Stage-Specific Prognosis, Evaluation And Treatment
Staging is a process that tells a doctor if the cancer has spread, and if it has, how far. Melanoma has five stages of disease, 0, I, II, III, IV. The three early stages of disease (0-II) are collectively referred to as localized disease. This means that as best as your doctor can tell the melanoma cells are confined to the site on the skin, referred to as the primary tumor. These stages are further defined by whether or not the melanoma cells have invaded beyond the outer layer of the skin into the underlying second layer (the dermis) and how deeply they have invaded based on the pathologist's measurements in millimeters under the microscope (referred to as thickness). Other pathology information that is used to stage these tumors are whether or not the skin on top of the primary tumor is broken (referred to as ulceration) and how many of the invasive cells in the dermis are dividing (referred to as mitotic rate). The stage definitions for localized disease are as follows:
Stage 0 (Melanoma in situ)
Description
- In this stage, the abnormal cells are non-invasive (have not penetrated into the skin) and found only in the top layer of skin (epidermis). Over time, these cells, if not removed, may become invasive and begin to infiltrate into the underlying layer of the skin (the dermis). In situ melanoma has no potential to spread to other areas of the body.
Prognosis
- Almost 100% curable
Evaluation:
- Except for a careful skin examination to detect the presence of other melanomas or skin cancers, no special tests are necessary.
Treatment
- Surgery (wide excision) to remove the tumor and a margin (~0.5 cm-1.0cm) of normal skin around it.
Stage Ia
Description
- Tumor is invasive but no more than 0.8 mm in thickness with no break in the skin (ulceration).
Prognosis
- Excellent, very high cure rate
Evaluation
- No specialized tests or X-rays are necessary
Treatment
- Wide excision with 1 cm margin of surrounding normal skin
Stage Ib
Description
- Tumor is invasive and no more than 0.8 mm in thickness and skin is ulcerated, or the tumor is between 0.8 mm and 1 mm in thickness, regardless of skin ulceration, or >1.0-2.0 mm without skin ulceration.
Prognosis
- Still very good with high chance for cure
Evaluation
- No specialized tests or X-rays
Treatment
- Wide excision with 1 cm margin of surrounding normal skin as well as a discussion about sentinel lymph node biopsy
Stage IIa
Description
- Tumor is invasive and between 1 mm and 2 mm in thickness with ulceration, or tumor is between 2 mm and 4 mm thick without ulceration.
Prognosis
- These patients have increasing risks for melanomas to have spread to the lymph nodes and/or to distant sites of the body at a level that may not cause any symptoms or be detected by your doctor’s physical examination
Evaluation
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- An ultrasound may be used to check the lymph nodes if your doctor is concerned about enlarged lymph nodes.. Additional imaging (i.e., CT scans) may also be considered, particularly in high-risk patients (i.e., Stage IIB, IIC) to determine if the melanoma has spread other sites in the body
Treatment
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- Wide excision with 1 or 2 cm margins of surrounding normal skin for stage IIA and IIB, 2 cm margins for stage IIC, and a discussion about sentinel lymph node biopsy (stages IIA, IIB, and IIC). Even if the sentinel lymph node examination is normal, adjuvant immunotherapy with pembrolizumab is approved for patients with Stage IIB or Stage IIC disease and may be recommended. Other adjuvant therapies are being evaluated in clinical trials and may be available in the future based on the results of those studies
- Wide excision with 1 or 2 cm margins of surrounding normal skin for stage IIA and IIB, 2 cm margins for stage IIC, and a discussion about sentinel lymph node biopsy (stages IIA, IIB, and IIC). Even if the sentinel lymph node examination is normal, adjuvant immunotherapy with pembrolizumab is approved for patients with Stage IIB or Stage IIC disease and may be recommended. Other adjuvant therapies are being evaluated in clinical trials and may be available in the future based on the results of those studies
Stage IIb
Description
- Tumor is invasive and between 2 mm and 4 mm in thickness with ulceration, or tumor is more than 4 mm thick without ulceration.
