or dendritic cells into higher epidermal layers

Clinical diagnostics are suitable for establishing a tentative diagnosis if the examiner is qualified. This includes a full body inspection of the integument as well as the adjacent, visible mucous membranes, with palpation of the lymphatic drainage areas and the regional lymph node stations.

Reflected light microscopy:

In the differential diagnosis of pigmentary lesions, qualified reflected-light microscopy leads to a demonstrable improvement in diagnostic confidence (grade of recommendation: A; level of evidence: 1b).

Qualified sequential digital reflected-light microscopy (also sequential digital dermoscopy) can significantly improve the early detection of malignant melanoma (recommendation grade B, evidence level 2b).

Primary excision:

If malignant melanoma is clinically suspected, it should be excised immediately with a small safety margin to allow for final histologic examination.

Post-excision:

If a histologically confirmed diagnosis of malignant melanoma exists, a radical re-excision of the surgical field with stage-dependent safety margins should be performed promptly (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: Here, the greatest 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. Tumor thickness measurement according to Breslow, ulceration and mitotic index have the greatest prognostic significance (see table for staging of malignant melanoma).

Histological 3-D-diagnostic allows a complete evaluation of the excision areas (see below microscopically controlled surgery). It is particularly useful at special anatomical sites (face, acral localizations) when safety distances cannot be maintained (see malignant melanoma, acrolentiginous melanoma).

Sonographic and scintigraphic organ and lymph node diagnosis:

High-resolution son ography: Sonographic measurement of the primary tumor provides important additional preoperative information for stage-appropriate surgical procedures. The tumor tissue appears as a homogeneous, echo-poor structure with sharp borders 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 by sonography. The following sonomorphologic parameters are used for evaluation: size, shape, boundary, echo pattern, perfusion pattern.

Peritumoral interstitial lymphatic drainage scintigraphy (PIL): This procedure, standardized for many years, is suitable to identify the regional lymph node groups. This is particularly necessary when melanomas are localized on the trunk, since regional lymphatic drainage cannot be predicted there. The special importance also arises in melanomas within the so-called lymphatic watersheds, since these melanomas can be drained bidirectionally or multidirectionally. Procedurally, PIL can be performed in conjunction with sentinel lymph node dissection (SNLD).

Sentinel Lymph Node Dissection (SLND): Imaging of the sentinel lymph node ("sentinel node") using scintigraphic and vital staining identification has become accepted as a refined lymph node staging procedure at all major melanoma centers. SLND is performed for tumor thicknesses Breslow ≥ 1.0 mm. In tumor thicknesses Breslow < 1.0 mm (0.75-1.0 mm) and the presence of other unfavorable prognostic parameters (Clark level IV/V, ulceration of the primary tumor; mitotic rate > 1, a younger age < 40 years), SLND should also be performed. In patients with tumor thickness > 4.0 mm, positive lymph node involvement at SLND has been shown to be a highly significant prognostic indicator of a shorter recurrence-free survival interval.

The primary draining lymph node identified by SLND is processed histologically and immunohistologically in section series. The exact histologic parameters to assess nodal tumor burden require further validation.

The value of a molecular biological workup of a tumor-infested sentinel lymph node is still subject to scientific discussion.

Detection of brain metastases: For this diagnostic indication, the highest diagnostic accuracy is available for cranial MRI (GCP).

Cross-sectional imaging: CT diagnostics, MRI or PET-CT diagnostics if necessary.

Melanocytic nevus, pigmented verruca seborrhoica, pigmented basal cell carcinoma, thrombosed hemangioma, clear cell sarcoma, cutaneous pigmented dermatofibroma, naevus spitz, naevus bleu, verrucae vulgares, clear cell acanthoma, eccrine hidrocystoma, pigmented spinocellular carcinoma, angiokeratoma, Kaposi's sarcoma, glomus tumor, cutaneous mastocytoma, neurofibroma, in case of nail pigmentation - subungual hematoma.

