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Melanoma (Evaluation and Management) (8th Edition AJCC)

last modified on: Fri, 02/11/2022 - 12:42

Melanoma (Evaluation and Management)

Return to: Cancer Care Principles

 see also: Sentinel Lymph Node Biopsy / Case Example Sentinel Lymph Node Biopsy and Melanoma Pathology Reporting Template

Case Example of Melanoma requiring parotidectomy (scroll to bottom of page): Parotidectomy with Facial Nerve DissectionPosterolateral Neck Dissection

 See Lecture "Melanoma Update" Dr. Hoffman to Iowa Derm Society April 2010 and updated 2011 with discussion re: staging and margins

Melanoma of the Head and Neck October 21 2011


Initial Evaluation

  1. History
    1. Identify history of sun exposure and family history of skin cancer.
    2. Identify change in character of "moles" or other skin lesions.
    3. Discuss any history of excision of skin cancers, including prior melanoma excision.
  2. Physical Examination
    1. Identify lesions suspicious for melanoma
      1. ABCDEs of Melanoma:
        1. A: Asymmetry
        2. B: Irregular Borders
        3. C: Color – nevus with >1 color
        4. D: Diameter of lesion > 6 mm (pencil eraser)
        5. E: Evolution – nevus has gone through sudden changes in size/shape/color
      2. Photograph the lesion
    2. Survey skin of head and neck; arrange dermatology consult for total body survey.
    3. Palpate neck for adenopathy.
  3. Biopsy   see:   Melanoma Pathology Reporting Template
    1. Document the location, extent and character of the lesion with a photograph before biopsy.
    2. Do not do a shave biopsy (the depth of invasion cannot be determined with this technique).
    3. Excisional biopsy is an appropriate diagnostic step with a 1 to 2 mm clinical margin of skin. Obtaining wider margins at the time of biopsy is discouraged because:
      1. Wider margins than 1-2 mm will interfere with accuracy of regional staging using lymphoscintigraphy and SLN bx
      2. Wider margins will potentially sacrifice tissue unnecessarily
    4. Wound healing in the interval from biopsy to definitive treatment may obscure accurate location of the primary tumor.
      1.  Photography of the lesion prior to biopsy with insertion of several photos in the chart is recommended.
      2. It is reasonable to leave sutures placed at the time of biopsy until time of definitive resection to serve as a marker.
    5. A punch biopsy with sampling of the most raised area is a reasonable alternative to excisional biopsy for larger tumors.
  4. Blood Studies
    1. There are currently no useful screening blood studies specific to melanoma. Standard evaluation with CBC, coagulation profile, renal function, and liver function studies are recommended. Abnormal liver function studies should be appropriately evaluated (ie, hepatitis work-up).
    2. Lactate Dehydrogenase (LDH) and C-reactive protein (CRP) have been used as markers for melanoma prognosis.
      1. The value in assessing LDH levels is limited to Stage IV disease.
  5. Radiographic Imaging
    1. Chest x-ray is routinely obtained for all but the earliest (Stage 1) cases of invasive melanoma if more advanced imaging of the chest is not done (such as PET/CT)
    2. Head and neck CT or MRI are of value for:
      1. Sinonasal melanoma to determine extent of primary tumor
      2. Thicker (>1.0 mm) melanoma to assist in
        1. Coregistration and identification of SLN in the course of lymphoscintigraphy
        2. Identification of anatomy and nodal distribution (?deep lobe of parotid nodes) in preparation for surgery
      3. Cases with palpable disease to determine the extent of metastases
    3. Consider chest CT if the melanoma is intermediate (>1.0 mm) to identify pulmonary metastases. This evaluation is important to help decision making if a morbid procedure is considered to treat local or regional disease. For example, planned treatment of a sinonasal melanoma with orbital exenteration may be modified if asymptomatic metastases are identified on chest CT.
    4. The role for PET imaging in management of melanoma is still evolving. Lymphoscintigraphy with SLN bx has supplanted the role for use of PET in assessing for occult regional metastases. PET is commonly used in the face clinically apparent regional metastases and aggressive melanomas (ie, sinonasal) at our institution. Other imaging is directed by symptoms.
  6. Pathological Considerations
    1. It may be difficult to discriminate between atypical melanocytic proliferations (dysplastic nevi) and invasive melanoma. Close consultation with the pathologist should include a low threshold for review of the biopsy material for second opinion.
    2. Melanoma may be difficult to discriminate from other "small blue cell tumors" and should be evaluated with immunohistochemistry when the routine histologic examination is inconclusive (as with mucosal and sinonasal melanoma). Immunohistochemistry stains that are positive to S-100 protein and HMB-45 are helpful in supporting the diagnosis of melanoma.
  7. Consultations
    1. Dermatology consultation is important to help in initial total-body evaluation and with lifelong surveillance.
  1. TREATMENT CONSIDERATIONS
    1. Considerations in determining surgical margins
      1. Breslow depth
        1. Melanoma in situ - 5mm
        2. 1~2mm - 1cm
        3. 2~4mm - 2cm
        4. >4mm - >2cm
      2. Margins on biopsy (whether biopsy margins are involved)
      3. Presence or absence of satellitosis
      4. Impact of margins on anatomic function
      5. Presence or absence of perineural spread
      6. Direction of lymphatic drainage
      7. Cosmesis
      8. Informed patient request
    2.  
      1. Conservative margins (1 cm) should be used for thin primary tumors 1 mm) and more extensive margins (up to 2 cm) for thicker tumors, tempered by functional considerations (ie, preservation of vital structures).
      2. Some suggest performing an asymmetrical excision rather than a circular or elliptical excision to include a larger margin in the direction of draining lymphatics.
    3. Lymph Node Dissection
      1. Perform with palpable disease in patients without evidence of distant metastases in whom the primary tumor and draining lymph nodes are resectable.
        1. Classic radical neck dissection is done for bulky infiltrating disease with lesions anterior to the mid part of auricle; may preserve spinal accessory nerve if it is not involved. Consider modification of radical neck dissection if the sternocleidomastoid muscle, internal jugular vein, or spinal accessory nerve are not involved.
        2. If the lesion is located above parotid, include parotidectomy (superficial lobe; lymph nodes generally absent from deep lobe) with neck dissection. Generally perform resection of entire lateral lobe of parotid with VII nerve preservation if palpable disease in parotid does not involve the facial nerve. Deep lobe of parotid usually does not harbor lymph nodes at risk. Extension of the parotidectomy to remove nodes from adjacent nodal basins (levels I,II,III and V) is determined individually.
        3. For lesions posterior to midpoint of auricle, usually perform posterolateral neck dissection (directed by lymphoscintigraphy and SLN bx as well as other radiography).
      2. Elective neck dissection
        1. Past dogma:
          1. Beneficial as prognosticator: survival is much greater if no lymph nodes are involved. . Questionable benefit to survival as therapeutic modality. Support was published for improved survival through elective neck dissection. Equally strong (actually stronger) support was published for observation of the neck with neck dissection performed only if metastases become clinically apparent.
          2. Formerly our approach included the following plan:
            1. Offer lymphadenectomy for lesions >=1.5 mm and <4.0 mm thick except for higher risk areas (BANS) (includes scalp and neck); consider for lesions >=0.75 mm and <4.0 mm in these areas.
            2. Rationale: potential benefit from lymphadenectomy for lesion >4.0 mm is negligible because of high occurrence of distant metastases and negligible for lesions <1.5 mm because of low risk for regional metastases.
          3. These decisions are made following a Tumor Board discussion. Endeavor to include an educated patient as an active participant in the final disposition.
        2. Current thinking:
          1. Elective 'lymphadenectomy' may still be supported when removal of the lymph node basin (ie parotidectomy or neck dissection) is done to improve the deep margin about a deeply invasive melanoma.
          2. We have adopted a more aggressive approach to use of sentinel lymph node (SLN) biopsy that now has replaced the use of elective neck dissection and is offered to all patients according to the algorithms presented within the individual TNM grouping listed above. In general: SLN bx if no clinically documented metastases are present and the primary lesion is any T classification other than T1a or Tis.
      3. Sentinel node biopsy
        1. Use of lymphoscintigraphy to identify primary echelon nodal drainage for melanoma has become standard.
        2. Sentinel node biopsy is advantageous in that it limits the extent of the surgical excision and also direct resources to more intensely study one or several isolated nodes rather than multiple. Sensitivity for detection of melanoma is increased through microscopic evaluation of multiple sections taken through each lymph node supplemented by immunohistochemistry.
        3. Lymphoscintigraphy may be useful in selected cases of head and neck melanoma to direct appropriate node sampling in the case of midline lesions or lesions about the auricle for which it is not clear whether a parotidectomy or posterolateral neck dissection is most appropriate.
        4. Sentinel node biopsy for desmoplastic melanoma although commonly performed should be considered on a case by case basis due to higher likelihood of distant rather than local spread. 
        5. See: sentinel lymph node biopsy protocol
    4. Role for Irradiation
      1. It was formerly considered that melanoma was radio-resistant.
      2. Current thought: High-dose-per-fraction radiation is of benefit for selected cases.
      3. We consider (through Tumor Board discussion of individual cases) the use of radiotherapy as an adjunct to surgery for high-risk cases for:
        1. Lesions with >4.0 mm depth of invasion
        2. Lesions associated with gross metastatic disease or microscopic disease identified on elective lymphadenectomy
        3. Aggressive histologic types (ie, desmoplastic, perineural spread)
        4. Recurrent melanoma
        5. Sinonasal melanoma
    5. Recommendations for Distant Metastatic Disease (stage IV)
      1. Limited – resection, if feasible or systemic therapy
        1. Systemic therapy should be followed by repeat scans and resectable disease following neoadjuvant therapy should be reassessed for surgery
        2. Completely resected patients with no evidence of disease can be observed or offered adjuvant treatment
        3. Incompletely resected should be treated as below for disseminated disease
      2. Disseminated Disease – Clinical trial, systemic therapy, local treatment, or best supportive care
        1. Extracranial metastasis
          1. Local options: injection with T-VEC, resection, or radiation
          2. Symptomatic: palliative resection and/or radiation for visceral, bone and CNS metastases
    6. Recommendations for Systemic Therapy—first line for unresectable or distant metastatic disease
      1. Immune checkpoint inhibitors – effective regardless of BRAAF mutation status
        1. Anti-PD-1:
          1. pembrolizumab
          2. nivolumab/ipilimumab
      2. BRAF V600-activating mutation (+IHC staining of tumor for VE1)
        1. BRAF/MEK inhibitor combination therapy
          1. Encorafenib/binimetnib
          2. Vemurafenib/cobimetinib
          3. Dabrafenib/trametinib

