Mutation testing is usually confined to stage III clinical trials. As the results of clinical trials become available and the range of chemotherapeutic agents available to patients increase, these recommendations are likely to be modified further. In remote and regional centers, where patients may not have access to clinical trials or multidisciplinary care, the staging recommendations will vary. Additional baseline staging for node-positive patients may include an FBC, liver and renal function tests.
In the U. In Australia, there are no guidelines on the need for or frequency of repeat staging investigations in the absence of specific symptoms that suggest the presence of metastasis. In the United States U. There is limited evidence on whether the guidelines have resulted in early resection of stage IV cancer. Final version of AJCC melanoma staging and classification. TNM staging categories for cutaneous melanoma.
Where this is not possible, adjuvant radiotherapy can be considered. The scar following removal of an invasive melanoma should be re-excised with a margin of between 1 and 2 cm, with the choice of excision margin determined primarily by the Breslow tumor thickness in millimeters see Table 5 below. While some uncertainty remains about specific subsets of melanoma patients, therapeutic elective lymph node resection is generally not recommended as adjuvant surgical treatment.
This is because there is no evidence to suggest a survival advantage and there is significant potential surgical morbidity, including postoperative lymphoedema.
Identification of suspicious lymph nodes on clinical examination should be followed by fine-needle aspiration and ultrasound imaging, MRI or PET. If nodal metastasis is confirmed histologically, immediate complete regional lymph node dissection is recommended. Completion lymph node dissection CLND following identification of micrometastasis on sentinel lymph node SLN biopsy is more controversial as the proportion of lymph node micrometastasis that progresses to symptomatic disease is not known.
It has been suggested that early detection of occult nodal disease provides greater regional control [ 14 ]. Patients who have completion lymph node dissection for micrometastatic disease develop fewer postoperative complications compared with patients who undergo therapeutic lymph node dissection for clinically palpable disease. Previous re-excision of the scar may decrease the efficacy of sentinel node biopsy because it interferes with the lymphatic drainage of the site.
Almost all patients with a high-risk invasive melanoma who are considering participating in an adjuvant therapy clinical trial subsequent to re-excision of the scar will require CLND for staging. Elective lymph node dissection should not be considered appropriate surgery with the exception of biopsy proven nodal disease.
Referral for ophthalmological examination can also be considered. The ability to detect the primary melanoma does not influence the management of the metastatic disease. Standard treatment options for Stage 0-IIA disease are limited to surgical resection with lymphatic mapping and appropriate lymph node dissection as described above.
In current literature, the use of adjuvant chemotherapy has not been shown to impact survival. Interferons IFN are potent immunomodulators that are commonly used in malignancies due to various antiangiogenic, anti-proliferative and pro-apoptotic proprieties [ 28 , 29 ]. Of these, high-dose interferon alpha 2b IFN-a2b has been the most widely evaluated for the use in the treatment of melanoma. The initial trials by the Eastern Cooperative Oncology Group [ 30 , 31 ] produced robust results. Subsequent comprehensive meta-analyses have illustrated the positive effects of IFN-a2b in high-risk melanoma patients.
Wheatley et al. In this initial review, the effect on overall survival remained less significant [ 32 ]. More recently, a Cochrane review of the use of IFN alpha in melanoma estimated significant reductions in the risk of recurrence HR 0. Pegylated Interferfon alpha-2b is a form of immunotherapy characterized by a longer half-life with a postulated improvement in toxicity incidence.
The results from EORTC illustrated a benefit in recurrence free survival and no change in overall survival [ 34 ]. This method of treatment was approved in by the FDA for treatment of melanoma with microscopic or gross nodal involvement based on these findings. These benefits must be balanced against considerable, but rapidly reversible, toxicity. Patients often develop significant constitutional symptoms such as severe fatigue and occasionally depression, as well as abnormal liver function tests, thyroid dysfunction and neutropenia.
Patients with systemic metastases require multidisciplinary specialist care and palliative care health professionals may play an integral role in the management of such disease. Surgical resection should be considered for oligometastatic melanoma in the brain, lung, liver or peritoneal cavity. Stereotactic radiotherapy has a demonstrated role for oligometastatic cerebral metastases, which are not suitable for resection. Radiotherapy is often recommended for palliation of cerebral, bone or soft tissue metastases.