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.

Primary tumour (see also therapy) with R1 resection:

Improved success of radiotherapy is achieved by 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 2013 S3 guideline recommends postoperative radiotherapy to improve tumor control in the lymph node station area under the following conditions:

• 3 affected lymph nodes
• Capsular rupture
• 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, 50-60 Gy total dose should be aimed for.

Radiotherapy for organ metastases:

Palliative use for brain metastases (for solitary metastases also single-stage stereotactic convergence irradiation) 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, currently no sufficient valid data are available.

Adjuvant therapy modalities

• Adjuvant immunotherapy: Patients in tumor stage III A-D (AJCC 2017) should be offered adjuvant therapy with an anti-PD1 antibody (nivolumab, pembrolizumab).
• Adjuvant targeted therapy ("targeted therapy"): Patients in tumor stage III A-D (AJCC 2017) with a BRAF V600E or V600K mutation should be offered adjuvant therapy with a BRAFand MEK inhibitor .
• Adjuvant chemotherapy: Dacarbazine should not be used in the adjuvant treatment of melanoma (recommendation grade A, evidence level 1a).
• Other adjuvant procedures: Vaccine therapy, limb perfusion, immunostimulation (levamisole and BCG), mistletoe therapy should not be used in the adjuvant treatment 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 two decades in the systemic treatment of advanced malignant melanoma. Several studies have demonstrated antitumor effects using recombinant α-interferon. This therapy is to 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 over 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), as well as 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 the disease-free period and overall survival in patients after excision of a melanoma > 4 mm and/or after removal of regional lymph node metastases (Kirkwood 1996). This therapy is approved. It belongs in the hands of an 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 that the sequential form of therapy is better tolerated with similar therapy results.
  • Pegylated interferons only need to be administered once a week (6 or 3 µg/kg bw/week). This improves the quality of life. They prolong recurrence-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 if an R0 situation appears to be technically possible and
    • no acceptable functional deficit is to be expected
    • there are positive predictive factors for the local procedure (long metastasis-free intervals, low number of metastases)
    • no more favorable alternatives are available.
• Metastatic melanoma (multiple or inoperable distant metastases):
  • Chemotherapy and chemoimmunotherapy. In 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 assessed. In stage IV, a distinction is made between a limited and an extensive metastatic pattern. Patients with a limited metastatic pattern with metastases in the skin, soft tissue, lymph nodes or lungs show higher response rates and a better prognosis. Patients with an extensive metastatic pattern with metastases in the liver, brain or generalized visceral metastases have a poorer prognosis.
  • 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 large selection of different therapeutic agents shows that so far none of the current treatment regimens has shown convincing effects in the majority of patients.
  • Chemotherapy for metastatic melanoma: The following cytostatic drugs are used in particular: dacarbazine, nitrosurea derivatives(fotemustine is soluble), vinca alkaloids ( vinblastine, vincristine), cisplatin and taxanes(paclitaxel). The only current new development in chemotherapeutics is the liposomal encapsulation of paclitaxel (approved as Abraxane). Dacarbazine: Dacarbazine (Deltimedac) is still considered the standard therapeutic agent with a response rate of 5.3-23% (depending on dosage). The disadvantage is that dacarbazine is not soluble. Fotemustine (Muphoran - approved for metastatic malignant melanoma): A response of brain metastases was observed with → Fotemustine (Muphorane). Temozolomide (Temodal): Alkylan with comparable response rate to dacarbazine, but lower toxicity than fotemustine. Temozolomide is a monochemotherapeutic agent that can be administered orally due to its excellent bioavailability. The response rates are comparable to those of 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 shown a prolonged recurrence-free interval and/or increased response rates (at the price of significantly increased toxicity) compared to monochemotherapy with dacarbazine in some protocols, none of these studies have so far demonstrated a significantly longer survival rate. In view of the low treatment success rates (long-term survival or even a cure appears possible in around 10% of all distant metastasized melanoma patients), the quality of life and the very limited lifespan of patients must be given particular consideration during treatment. Therefore, based on the current data, patients with metastatic malignant melanoma should only be treated with monotherapeutic approaches (e.g. dacarbazine/temozolomide) outside of studies; possibly in combination with alfa interferon. Biochemotherapeutics or polychemotherapeutics should only be used in controlled studies by specialized oncological-dermatological centers.
• Alternative: "Targeted" therapy approaches:
  • Imatinib (used for C -kit-mutated malignant melanomas): In mucosal malignant melanoma (see below melanoma, malignant, mucosal melanoma) and acrolentiginous malignant melanoma, up to about 15% C-Kit mutations are detected. A number of case reports are now available which show that extremely successful treatment results can be achieved in C-Kit mutants using 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 various Tyrosine kinase inhibitors are being initiated for this relatively narrow patient segment with high-risk melanomas.
  • B-Raf inhibitors (see B-RAF and Raf kinases below): 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 around 60% of all primary melanoma tumors and metastases (melanomas in sunlight-exposed locations). In studies, 70% of treated patients (V600E mutation of the B-Raf gene) showed partial or complete remissions. Vemurafenib has now been approved as Zelboraf and is available for correspondingly mutated melanomas.