Currently open Melanoma Tissue Bank

  1. Bank tissue from melanoma for correlative studies.
    1. Serum, flash frozen tumor tissue, DNA, RNA
    2. Bank has images, pathology review and can link to information.
    3. Prospectively collecting for patients.
       

Former Trials Now Closed:

  1. Phase I/II Study Epigenetic Modification of Chemosensitivity and Apoptosis in MetastaticMelanoma: Treatment of a Resistant Disease Using Decitabine, Temozolomide and Panobinostat
    1. Currently in the phase 1 portion, assess the safety of combining a hypomethylating agent, a histone deacetylase inhibitor with standard chemotherapy. These agents modify the epigenetic expression of melanoma and we hypothesize improvement in chemotherapy induced cell kill.
    2. Inclusion:
      1. Any patient with metastatic melanoma treated with chemo or immunotherapy or not.
      2. Brain mets allowed only if prior treatment with radiation.
  2. A Randomized Ph III Study of Tasisulam Administered as an IV Infusion on Day 1 of a 28-Day Cycle vs. Taxol as Second-Line Treatment in Pts with Unresectable or Metastatic Melanoma
    1. Second line treatment after Temodar failure.
    2. RR in the phase II are 18% for single agent Tasisulam
    3. blocks mitochondrial function.
  3. Phase Ib/II Study of ALT-801 with Cisplatin in Pts with Metastatic Melanoma
    1. IL-2 like substance, much less toxic than IL-2 itself.
    2. Patient needs to be HLA-A2 positive, tumor needs to express p53
    3. Outpatient treatment, better tolerated than IL-2 thus far
    4. Phase 1 data 3 patients with melanoma treated one with CR, the other 2 with stable disease
    5. Phase Ib currently open to accrual at the university.