Prognosis
- These patients have increasing risks for melanomas to have spread to the lymph nodes and/or to distant sites of the body at a level that may not cause any symptoms or be detected by your doctor’s physical examination
Evaluation
- An ultrasound may be used to check the lymph nodes if your doctor is concerned about enlarged lymph nodes.. Additional imaging (i.e., CT scans) may also be considered, particularly in high-risk patients (i.e., Stage IIB, IIC) to determine if the melanoma has spread other sites in the body
Treatment
- Wide excision with 1 or 2 cm margins of surrounding normal skin for stage IIA and IIB, 2 cm margins for stage IIC, and a discussion about sentinel lymph node biopsy (stages IIA, IIB, and IIC) Even if the sentinel lymph node examination is normal, adjuvant immunotherapy with pembrolizumab is approved for patients with Stage IIB or Stage IIC disease and may be recommended. Other adjuvant therapies are being evaluated in clinical trials and may be available in the future based on the results of those studies
Stage IIc
Description
- Tumor is invasive and greater than 4 mm in thickness with ulceration.
Prognosis
- These patients have increasing risks for melanomas to have spread to the lymph nodes and/or to distant sites of the body at a level that may not cause any symptoms or be detected by your doctor’s physical examination
Evaluation
- An ultrasound may be used to check the lymph nodes if your doctor is concerned about enlarged lymph nodes.. Additional imaging (i.e., CT scans) may also be considered, particularly in high-risk patients (i.e., Stage IIB, IIC) to determine if the melanoma has spread other sites in the body
Treatment
- Wide excision with 1 or 2 cm margins of surrounding normal skin for stage IIA and IIB, 2 cm margins for stage IIC, and a discussion about sentinel lymph node biopsy (stages IIA, IIB, and IIC) Even if the sentinel lymph node examination is normal, adjuvant immunotherapy with pembrolizumab is approved for patients with Stage IIB or Stage IIC disease and may be recommended. Other adjuvant therapies are being evaluated in clinical trials and may be available in the future based on the results of those studies
Stage IIIa
Description
- Cancer has invaded into the lymphatic system and spread to the regional lymph nodes, and/or the nearby skin and soft tissues (referred to as in-transit disease), but has not metastasized to other parts of the body. Prognosis within Stage III is highly variable, and depends on factors such as whether the tumor in the lymph node is clinically apparent, the number of involved lymph nodes, the presence of tumor deposits located between the primary site and the regional lymph node basin (so called “in-transit disease”), as well as certain features of the primary melanoma.
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Stage IIIA: T1a/b, orT2a N1a or N2a Stage IIIB: T0 N1b/1c T1a/b, or T2a N1b/c, or N2b T2b or T3a N1a or N2b Stage IIIC: T0 N2b/c, N3b/c T1a-T3a N2c or N3a/b/c T3v or T4a Any N > 1 T4b N1a-N2c Stage IIID: T4b N3a/b/c - Primary tumor may be any thickness and is NOT ulcerated. Cancer has spread to 1-3 regional lymph nodes which are not big enough to be felt on physical examination, and can only be seen when the nodes are viewed under a microscope.
Prognosis
- A range of prognoses depending on the extent of lymphatic spread. The earliest stage, IIIA, include patients who have undergone a sentinel lymph node biopsy as part of their treatment for an earlier stage of disease, and melanoma cells were found in the node. These patients have a much better outlook than patients who develop disease in lymph nodes large enough to feel or who have developed in-transit tumors (stages IIIB, IIIC, IIID)
Evaluation
- These patients will often have CT or PET scans of the body and MRI of the brain performed. Blood work is usually not necessary, but a test on the tumor might be performed to see if a BRAF genetic mutation is present.
Treatment
- A wide excision of the primary tumor if still present should be done. For patients with a positive sentinel lymph node, there is strong evidence that immediate removal of further lymph nodes does not improve survival. Although the information learned from removing and evaluating more lymph nodes is can be helpful in terms of estimating prognosis, the side effects of additional lymph node removal (especially long-term swelling and nerve problems) can be substantial. Increasingly, patients with positive sentinel lymph nodes are being followed with serial ultrasound evaluations of the lymph node basin, and offered lymph node removal if the melanoma returns in the lymph node basin and nowhere else.
- For patients with clinically enlarged node(s) proven to contain metastatic melanoma, and no disease elsewhere, the standard approach would be to remove the affected nodes and all other nodes in that nodal basin. However, even this practice is evolving with the development of increasingly effective systemic therapies.