  • Dabrafenib (oral BRAF inhibitor): Dabrafenib was approved throughout the EU by the European Commission in August 2013. In the pivotal phase III trial (BREAK-3), monotherapy with the oral BRAF inhibitor dabrafenib was associated with a significant prolongation of progression-free survival in distant metastatic melanoma patients (n=187) compared to monochemotherapy with DTIC (6.9 months vs. 2.7 months).

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

  • CTLA-4 antibodies (see also CD152): The use of CTLA-4 antibodies (antibodies against the cytotoxic T-lymphocyte antigen 4 = ipilimumab - approved as Yervoy®-, Tremelimumab®) has been tested in several larger studies (phase II) in metastatic malignant melanoma. Previous study results showed a survival benefit in the advanced stage of the disease in patients who had previously received chemotherapy. The response rates were between 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 anti-PD-1 antibodies below) block the interaction between programmed cell death and its ligand PDL1. Programmed death (PD-1) is an important receptor protein that is 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 weakened. The T-cell response (e.g. against the tumor tissue) is enhanced, while an immunosuppressive response is suppressed. Nivolumab is approved as Opdivo® for the treatment of metastatic malignant melanoma. The effect of nivolumab can be enhanced by combination therapy with ipilimumab (results of the Checkmate 067 study).
  • Combination therapy (ipilimumab/nivolumab): For stage IV melanoma, a clear advantage in the median progression-free survival (PFS) was found in a large three-arm phase r study in patients who had not received prior treatment (PFS ipilimumab group: 2.9 months; PFS nivolumab group: 6.9 months, PFS combination group: 11.5 months)
• Further monotherapeutic and combination therapies:
  • The therapeutic approaches with sorafenib, carboplatin, paclitaxel, dacarbazine with and without oblimersen, temozolomide, elesclomol, Bcl 2 antisense oligonucleotides (see oblimersen below) and inhibitors of tumor angiogenesis (E7080 = potent inhibitor of VEGFR1/2and VEGFR3) are currently being tested in various study protocols.
• Experimental:
  • Rituximab: In a smaller study, the CD20 antibody rituximab (MabThera) was tested with good success in patients with advanced malignant melanoma. The results should be verified in a larger multicenter study.
  • Pembrolizumab: The monoclonal "check-point blocker", an antibody against PD-1, is expected to be successful. FDA approval has been granted for patients with metastatic melanoma following pre-treatment with ipilimumab and a BRAF inhibitor.
  • Immunization therapies with the MAGE-A3 protein (ASCI) have not yet been approved for metastatic melanoma.
  • T-VEC (Talimogene Iaherparepvec): This is a genetically modified herpes simplex virus (HSV-1) that is injected intralesionally into the metastases. After intralesional application, the virus infects tumor cells