4.FOLLOW-UP AFTER TREATMENT

  1. Modify significantly according to prognosis
  2. Avoidance of sun exposure
  3. Surveillance as per NCCN Guidelines (ref Coit et al 2010)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. Stage IA to IIA: Comprehensive H&P with specific emphasis on the regional nodes and skin every 6-12 months for five years and annually thereafter. Routine lab or imaging not useful in this group.
    3. Stage IIB-IV melanoma, NED: Comprehensive H&P every 3-6 months for 2 years; then every 3-12 months for 3  years and annually thereafter. CXR, CT, MRI and/or PET/CT can be considered to screen for recurrent or metastatic disease at the discretion of the physician. Because most recurrences manifest within the first 3 years, routine imaging is not recommended beyond 3-5 years.
  4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

AJCC 8th Edition

(Gershenwald 2018, Elmore 2018)

Primary Tumor Definition (T)

  1. T category determined by tumor thickness in millimeters (mm)
  2. TX: Primary tumor thickness cannot be assessed
  3. T0: No evidence of primary tumor
  4. T1: < 1.0 mm
    1. T1a: <0.8 mm without ulceration (U-)
    2. T1b: <0.8 mm with ulceration (U+)
    3. 0.8-1.0 lesions are T1 regardless of ulceration status
  5. T2: >1.0-2.0 mm
    1. T2a: >1.0-2.0 without ulceration
    2. T2b: >1.0-2.0 with ulceration
  6. T3: >2.0-4.0 mm
    1. T3a: >2.0-4.0 mm without ulceration
    2. T3b: >2.0-4.0 mm with ulceration
  7. T4: >4.0 mm
    1. T4a: >4.0 mm without ulceration
    2. T4b: >4.0 mm with ulceration

Regional Lymph Node Definition (N)

  1. NX: Regional nodes not assessed
  2. N0: No regional metastasis
  3. N1: One tumor involved node or any in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes
    1. N1a: One clinically occult node (SLN biopsy)
    2. N1b: One clinically detected node
    3. N1c: No regional lymph node disease
      1. Presence of in-transit, satellite, and/or microsatellite metastases
  4. N2: Two or three tumor involved nodes or any in-transit, satellite, and/or microsatellite metastases with one tumor-involved node
    1. N2a: Two or three clinically occult nodes (SLN biopsy)
    2. N2b: Two or three nodes, at least one of which was clinically detected
    3. N2c: One clinically occult or clinically detected
      1. Presence of in-transit, satellite, and/or microsatellite metastases
  5. N3: Four or more tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases
    1. N3a: Four or more clinically occult nodes (SLN biopsy)
    2. N3b: Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes
    3. N3c: Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes
      1. Presence of in-transit, satellite, and/or microsatellite metastases

Distant Metastasis Definition (M)

  1. M0: No evidence of distant metastasis
  2. M1: Evidence of distant metastasis
    1. M1a: Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph node
      1. M1a(0): LDH not elevated
      2. M1a(1): LDH elevated
    2. M1b: Distant metastasis to lung with or without M1a sites of disease
      1. M1b(0): LDH not elevated
      2. M1b(1): LDH elevated
    3. M1c: Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease
      1. M1c(0): LDH not elevated
      2. M1c(1): LDH elevated
    4. M1d: Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease
      1. M1c(0): LDH not elevated
      2. M1c(1): LDH elevated

Principles of Surgical Margins for Wide Local Excision of Primary Melanoma (NCCN Guidelines)

Tumor Thickness Recommended Clinical Magins
In situ 0.5-1.0 cm
<1 mm 1.0 cm
>1-2 mm 1.0-2.0 cm
>2-4 mm 2.0 cm
>4 mm 2 cm

Modifications from 7th Edition AJCC 

  1. Definition of Primary Tumor (T)
    1. All principal T-category tumor thickness ranges are maintained, but T1 now is subcategorized by tumor thickness strata at 0.8 mm threshold.
    2. Tumor mitotic rate was removed as a staging criterion for T1 tumors, but remains an overall important prognostic factor that should continue to be recorded for all patients with T1-T4 primary cutaneous melanoma.
      1. T1a melanomas now are defined as nonulcerated and <0.8 mm in thickness.
      2. T1b melanomas now are defined as 0.8 to 1.0 mm in thickness regardless of ulceration status or ulcerated melanomas <0.8 mm in thickness.
      3. T0 should be used if there is no evidence of a primary tumor (e.g. in a patient who presents with axillary metastasis and no known primary tumor). Staging may be based on clinical suspicious of a primary cutaneous melanoma, with the tumor categorized as T0. (Tis, not T0, designates melanoma in situ).
      4. Tumor thickness measurements now are recorded to the nearest 0.1 mm, not the nearest 0.01 mm, because of the impracticality and imprecision of measurements
      5. Tis (melanoma in situ), T0 (no evidence of a primary tumor), and TX (tumor thickness cannot be determined) may now be used as the T category designation for stage groupings.
  2. Definition of Regional Lymph Node (N)
    1. Number of tumor-involved regional lymph nodes is maintained.
    2. Previously empirically defined "microscopic" and "macroscopic" descriptors are redefined as "clinically occult" (i.e. clinical Stage I-II with nodal metastasis determined at sentinel node biopsy) and "clinically detected" regional node disease (clinical Stage III), respectively.
    3. Sentinel node tumor burden is considered a regional disease prognostic factor that should be collected for all patients with positive sentinel nodes, but it is not used to determine N-category groupings.
    4. Non-nodal regional disease (i.e., microsatellites, satellites, and in-transit cutaneous and/or subcutaneous metastases) is more formally stratified by N category according to the number of tumor-involved lymph nodes.
      1. Presence of microsatellites, satellites, or in-transit metastases is now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any.
    5. "Gross" extranodal extension no longer is used as an N-category criterion (but the presence of "matted nodes" is retained).
  3. Definition of Distant Metastasis (M)
    1. M1 is now defined by both anatomic site of distant metastatic disease and serum lactate dehydrogenase (LDH) value for all anatomic site subcategories.
    2. Descriptions of distant anatomic sites of disease are clarified in M subcategories.
    3. Descriptors were added to the M1 subcategory designation that provide LDH status for all sites of distant disease.
    4. New M1d designation was added to include distant metastasis to the central nervous system (CNS) with or without any other distant sites of disease; M1c no longer includes CNS metastasis.
    5. Elevated LDH level no longer define M1c
  4. AJCC Prognostic Stage Groups
    1. No overall changes were made in the T subcategories, but definitions of T1a and T1b were refined. In addition, while the stage group for cT1bN0 remains clinical Stage IB, the stage group for pT1bN0 now is pathological Stage IA.
    2. N category now comprises four stage groups rather than three, and these groups are based on multivariable models, including T-category elements (tumor thickness and ulceration) and N-category elements (number of tumor-involved nodes, satellites/in-transits/microsatellites), demonstrating a significant impact of primary tumor factors in assigning N stage groups.
    3. Clarification is provided that Stage IV is not further stage grouped (i.e., M1c is Stage IV not Stage IVc).