Isolated limb perfusion, radiotherapy or topical immunotherapy may be used to control in transit cutaneous metastases [ 35 ]. With respect to the use of chemotherapeutic agents in Stage IV disease, cytotoxic therapies have long been held as the standard of treatment, although with limited success as discussed below. Over the recent period, new systemic therapeutic agents have been shown to improve on results obtained by the previous cytotoxic agents.
Utilizing these agents, various single agent regimens with trametinib, and MEK and BRAF inhibitors have resulted in significant short-term survival advantage. An initial response is almost universal, but frequently short-lived. Tumor resistance to these agents is generally not reversed by substitution with a different single agent, but this may still be considered. The best response is seen in combination therapy with a BRAF inhibitor and a MEK inhibitor and in particular when dual therapy is used at the outset.
Durable responses can be seen with ipilimumab which extend beyond 4 years. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks the T cell surface protein CTLA-4 that has immunoregulatory functions [ 36 ]. A durable response can be seen with ipilimumab, more so that what targeted therapy has produced [ 37 ]. Despite the significant improvement in prognosis, the use of Ipilimumab is characterised by significant toxicity including rash, colitis and hepatitis. Ipilimumab was approved in March , by the FDA, for metastatic melanoma [ 40 ].
Nivolumab is an antibody against the programmed cell death receptor PD-1 that has also been shown to induce melanoma regression [ 41 ].
Risk of Melanoma Recurrence After Diagnosis of a High-Risk Primary Tumor
One third of patients had rapid and deep tumor regression [ 43 ]. The BRAF inhibitors have a unique toxicity profile including arthritis, photosensitivity, dermatitis, keratosis pilaris, hyperkeratotic palms and soles and the development of non-melanoma skin cancer [ 46 , 47 ].
Vemurafenib is an inhibitor of the oncogenic BRAF kinase [ 50 ]. It received approval by the FDA in the U. In most patients, the melanoma relapses as a result of the development of alternate oncogenic pathways. There is a rationale that combination chemotherapy with ipilimumab or IL-2 may delay loss of response and relapse [ 51 ]. Further studies examining combined targeted therapies and immunotherapy treatments are currently underway [ 53 ]. Dabrafenib is another BRAF inhibitor that when used as monotherapy has a similar benefit to vemurafenib [ 54 ].
The standard therapy for advanced disease up until recently has been dacarbazine. Temozolomide is an oral analog of dacarbazine with similar efficacy, however it more readily crosses the blood-brain barrier and has activity against brain metastases [ 59 ]. Fotemustine has demonstrated higher response rates than dacarbazine but with no improvement in overall survival, although like temozolomide appears to be active against brain metastases [ 60 ].
Various combinations of targeted systemic therapies are currently subject to phase II clinical trials in the U. The proposed benefit is based on theories of prevention the development of MAPK-dependant resistance mechanisms and by reducing BRAF-inhibitor related toxicities in the nonmelanoma BRAF wild-types as discussed above [ 53 , 57 ]. Sentinel lymph node biopsy should now be discussed with all patients with a high-risk invasive melanoma.
Where possible, patients with primary invasive melanoma should be given the option of early review ideally within two weeks in a specialist multidisciplinary clinic where assessment for sentinel node biopsy, surgical re-excision of the scar and genotyping of any lymph node melanoma can be performed.
While primary radiotherapy is occasionally used for unresectable lentigo maligna or invasive melanoma, it is more commonly used as adjuvant radiotherapy for cutaneous melanoma likely to recur locally. Radiotherapy is not advised for local control of inadequately excised tumors—instead every effort should be made to achieve good margins. Adjuvant radiotherapy is also used to prevent recurrence following regional lymph node resection. Common indications include more than three nodes with metastasis, a large tumor mass in a single node, or extracapsular spread. There is no data to suggest that adjuvant radiotherapy improves overall survival [ 63 ].