- After surgery, additional treatments, called adjuvant therapy, may be recommended. Options would include pembolizumab or nivolumab; for patients with a BRAF V600 mutation, targeted therapy with dabrafenib and trametinib is also an option. As discussed above, each of these treatments is associated with significant potential side effects, and each treatment has significant limitations.
- For patients with enlarged lymph nodes that are surgically resectable, there is growing evidence that also giving systemic treatment before surgery, called neoadjuvant therapy, may be beneficial. In several clinical trials, the response seen in tumors removed at the time of surgery is very helpful in predicting the risk of disease recurrence. In many patients who have had an excellent response to neoadjuvant treatment, adjuvant therapy has been withheld, but definitive trials to determine if this is the best approach or not are ongoing.
- Other treatments might be become available depending on the results of clinical trials that have been completed. Your doctor might recommend radiation therapy in the area where the lymph nodes were removed. If the disease is confined to an extremity, described as in-transit disease, a limb perfusion or infusion might be recommended.
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Stage IIIb
Description
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- Primary tumor may be any thickness and is NOT ulcerated. Cancer has spread to 1-3 regional lymph nodes. The nodes are big enough to be felt on physical examination and node metastasis is confirmed with a microscope.
- Primary tumor may be any thickness and IS ulcerated. Cancer has spread to 1-3 regional lymph nodes which are not big enough to be felt on physical examination, and can only be seen when the nodes are viewed under a microscope.
- Primary tumor may be any thickness and is NOT ulcerated. Cancer has spread to small areas of nearby skin (satellite tumors) or to the area between the primary tumor and regional lymph node basin (in-transit metastasis). Cancer has not spread to the lymph nodes.
- Primary tumor may be any thickness and IS ulcerated. Cancer has spread to 1-3 regional lymph nodes which are not big enough to be felt on physical examination, and can only be seen when the nodes are viewed under a microscope.
- Primary tumor may be any thickness and is NOT ulcerated. Cancer has spread to 1-3 regional lymph nodes. The nodes are big enough to be felt on physical examination and node metastasis is confirmed with a microscope.
Prognosis
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- A range of prognoses depending on the extent of lymphatic spread. The earliest stage, IIIA, include patients who have undergone a sentinel lymph node biopsy as part of their treatment for an earlier stage of disease, and melanoma cells were found in the node. These patients have a much better outlook than patients who develop disease in lymph nodes large enough to feel or who have developed in-transit tumors (stages IIIB, IIIC, IIID)
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Evaluation
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- These patients will often have CT or PET scans of the body and MRI of the brain performed. Blood work is usually not necessary, but a test on the tumor might be performed to see if a BRAF genetic mutation is present.
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Treatment
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- A wide excision of the primary tumor if still present should be done. For patients with a positive sentinel lymph node, there is strong evidence that immediate removal of further lymph nodes does not improve survival. Although the information learned from removing and evaluating more lymph nodes is can be helpful in terms of estimating prognosis, the side effects of additional lymph node removal (especially long-term swelling and nerve problems) can be substantial. Increasingly, patients with positive sentinel lymph nodes are being followed with serial ultrasound evaluations of the lymph node basin, and offered lymph node removal if the melanoma returns in the lymph node basin and nowhere else.
- For patients with clinically enlarged node(s) proven to contain metastatic melanoma, and no disease elsewhere, the standard approach would be to remove the affected nodes and all other nodes in that nodal basin. However, even this practice is evolving with the development of increasingly effective systemic therapies.
- After surgery, additional treatments, called adjuvant therapy, may be recommended. Options would include pembolizumab or nivolumab; for patients with a BRAF V600 mutation, targeted therapy with dabrafenib and trametinib is also an option. As discussed above, each of these treatments is associated with significant potential side effects, and each treatment has significant limitations.
- For patients with enlarged lymph nodes that are surgically resectable, there is growing evidence that also giving systemic treatment before surgery, called neoadjuvant therapy, may be beneficial. In several clinical trials, the response seen in tumors removed at the time of surgery is very helpful in predicting the risk of disease recurrence. In many patients who have had an excellent response to neoadjuvant treatment, adjuvant therapy has been withheld, but definitive trials to determine if this is the best approach or not are ongoing.
- Other treatments might be become available depending on the results of clinical trials that have been completed. Your doctor might recommend radiation therapy in the area where the lymph nodes were removed. If the disease is confined to an extremity, described as in-transit disease, a limb perfusion or infusion might be recommended.