 

Stage 0: TisN0M0 Melanoma in situ, lentigo maligna (8th Edition AJCC)

Definition: Histopathologic diagnosis based on criteria of melanoma cells being confined to the epidermis above the basement membrane. Histopathologic analysis shows basilar melanocytic atypia, hyperplasia, and spread along the basement membrane or throughout the epidermis (pagetoid spread). Clinically, the lesions are often macules (flat within the level of the skin) with irregular borders and variation of color, though the clinic presentation is variable.

  • Subtypes of MIS (melanoma in situ) include lentigo maligna and superficial spreading.
    • Lentigo maligna presents as a flat macule with geographic shape with coloration from tan to brown to black.
    • Superficial spreading melanoma presents as a slow growing plaque (elevated, flat lesion) with pigment variation mixture of brown, black, blue, red, and gray regions.

Recommended margins: Standard excision with 5 mm margins results in postive margins up to 33% of cases (2013 Kunishige et al). For this reason, MIS is often excised in a staged procedure, taking 5 mm (or greater) margins and doing final reconstruction after final pathology has been reviewed. If the final pathology shows areas of invasion in the specimen or involved peripheral margins, additional margins can then be taken as needed for appropriate stage.

  • Our practice at the University of Iowa is to most commonly resect melanoma in situ employing Mohs surgery. For those cases with an invasive component warranting sentinel node biopsy (greater than a T1a melanoma -- not melanoma in situ) we will endeavor to obtain clear margins with 5-9 mm periphery of normal tissue about the resection and save the Mohs resection for peripheral clearance after the resection so as to not interfere with lymphatic drainage prior to sentinel node biopsy.
  • For those cases that are not in need of a sentinel node biopsy (such as T1a melanoma surrounded by melanoma in situ, known metastases, or other reasons for not performing a sentinel node biopsy) we will commonly perform a 'moat procedure' (see:Case Example Lip Reconstruction Peri-alar Crescentic Advancement Flap  and Case Example Split Thickness Skin Graft STSG Zimmer Dermatome settings).  The moat procedure' involves Mohs surgery to clear periphery (often closing the 'moat' defect around the tumor) for subsequent resection of the central portion with confidence that the reconstruction can be done with clear margins.

 

Stage IA:  T1aN0M0 (8th Edition AJCC)

Stage IA:  T1aN0M0

(AJCC 8th edition, 2018)

Breslow: < 0.8 mm

T1a: no ulceration (U-)

5 yr survival = 99%

(ref Keung et al. 2018)

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO (ref Keilholz et al. 2020)

1 cm

no

no§

no

no

no

no

NCCN (ref Swetter et al. 2021)

1 cm

no

no♦

no

no

no

no

University of Iowa

1 cm*

no**

no

no

no

no

no

§comment: SLNB can be discussed in pT1a for special cases [e.g. ≥3 mitoses/mm², a positive deep margin or when Breslow thickness cannot be reliably determined (pTx)]

♦comment: if patient's risk of positive SLN is <5% (T1a melanoma), NCCN does NOT recommend SLNB.  If there is clinical uncertainty about the microstaging or, in the rare event that a conventional high-risk feature is present (e.g., ulceration, high mitotic rate, lymphovascular invasion), SLNB can be discussed

*comment: margins are not inviolate and may be modified by proximity to critical structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna extending beyond the 1 cm margin encompassing melanoma

Follow-up

  1. Modify significantly according to prognosis
  2. Avoidance of sun exposure
  3. Stage IA-IIA Surveillance as per NCCN Guidelines (ref Swetter et al 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. Comprehensive H&P with emphasis on regional nodes and skin every 6-12 months x 5 years, then annually as clinically indicated
    3. Routine surveillance imaging without symptoms/signs NOT recommended
    4. Routine blood testing NOT recommended
  4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance

_________

References/Suggested Reading:

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.

Stage IB: T1bN0M0, T2aN0M0

Stage IB: 

  • T1bN0M0
  • T2aN0M0

 (AJCC 8th edition)

Breslow     

  • T1:< 1.0 mm
  • T2: >1.0-2.0 mm

T1b:

  • <0.8 mm with ulceration
  • 0.8-1.0 mm +/- ulceration

T2a:

  • >1.0 - 2.0 mm w/o ulceration

5 yr survival = 97% (ref Keung et al. 2018)

 

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes§

no

no

no

no

NCCN  (Swetter et al 2021)

1 cm

no

yes♦

no

no

no

no

University of Iowa

1 cm*

no**

yes

no

no

consider: PNI, desmoplastic

no

 

§comment: SLNB should be discussed with patients with stage pT1b and is recommended in patients with stage pT2a or higher (ref. Keilholz et al.)

♦comment: For patients with clinical stage IB, the probability of a postive SLNB is 5%-10% and NCCN recommends discussing and considering SLNB for these patients (ref. Swetter et al.)