Radiation can reduce relapse free survival, but in some cases it results in lowered quality of life due to lymphedema [ 64 ]. Significant consideration should be given to the lymphedma risk when planning for adjuvant radiation, and the anticipated benefit in reducing relapse in the locoregional area should outweigh the projected lymphedema risk. All patients diagnosed with invasive melanoma require periodic follow-up that includes examination and palpation for local recurrence, in transit metastasis, lymph node metastasis and hepatomegaly.
Additional examination and investigation should be guided by reported symptoms. This risk is also influenced by other risk factors including family history, skin type, hair color and the presence of significant solar skin damage including non-melanoma skin cancer. It is recommended that all melanoma patients, including those with in situ melanoma, have a complete skin check at least once a year for life following the diagnosis of melanoma.
As there is a familial tendency to melanoma, all first-degree relatives of a patient diagnosed with melanoma should be encouraged to go for a full skin examination to identify a previously unsuspected melanoma and to assess risk of future development of melanoma. Relatives assessed to be at high risk should be offered a surveillance program. Melanoma in a pregnant woman should be treated no differently to melanoma in a non-pregnant woman. Termination of a pregnancy may be considered if there is a pressing need to start radiotherapy or chemotherapy with traditional agents that will harm the fetus.
HRT or oral contraceptives are not contraindicated in women who have had a melanoma. It is common to advise women to avoid pregnancy for two years after apparent successful treatment of a high-risk melanoma during pregnancy, in accordance with the risk of metastatic recurrence. While melanoma is popularly attributed to UV-B radiation, the actual UV action spectrum that causes melanoma is unknown.
A number of animal models recently identified UV-A as important in melanoma induction [ 66 ]. In view of this as well as the systemic immunosuppression associated with UV-A exposure, it is prudent to recommend melanoma patients avoid solaria that predominantly emit UV-A and take precautions to minimise solar UV exposure. Some patients may require serial serum vitamin D estimation and oral vitamin D replacement if deficient.
When first-degree relatives of the melanoma patient attend for their skin check, they should also receive advice regarding both primary and secondary prevention of melanoma. In particular, they should be advised to avoid solaria and take precautions to minimise solar UV exposure by employing the Slip, Slop, Slap technique. Furthermore, they should be educated on the importance of an early detection of melanoma and advised to seek medical assistance immediately should they suspect the development of a melanoma. There is a growing body of evidence that the patients with melanoma are also susceptible to other malignancies.
While the risk of other solar-induced skin cancers is obvious, the relative risk associated with various internal malignancies is less obvious. These risks should be assessed in conjunction with any family history of internal malignancy, smoking and other cancer risk factors to determine whether any additional screening is appropriate. Patients with invasive melanoma and their families will have complex social, psychological and financial issues. Life insurance and income protection insurance may be declined even for people with thin melanomas.
The nature and intensity of these issues will vary from person to person and with disease severity. In our clinic, all patients are encouraged to make contact with a psychologist soon after diagnosis to establish a relationship should help be required subsequently. Many patients with ordinary curable melanoma benefit from this service. Excluding non-melanoma skin cancer, melanoma is now the third most common cancer in Australia. Up until , the gradual reduction in mortality has occurred as a direct result of improved rates of early diagnosis without concomitant improvement in the survival of advanced disease.
Unfortunately these agents are not suitable for BRAF-negative tumors, are not curative and most patients ultimately relapse and die. The role of these agents as adjuvant therapy to improve survival for high-risk melanoma patients is potentially of even greater significance and is currently being investigated.
These agents are expensive and consideration of enrolment of patients in appropriate clinical trials remains a high priority.
In order for melanoma patients to be eligible to participate in clinical trials, patients diagnosed with invasive melanoma should be referred to a specialist multidisciplinary clinic for staging, consideration of surgical re-excision of the scar, options regarding adjuvant therapy and consideration of appropriate therapy for metastatic disease.
National Center for Biotechnology Information , U. Journal List Healthcare Basel v. Healthcare Basel. Published online Dec Find articles by Neiraja Gnaneswaran. Rodney Sinclair 2 Epworth Dermatology, Suite 5. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Melanomas are a major cause of premature death from cancer. Keywords: melanoma, melanocyte, melanin, nevus, skin cancer, malignant melanoma, nodular melanoma, moles, cancer.