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

  • Hyperthermia: The limited success of conventional therapies for metastatic melanoma has led to the investigation of increasingly complementary treatment options. For inoperable melanoma metastases, a local response with surface hyperthermia and deep regional hyperthermia with or without a 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 from the outside using an applicator with ultrasound (radio or microwaves). If larger areas of the body are treated, this is often done with a ring applicator. The cytotoxic properties of chemotherapy and radiotherapy are enhanced by controlled overheating in an additive and sometimes supraadditive manner.
• Metastatic melanoma (locoregional metastases):
  • Patients with satellite or intransit metastases should be enrolled in clinical trials if possible.
  • Intratumoral electrochemotherapy: Local procedures are used such as intratumoral electrochemotherapy with bleomycin or cisplatin, intratumoral injection with Il-2.
  • Hyperthermic limb perfusion: In patients with rapidly growing multiple skin and subcutaneous metastases confined to one limb, hyperthermic limb perfusion can be performed (careful consideration of the pros and cons).
• Supportive therapies: see below. Cytostatic drugs, supportive therapy; see below. Common toxicity criteria.

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!

• 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.

Subtypes of malignant melanoma

Safety distances OP

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

Irradiation

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

• 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.

• Currently, a follow-up period of 10 years is common (see table Follow-up regimen); 90% of metastases occur in the first 5 postoperative years.
• Lifelong follow-up is recommended. For the first 5 years, 1/4 to 1/2 annual examination intervals, then 1/2 annually.
• In patients with melanoma in situ, annual light microscopy-controlled follow-up is sufficient. Caveat. Increased risk for second melanoma!
• Full body examination with inspection and palpation of the excision site and surrounding area and peripheral lymph node status are necessary at each follow-up visit.
• Psychosocial care should also not be neglected.
• The current guideline recommends that every melanoma patient be informed of the possibility of a rehabilitation measure (general curative procedure or follow-up curative rehabilitation measure (AR; formerly: AHB)) according to § 15 or § 31 SGB VI.
• Note! About 60% of malignant melanomas are discovered by the patient himself and about 10% by his partner. Recurrences are mostly detected by the patient or a relative (> 70%) and only about 25% by routine follow-up!
• Depending on the risk of metastasis (from 1.0 mm tumor thickness) in stage I and II AJCC 2009: laboratory (if necessary with S100; LDH and MIA i.S.), apparative diagnostics 2 times/year (sonography of the peripheral lymph node stations).
• From stage III AJCC 2009 onwards, closer monitoring and additional diagnostics every 6 months (chest X-ray, abdominal ultrasonography, possibly CT, or MRI or PET-CT if the clinical question is appropriate).

• For the special features of malignant melanoma in children and adolescents, see below Melanoma, malignant, juvenile.
• For early detection of recurrences, history and clinical examination are of utmost importance. Especially in thin melanomas (< 1.0 mm), apparative diagnostics are negligible. Here, risk of false positive results with consecutive cost-intensive spreading diagnostics. A relatively new option in the treatment of skin metastases is the topical use of immunomodulators.
• Imiquimod: (3 times/week occlusive overnight and 2 times/day 6-8 hrs occlusive) is reported to have resulted in complete remission of metastases in case reports. However, the number of treatment failures appears to be significant. Similarly, the development of lentigo maligna melanomas has been observed during treatment of lentigo maligna with imiquimod.
• In a proportion of malignant melanomas, loss ofmethylthioadenosine phosphorylase (MTAP) expression is detected in vitro as well as in vivo. This loss seems to correlate with a poorer response to interferon therapy.
• Other possible therapeutic approaches in stage IIIB/IV are multipeptide vaccines (melan-A, gp 100, tyrosinase), but these need to be verified in larger study approaches.

S.a. Newsletter: Who-thinks-of-melanoma-at-night-blindness

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