*comment: margins are not inviolate and may be modified by proximity to critical structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna extending beyond the 1 cm margin encompassing melanoma

________
Follow-up

  1. Modify significantly according to prognosis
  2. Avoidance of sun exposure
  3. Stage IA-IIA Surveillance as per NCCN Guidelines (ref Swetter et al 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. Comprehensive H& with emphasis on regional nodes and skin every 6-12 months x 5 years, then annually as clinically indicated
    3. Routine surveillance imaging without symptoms/signs NOT recommended
    4. Routine blood testing NOT recommended
  4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance

Refernces/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.

Stage IIA: T2bN0M0, T3aN0M0

Stage IIA:

  • T2bN0M0
  • T3aN0M0

(AJCC 8th edition)

Breslow:

  • T2: >1.0 - 2.0 mm
  • T3: >2.0 - 4.0 mm

T2b:

  • >1.0-2.0 mm with ulceration (U+)

T3a:

  • >2.0-4.0 mm without ulceration (U-)

5 yr survival = 94% (ref Keung et al. 2018)

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

no

no

no

no

NCCN

1 - 2 cm

no

yes

no#

no#

no

no

University of Iowa

1 -2 cm*

no**

yes

no#

no#

consider: PNI, desmoplastic

no

                 

*comment: margins are not inviolate and may be modified by proximity to critical structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna extending beyond the 1 cm margin encompassing melanoma

#comment: consider nodal basin US prior to SLNB for melanoma patients with equivocal regional LN physical exam. Nodal basin US is NOT a substitute for SLNB.

_______

Follow-up

  1. Modify significantly according to prognosis
  2. Avoidance of sun exposure
  3. Surveillance for Stage IA to IIA as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P every 6-12 months x 5 years, then as clinically indicated
    3. Routine blood tests NOT recommended
    4. Routine imaging to screen for asymptomatic metastatic disease NOT recommended
  4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance

________

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.

Stage IIB: T3bN0M0, T4aN0M0

Stage IIB:

  • T3bN0M0
  • T4aN0M0

(AJCC 8th edition)

Breslow:

  • T3: >2.0-4.0 mm
  • T4:>4.0 mm

T3b:

  • >2.0 - 4.0 mm with ulceration (U+)

T4a:

  • >4.0 mm without ulceration (U-)

5 yr survival = 87%

 

(ref Keung et al. 2018)

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

no

no

no

no

NCCN

2 cm

no

yes

no#

no#

no

no

University of Iowa

2 cm*

no**

yes

yes

yes

consider: PNI, desmoplastic

no

                 

 

*comment: margins are not inviolate and may be modified by proximity to critical structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna extending beyond the 1 margin encompassing melanoma

#comment: consider nodal basin US prior to SLNB for melanoma patients with equivocal regional LN physical exam. Nodal basin US is NOT a substitute for SLNB.

_________

Follow-up:

Modify significantly according to prognosis

  1. Avoidance of sun exposure
  2. Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1.  As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
  3. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.

Stage IIC: T4bN0M0

Stage IIC:

T4bN0M0

(AJCC 8th Edition)

Breslow:

  • T4: >4.0 mm

T4b:

  • >4.0 mm with ulceration (U+)

5 yr survival = 82%

 

(ref Keung 2018)

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

no

no

no

 

NCCN

2 cm

no

yes

no#

no#

no

no♦ (ref Maio et al. 2018)

University of Iowa

2 cm*

no**

yes

yes

yes

consider: PNI, desmoplastic

no

                 

*comment: margins are not inviolate and may be modified by proximity to critical
structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna extending beyond the 1 cm margin encompassing melanoma

#comment: Consider nodal basin US prior to SLNB for melanoma patients with equivocal regional lymph node physical exam. Nodal basin US is NOT a substitute for SLNB

♦comment: BRIM8 trail showed that in select patients with resected AJCC 7th Edition stage IIC-III disease and BRAF V600 mutation, adjuvant treatment with the BRAF inhibitor, vemurafenib monotherapy improved disease free survival (DFS) and possibly DMFS compared to placebo.  The impact on overall survival (OS) was not statistically significant. Vermuranfenib monotherapy was a/w higher rates of toxicity compared to placebo and is NOT FDA approved for adjuvant treatment of melanoma.

_________

Follow-up

Modify significantly according to prognosis

  1. Avoidance of sun exposure
  2. Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1. As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
    5. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

References/Suggested Reading:

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.
  4. Maio M, Lewis K, Demidov L, et al. Adjuvant vemurafenib in resected BRAF(V600) mutation-positive melanoma (BRIM8): a randomized, double-blind, placebo-controlled, multicentere, phase 3 trial. Lancet Oncol 2018; 19:510-520.

Stage IIIA: T1a-T2a; N1a/N2a; M0

Stage IIIA:

  • T1aN1aM0
  • T1aN2aM0
  • T1bN1aM0
  • T1bN2aM0
  • T2aN1aM0
  • T2aN2aM0

(AJCC 8th edition)

5-yr survival: 93% (ref Keung et al. 2018)

N1: 1 tumor-involved node or transit, satellite and/or microsatellite metastases with no tumor-involved nodes

  • N1a: 1 clinically occult (dtected by SLNB)

N2: 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node

  • N2a: 2 or 3 clinically occult (detected by SLNB)

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

yes

yes

no

consider but not routine use#

NCCN

per T

no

yes§

yes

yes

consideration is appropriate

yes♦

University of Iowa

per T*

no**

yes

yes

yes

yes***

yes

*comment: margins are not inviolate and may be modified by proximity to critical
structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna
extending beyond the 1cm  margin encompassing melanoma

*** interactions between radiation therapy and systemic therapies (BRAF inhibitors, IFN alpha-2b, immune checkpoint inhibitors) need to be carefully considered as there is increased risk for toxicity, esp. when utilizing higher doses of radiation; Should hold BRAF and/or MEK inhibitors for >3 days before and after fractionated radiation therapy and >1 day before and after SRS.