Introduction Melanomas are malignant tumors derived from melanocytes. Table 1 Suggested patient history. History Significance How long has the lesion been present? Newly acquired lesions that persist for longer than one or two months may indicate neoplasm, particularly if the patient is in an older age group Has a pigmented lesion changed in color or shape?
Alteration in shape or color may point towards malignancy Has there been any bleeding? Some benign lesions bleed, e. Basal cell carcinomas may also bleed. In general, melanomas bleed only when well advanced, and in such cases the diagnosis is usually obvious Does the lesion itch? Benign naevi or irritated seborrhoeic keratosis may itch when irritated by clothing, etc. While early melanomas are usually asymptomatic, some melanoma may develop an abnormal sensation that patients often find difficult to accurately describe Is there a history of occupational sun exposure, or has the patient lived or worked in the tropics?
Skin cancers in general are related to life-time sun exposure. Malignant melanomas may be related to a single severe episode of sunburn, particularly in childhood Is there a family history of skin cancer? This may indicate a genetic susceptibility, inherited skin type or condition such as dysplastic naevus syndrome.
Open in a separate window. Table 2 Characteristics of benign vs. Clinical Subtypes There are several types of melanoma. Treatment There are 9 steps in the management of invasive melanoma of the superficial spreading and nodular sub-types. Table 3 Assessment of skin cancer risk. High risk Medium risk Low risk Skin check frequency Annual full-body skin checks recommended One-off full-body skin check recommended with the frequency of re-examination required determined at initial skin check Patient self-examination recommended Type I skin with red hair age over 30 age 20—29 below age 20 Type I skin without red hair age over 40 age 30—39 below age 20 Type II skin age over 60 age 40—59 below age 40 Type III skin - over 60 below age 60 Type IV and V skin - - all ages Family history melanoma in first-degree relative NMSC in first-degree relative - Past history non-melanoma skin cancer NMSC or more than 20 solar keratosis solar keratosis, multiple episodes of sunburn -.
Step 2: Tumor Staging Histological staging should be provided by the pathologist in the form of a synoptic report. Step 4: Adjuvant Surgery While some uncertainty remains about specific subsets of melanoma patients, therapeutic elective lymph node resection is generally not recommended as adjuvant surgical treatment. Step 5: Adjuvant Chemotherapy and Radiotherapy 4. Stage 0-IIA Disease Standard treatment options for Stage 0-IIA disease are limited to surgical resection with lymphatic mapping and appropriate lymph node dissection as described above. Stage IV Disease Patients with systemic metastases require multidisciplinary specialist care and palliative care health professionals may play an integral role in the management of such disease.
Durable responses can be seen with ipilimumab which extend beyond 4 years 4.
Cytotoxic Chemotherapy The standard therapy for advanced disease up until recently has been dacarbazine. Combination Targeted Therapies Various combinations of targeted systemic therapies are currently subject to phase II clinical trials in the U. Step 6: Adjuvant Radiotherapy While primary radiotherapy is occasionally used for unresectable lentigo maligna or invasive melanoma, it is more commonly used as adjuvant radiotherapy for cutaneous melanoma likely to recur locally. Step 7: Follow-Up Examination for Metastasis and Subsequent Primary Melanoma All patients diagnosed with invasive melanoma require periodic follow-up that includes examination and palpation for local recurrence, in transit metastasis, lymph node metastasis and hepatomegaly.
Step 8: Lifestyle Modifications to Reduce Risk of Metastasis and Subsequent Primary Melanoma Melanoma in a pregnant woman should be treated no differently to melanoma in a non-pregnant woman. Step 9: Counseling Patients with invasive melanoma and their families will have complex social, psychological and financial issues. Conclusions Excluding non-melanoma skin cancer, melanoma is now the third most common cancer in Australia. Conflicts of Interest The authors declare no conflict of interest.
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- Stage 0 (or melanoma in situ)?
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Treatment of Melanoma Skin Cancer, by Stage
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Stages of melanoma - Melanoma Institute Australia
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