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Stage IIIc
Description
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- Primary tumor may be any thickness and IS ulcerated. Cancer has spread to 1-3 regional lymph nodes. The nodes are big enough to be felt on physical examination and node metastasis is confirmed with a microscope.
- Primary tumor may be any thickness and IS ulcerated. Cancer has spread to small areas of nearby skin (satellite tumors) or to the area between the primary tumor and regional lymph node basin (in-transit metastasis). Cancer has not spread to the lymph nodes.
- Primary tumor may be any thickness and may or may not be ulcerated. Cancer has spread to 4 or more regional lymph nodes, OR to a group of lymph nodes clustered together.
- Primary tumor may be any size and may or may not be ulcerated. Cancer has spread to small areas of nearby skin (satellite tumors) or to the area between the primary tumor and regional lymph node basin (in-transit metastasis) and to nearby lymph nodes.
- Primary tumor may be any thickness and may or may not be ulcerated. Cancer has spread to 4 or more regional lymph nodes, OR to a group of lymph nodes clustered together.
- Primary tumor may be any thickness and IS ulcerated. Cancer has spread to small areas of nearby skin (satellite tumors) or to the area between the primary tumor and regional lymph node basin (in-transit metastasis). Cancer has not spread to the lymph nodes.
- Primary tumor may be any thickness and IS ulcerated. Cancer has spread to 1-3 regional lymph nodes. The nodes are big enough to be felt on physical examination and node metastasis is confirmed with a microscope.
Prognosis
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- A range of prognoses depending on the extent of lymphatic spread. The earliest stage, IIIA, include patients who have undergone a sentinel lymph node biopsy as part of their treatment for an earlier stage of disease, and melanoma cells were found in the node. These patients have a much better outlook than patients who develop disease in lymph nodes large enough to feel or who have developed in-transit tumors (stages IIIB, IIIC, IIID)
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Evaluation
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- These patients will often have CT or PET scans of the body and MRI of the brain performed. Blood work is usually not necessary, but a test on the tumor might be performed to see if a BRAF genetic mutation is present.
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Treatment
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-
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- A wide excision of the primary tumor if still present should be done. For patients with a positive sentinel lymph node, there is strong evidence that immediate removal of further lymph nodes does not improve survival. Although the information learned from removing and evaluating more lymph nodes is can be helpful in terms of estimating prognosis, the side effects of additional lymph node removal (especially long-term swelling and nerve problems) can be substantial. Increasingly, patients with positive sentinel lymph nodes are being followed with serial ultrasound evaluations of the lymph node basin, and offered lymph node removal if the melanoma returns in the lymph node basin and nowhere else.
- For patients with clinically enlarged node(s) proven to contain metastatic melanoma, and no disease elsewhere, the standard approach would be to remove the affected nodes and all other nodes in that nodal basin. However, even this practice is evolving with the development of increasingly effective systemic therapies.
- After surgery, additional treatments, called adjuvant therapy, may be recommended. Options would include pembolizumab or nivolumab; for patients with a BRAF V600 mutation, targeted therapy with dabrafenib and trametinib is also an option. As discussed above, each of these treatments is associated with significant potential side effects, and each treatment has significant limitations.
- For patients with enlarged lymph nodes that are surgically resectable, there is growing evidence that also giving systemic treatment before surgery, called neoadjuvant therapy, may be beneficial. In several clinical trials, the response seen in tumors removed at the time of surgery is very helpful in predicting the risk of disease recurrence. In many patients who have had an excellent response to neoadjuvant treatment, adjuvant therapy has been withheld, but definitive trials to determine if this is the best approach or not are ongoing.
- Other treatments might be become available depending on the results of clinical trials that have been completed. Your doctor might recommend radiation therapy in the area where the lymph nodes were removed. If the disease is confined to an extremity, described as in-transit disease, a limb perfusion or infusion might be recommended.
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Stage IV
Description
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- Cancer has invaded distant organs and other parts of the body. While melanoma can spread anywhere in the body the most common sites are to distant skin and lymph node groups, lung, liver, and brain. Prognosis, thus the staging system, in Stage IV melanoma has historically depended on factors such as where the metastases are located (remote skin, nodal or subcutaneous sites, lung, or other major organs, and by whether or not the LDH is normal or elevated). With the advent of effective new treatments, it is becoming increasingly apparent that prognosis in Stage IV melanoma in large part also depends on whether a patient responds to treatment.