#comment: there may be some subsets of stage IIIA patients with higher risk of relpase (tumor burder in sentinel node >1mm).  In these patients, discussion of risk reduction and long-term side-effects of adjuvant therapy can be considered.

§comment: sentinel node positive, consider imaging for baseline staging, nodal basin US surveillence (preferred) or completion lymph node dissection (CLND)

♦comment: consider BRAF mutation testing. Options for systemic therapy:

  • Preferred regimens (ref. Swetter et al.)
    • nivolumab
    • pembrolizumab
    • dabrafebib/trametinib for patients with BRAF V600-activating mutation
  • Observation

________

Follow-up

  1. Avoidance of sun exposure
  2. Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1. As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
      4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.

Stage IIIB: T0-T3a; N1a-N2b; M0

Stage IIIB:

  • T0N1bM0
  • T0N1cM0
  • T1aN1bM0
  • T1aN1cM0
  • T1aN2bM0
  • T1bN1bM0
  • T1bN1cM0
  • T1bN2bM0
  • T2aN1bM0
  • T2aN1cM0
  • T2aN2bM0
  • T2bN1bM0
  • T2bN1cM0
  • T2bN2aM0
  • T2bN2bM0
  • T3aN1bM0
  • T3aN1cM0
  • T3aN2aM0
  • T3aN2bM0

(AJCC 8th edition)

5-yr survival: 83% (ref Keung et al. 2018)

N1: 1 tumor-involved node or transit, satellite and/or microsatellite metastases with no tumor-involved nodes

  • N1a: 1 clinically occult (dtected by SLNB)
  • N1b: 1 clinically detected
  • N1c: No regional lymph node disease

N2: 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node

  • N2a: 2 or 3 clinically occult (detected by SLNB)
  • N2b: 2 or 3, at least 1 of which was clinically detected
  • N2c: 1 clinically occult or clinically detected

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

yes

yes

no

consider but not routine use#

NCCN

per T

no

yes§

yes

yes

consideration is appropriate

yes♦

University of Iowa

per T*

no**

yes

yes

yes

yes***

yes

*comment: margins are not inviolate and may be modified by proximity to critical
structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna
extending beyond the 1cm margin encompassing melanoma

*** interactions between radiation therapy and systemic therapies (BRAF inhibitors, IFN alpha-2b, immune checkpoint inhibitors) need to be carefully considered as there is increased risk for toxicity, esp. when utilizing higher doses of radiation; Should hold BRAF and/or MEK inhibitors for >3 days before and after fractionated radiation therapy and >1 day before and after SRS.

#comment: T-VEC is a local injection therapy for unresectable metastatic melanoma lesions that was approved based on results from a phase III trial [Harrington et al]

§comment: sentinel node positive, consider imaging for baseline staging, nodal basin US surveillence (preferred) or completion lymph node dissection (CLND)

♦comment: consider BRAF mutation testing. Options for systemic therapy:

  • Preferred regimens (ref. Swetter et al.)
    • nivolumab
    • pembrolizumab
    • dabrafebib/trametinib for patients with BRAF V600-activating mutation
  • Observation

________

Follow-up

  • Avoidance of sun exposure
  • Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1. As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
      4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

return to: Melanoma (Evaluation and Management) 

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.
  4. Harrington KJ, Andtbacka RH, Collichio F, et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase IIIOPTiMtrial.Onco Targets Ther. 2016;9:7081-7093.

Stage IIIC: T0-T4b; N2b-N2c; M0

Stage IIIC:

  • T0N2bM0
  • T0N2cM0
  • T0N3bM0
  • T0N3cM0
  • T1aN2cM0
  • T1aN3aM0
  • T1aN3bM0
  • T1aN3cM0
  • T1bN2cM0
  • T1bN3aM0
  • T1bN3bM0
  • T1bN3cM0
  • T2aN2cM0
  • T2aN3aM0
  • T2aN3bM0
  • T2aN3cM0
  • T2bN2cM0
  • T2bN3aM0
  • T2bN3bM0
  • T2bN3cM0
  • T3aN2cM0
  • T3aN3aM0
  • T3aN3bM0
  • T3aN3cM0
  • T3bN1aM0
  • T3bN1bM0
  • T3bN1cM0
  • T3bN2aM0
  • T3bN2bM0
  • T3bN2cM0
  • T3bN3aM0
  • T3bN3cM0
  • T4aN1aM0
  • T4aN1bM0
  • T4aN1cM0
  • T4aN2aM0
  • T4aN2bM0
  • T4aN2cM0
  • T4aN3aM0
  • T4aN3cM0
  • T4bN1aM0
  • T4bN1bM0
  • T4bN1cM0
  • T4bN2aM0
  • T4bN2bM0
  • T4bN2cM0

5-yr survival: 69% (ref Keung et al. 2018)

N1: 1 tumor-involved node or transit, satellite and/or microsatellite metastases with no tumor-involved nodes

  • N1a: 1 clinically occult (dtected by SLNB)
  • N1b: 1 clinically detected
  • N1c: No regional lymph node disease

N2: 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node

  • N2a: 2 or 3 clinically occult (detected by SLNB)
  • N2b: 2 or 3, at least 1 of which was clinically detected
  • N2c: 1 clinically occult or clinically detected

N3: >4 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with >2 tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases

  • N3a: >4 clinically occult (i.e., detected by SLNB)
  • N3b: >4, at least 1 of which was clinically detected, or presence of any number of matted nodes
  • N3c: >2 clinically occult or clinically detected and/or presence of any number of matted nodes

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

yes

yes

no

consider but not routine use#

NCCN

per T

no

yes§

yes

yes

consideration is appropriate

yes♦

University of Iowa

per T*

no**

yes

yes

yes

yes***

yes

*comment: margins are not inviolate and may be modified by proximity to critical
structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna
extending beyond the 1cm margin encompassing melanoma

*** interactions between radiation therapy and systemic therapies (BRAF inhibitors, IFN alpha-2b, immune checkpoint inhibitors) need to be carefully considered as there is increased risk for toxicity, esp. when utilizing higher doses of radiation; Should hold BRAF and/or MEK inhibitors for >3 days before and after fractionated radiation therapy and >1 day before and after SRS.

#comment: #comment: T-VEC is a local injection therapy for unresectable metastatic melanoma lesions that was approved based on results from a phase III trial [Harrington et al]

§comment: sentinel node positive, consider imaging for baseline staging, nodal basin US surveillence (preferred) or completion lymph node dissection (CLND)

♦comment: consider BRAF mutation testing. Options for systemic therapy:

  • Preferred regimens (ref. Swetter et al.)
    • nivolumab
    • pembrolizumab
    • dabrafebib/trametinib for patients with BRAF V600-activating mutation
  • Observation

________

Follow-up

  • Avoidance of sun exposure
  • Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1. As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
      4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.
  4. Harrington KJ, Andtbacka RH, Collichio F, et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase IIIOPTiMtrial.Onco Targets Ther. 2016;9:7081-7093.

Stage IIID: T4b; N3a-N3c; M0

Stage IIID:

  • T4bN3aM0
  • T4bN3bM0
  • T4bN3cM0

5-yr survival: 32% (ref Keung et al. 2018)

N1: 1 tumor-involved node or transit, satellite and/or microsatellite metastases with no tumor-involved nodes

  • N1a: 1 clinically occult (dtected by SLNB)
  • N1b: 1 clinically detected
  • N1c: No regional lymph node disease

N2: 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node

  • N2a: 2 or 3 clinically occult (detected by SLNB)
  • N2b: 2 or 3, at least 1 of which was clinically detected
  • N2c: 1 clinically occult or clinically detected

N3: >4 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with >2 tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases

  • N3a: >4 clinically occult (i.e., detected by SLNB)
  • N3b: >4, at least 1 of which was clinically detected, or presence of any number of matted nodes
  • N3c: >2 clinically occult or clinically detected and/or presence of any number of matted nodes

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

1 cm

no

yes

yes

yes

no

consider but not routine use#

NCCN

per T

no

yes§

yes

yes

consideration is appropriate

yes♦

University of Iowa

per T*

no**

yes

yes

yes

yes***

yes

*comment: margins are not inviolate and may be modified by proximity to critical
structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna
extending beyond the 1cm margin encompassing melanoma

*** interactions between radiation therapy and systemic therapies (BRAF inhibitors, IFN alpha-2b, immune checkpoint inhibitors) need to be carefully considered as there is increased risk for toxicity, esp. when utilizing higher doses of radiation; Should hold BRAF and/or MEK inhibitors for >3 days before and after fractionated radiation therapy and >1 day before and after SRS.#comment: #comment: T-VEC is a local injection therapy for unresectable metastatic melanoma lesions that was approved based on results from a phase III trial [Harrington et al]

§comment: sentinel node positive, consider imaging for baseline staging, nodal basin US surveillence (preferred) or completion lymph node dissection (CLND)

♦comment: consider BRAF mutation testing. Options for systemic therapy:

  • Preferred regimens (ref. Swetter et al.)
    • nivolumab
    • pembrolizumab
    • dabrafebib/trametinib for patients with BRAF V600-activating mutation
  • Observation

________

Follow-up

  • Avoidance of sun exposure
  • Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1. As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
      4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.
  4. Harrington KJ, Andtbacka RH, Collichio F, et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase IIIOPTiMtrial.Onco Targets Ther. 2016;9:7081-7093.

Stage IV: AnyT; AnyN; M1a-d

Stage IV:

  • AnyTAnyNM1a
  • AnyTAnyNM1b
  • AnyTAnyNM1c
  • AnyTAnyNM1d

5-yr survival: <10% (ref Keung et al. 2018)

  • landscape and treatment options and prognosis for stage IV continue to rapidly evolve

N1: 1 tumor-involved node or transit, satellite and/or microsatellite metastases with no tumor-involved nodes

  • N1a: 1 clinically occult (dtected by SLNB)
  • N1b: 1 clinically detected
  • N1c: No regional lymph node disease

N2: 2 or 3 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node

  • N2a: 2 or 3 clinically occult (detected by SLNB)
  • N2b: 2 or 3, at least 1 of which was clinically detected
  • N2c: 1 clinically occult or clinically detected

N3: >4 tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with >2 tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases

  • N3a: >4 clinically occult (i.e., detected by SLNB)
  • N3b: >4, at least 1 of which was clinically detected, or presence of any number of matted nodes
  • N3c: >2 clinically occult or clinically detected and/or presence of any number of matted nodes

M1: 8th edition of AJCC stage IV patients are categorized by site of disease and serum lactate dehydrogenase (LDH).

  • M1a: non-visceral distant cutaneous, subcutaneous, or nodal sites
    • M1a(0): LDH not eleveated
    • M1a(1): LDH elevated
  • M1b: lung
    • M1b(0): LDH not elevated
    • M1b(1): LDH elevated
  • M1c: non-CNS visceral sites
    • M1c(0): LDH not elevated
    • M1c(1): LDH elevated
  • M1d: CNS sites
    • M1d(0): LDH not elevated
    • M1d(1): LDH elecated

 

Margins

Mohs?

SLN bx

PET

CT

Radiation

Adjuvant

ESMO

No need to resect

no

yes

yes

yes

no

consider but not routine use#

NCCN

Per T

no

yes§

yes

yes

Yes***

yes♦

University of Iowa

per T*

no**

yes

yes

yes

yes***

yes

*comment: margins are not inviolate and may be modified by proximity to critical
structures with attention to lymphatic drainage patterns

**comment: Mohs surgery may be considered for melanoma with lentigo maligna
extending beyond the 1cm margin encompassing melanoma

***interactions between radiation therapy and systemic therapies (BRAF inhibitors, IFN alpha-2b, immune checkpoint inhibitors) need to be carefully considered as there is increased risk for toxicity, esp. when utilizing higher doses of radiation; Should hold BRAF and/or MEK inhibitors for >3 days before and after fractionated radiation therapy and >1 day before and after SRS.