- Stage IV M0: No evidence of distant metastasis
- Stage IV M1a: Metastasis to distant skin, distant soft tissues, or distant lymph nodes
- Stage IV M1b: Metastasis to the lungs, with or without M1a sites of disease.
- Stage IV M1c: Metastasis to non-central nervous system (CNS) sites/or organs, with or without M1a or M1b sites of disease
- Stage IV M1d: Metastasis to the CNS, with our without any other distant metastases
- For each M stage, addition staging indicates whether the serum LDH level, which is an important prognostic factor in this disease, is elevated or not:
- (0): Serum LDH is not elevated above institutional normal range
- Serum LDH is elevated above institutional normal range
- As an example, a patient with distant metastasis to the lungs with an elevated serum LDH would be Stage M1b (1).
- Cancer has invaded distant organs and other parts of the body. While melanoma can spread anywhere in the body the most common sites are to distant skin and lymph node groups, lung, liver, and brain. Prognosis, thus the staging system, in Stage IV melanoma has historically depended on factors such as where the metastases are located (remote skin, nodal or subcutaneous sites, lung, or other major organs, and by whether or not the LDH is normal or elevated). With the advent of effective new treatments, it is becoming increasingly apparent that prognosis in Stage IV melanoma in large part also depends on whether a patient responds to treatment.
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Prognosis
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- Prognosis for patients with Stage IV disease is principally determined by (1) the extent of disease (i.e., what organs has the cancer spread to), and (2) the serum LDH (which is generally a surrogate for tumor burden). Multiple studies also support that patients with either uveal melanoma or mucosal melanoma usually have shorter survival than patients with stage IV disease from cutaneous melanoma. While historically the prognosis for patients with Stage IV melanoma have been very poor (i.e., average survival less than 1 year), outcomes for patients have improved dramatically over the last decade due to the development of many effective systemic therapies, particularly immunotherapies and targeted therapies. Prognosis in Stage IV patients is now also highly dependent upon responsiveness to such treatments.
For staging purposes, metastatic disease is subdivided as follows:- M1a - Remote nodes, soft tissue
- M1b - Lung
- M1c -Visceral other than lung, or any site with elevated LDH
- Prognosis for patients with Stage IV disease is principally determined by (1) the extent of disease (i.e., what organs has the cancer spread to), and (2) the serum LDH (which is generally a surrogate for tumor burden). Multiple studies also support that patients with either uveal melanoma or mucosal melanoma usually have shorter survival than patients with stage IV disease from cutaneous melanoma. While historically the prognosis for patients with Stage IV melanoma have been very poor (i.e., average survival less than 1 year), outcomes for patients have improved dramatically over the last decade due to the development of many effective systemic therapies, particularly immunotherapies and targeted therapies. Prognosis in Stage IV patients is now also highly dependent upon responsiveness to such treatments.
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Evaluation
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- Evaluation: PET scan and/or CT scans should be performed to evaluate for sites of metastasis in the body. In addition, either an MRI (preferred) or a CT scan of brain should be performed to evaluate for CNS metastasis. A biopsy of one of the sites of disease might be performed to confirm that the abnormalities seen on the imaging tests represent spread of melanoma. Such biopsies may also be used to test for gene mutations in the tumor that can indicate responsiveness to approved targeted therapies (i.e., the BRAF V600 mutation for BRAF and MEK inhibitors). Blood work, including LDH, is usually obtained to assess your general health in preparation for treatment. Special blood tests may be required for clinical trials
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Treatment
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- Several options are now available. While great progress has been made with approval of several new therapies, such as immunotherapy and targeted therapy, and while a small proportion of patients receiving each class of treatment will experience long-term survival, there are many patients whose metastatic melanoma will not respond completely. Your doctor may therefore offer you participation in a clinical trial, using either new agents or combinations of currently approved agents. Surgery and/or radiation may also provide clinical benefit in patients with limited sites of disease, or to improved symptoms caused by large or problematic metastases. Optimally, treatment of patients with Stage IV melanoma should be supervised by a multidisciplinary team of melanoma specialists.
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