#comment: #comment: T-VEC is a local injection therapy for unresectable metastatic melanoma lesions that was approved based on results from a phase III trial [Harrington et al]

§comment: sentinel node positive, consider imaging for baseline staging, nodal basin US surveillence (preferred) or completion lymph node dissection (CLND)

♦comment: consider BRAF mutation testing. Options for systemic therapy:

  • Preferred regimens (ref. Swetter et al.)
    • nivolumab
    • pembrolizumab
    • dabrafebib/trametinib for patients with BRAF V600-activating mutation
  • Observation

________

Follow-up

  • Avoidance of sun exposure
  • Surveillance for Stage IIB-IV as per NCCN Guidelines (ref Swetter et al. 2021)
    1. All melanoma patients: Skin examination and surveillance at least once a year for life is recommended
    2. H&P:
      1. every 3-6 months x 2 years then,
      2. every 3-12 months x 3 years then,
      3. as clinically indicated
    3. Routine blood tests are not recommended
    4. Imaging:
      1. As indicated to investigate specific signs/symptoms
      2. Consider every 3-12 months x 2 years then, every 6-12 months x 3 years to screen for recurrence or metastatic disease
      3. Routine imaging to screen for asymptomatic recurrence or metastatic disease is NOT recommended after 3-5 years, depending on risk of relapse
      4. All patients with melanoma treated for cure should have at least yearly follow-up with dermatology to permit total-body surveillance.

References/Suggested Reading

  1. Swetter, S. M., Thompson, J. A., Albertini, M. R., Barker, C. A., Baumgartner, J., Boland, G., Chmielowski, B., DiMaio, D., Durham, A., Fields, R. C., Fleming, M. D., Galan, A., Gastman, B., Grossmann, K., Guild, S., Holder, A., Johnson, D., Joseph, R. W., Karakousis, G., Kendra, K., Lange, J. R., Lanning, R., Margolin, K., Olszanski, A. J., Ott, P. A., Ross, M. I., Salama, A. K., Sharma, R., Skitzki, J., Sosman, J., Wuthrick, E., McMillian, N. R., & Engh, A. M. (2021). NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021, Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw, 19(4), 364-376. Retrieved Jun 14, 2021, from https://jnccn.org/view/journals/jnccn/19/4/article-p364.xml
  2. Keung, Emily Z, and Jeffrey E Gershenwald. “The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care.” Expert review of anticancer therapy vol. 18,8 (2018): 775-784. doi:10.1080/14737140.2018.1489246
  3. Keilholz U, Ascierto PA, Dummer R, Robert C, Lorigan P, van Akkooi A, Arance A, Blank CU, Chiarion Sileni V, Donia M, Faries MB, Gaudy-Marqueste C, Gogas H, Grob JJ, Guckenberger M, Haanen J, Hayes AJ, Hoeller C, Lebbé C, Lugowska I, Mandalà M, Márquez-Rodas I, Nathan P, Neyns B, Olofsson Bagge R, Puig S, Rutkowski P, Schilling B, Sondak VK, Tawbi H, Testori A, Michielin O. ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee. Ann Oncol. 2020 Nov;31(11):1435-1448. doi: 10.1016/j.annonc.2020.07.004. Epub 2020 Aug 4. PMID: 32763453.
  4. Harrington KJ, Andtbacka RH, Collichio F, et al. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the phase IIIOPTiMtrial.Onco Targets Ther. 2016;9:7081-7093.

 

Melanoma Research at the U of Iowa

         Contact researchers for all patients with melanoma:  Clinical Data Registry and Tissue Procurement
 


SUGGESTED READING
  1. Gershenwald JE, Scolyer RA Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond. Ann Surg Oncol. 2018 Aug;25(8):2105-2110. doi: 10.1245/s10434-018-6513-7. Epub 2018 May 30.
  2. Elmore JG, Elder DE, Barnhill RL, Knezevich SR, Longton GM, Titus LJ, Weinstock MA, Pepe MS, Nelson HD, Reisch LM, Radick, AC, Piepkorn MW. Concordance and Reproducibility of Melanoma Staging According to the 7th vs 8th Edition of the AJCC Cancer Staging Manual. JAMA Netw Open. 2018 May;1(1):e180083. doi: 10.1001/jamanetworkopen.2018.0083. PMID: 30556054 Free PMC article.
  3. Ang KK, Byers RM, Peters LJ, Maor MH, Wendt CD, Morrison WH, Hussey DH, Goepfert H. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma. Arch Otolaryngol Head Neck Surg. 1990;16:169-172.
  4. Ardizzoni A, Grinmaldi A, Repetto L, et al. Stage I and II melanoma: the value of metastatic work-up. Oncology. 1987;44:87.
  5. Balch CM. Excising melanomas: how wide is enough? And how to reconstruct? J Surg Oncol. 1990;44:135-137.
  6. Balch CM. The role of elective lymph node dissection in melanoma: rationale, results, and controversies. J Clin Oncol. 1988;6:163-172.
  7. Balch C, Buzaid AC, Soong SJ, et al. Final version of the AJCC staging system for cutaneous melanoma. J Clin Oncol, 19:3635-3648, 2001.
  8. Cady B. Prophylactic lymph node dissection in melanoma: does it help? J Clin Oncol. 1988;6:2-4.
  9. Iscoe N, Kersey P, Gapski J et al. Predictive value of staging investigations in patients with clinical stage I malignant melanoma. Plast Reconstr Surg. 1987;80:233.
  10. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol. 1996; 4:7-17.
  11. Koh HK. Cutaneous melanoma. N Engl J Med. 1991;325:171-182.
  12. Medina JE. Malignant melanomas. In: Myers EN, Suen JY, eds. Cancer of the Head and Neck. New York: Churchill Livingston; 1989:273-309.
  13. McCarthy WH, Shaw HM, Milton GW. Efficacy of elective lymph node dissection in 2,347 patients with clinical stage I malignant melanoma. Sur Gynecol Obstet. 1985;161:575-580.
  14. NIH Consensus Development Panel on Early Melanoma. Diagnosis and treatment of early melanoma. JAMA 1992;268:1314-1319.
  15. Overgaard J. The role of radiotherapy in recurrent and metastatic malignant melanoma: a clinical radiobiological study. Int J Radiat Oncol Biol Phys. 1986;12:867-872.
  16. Overgaard J, Overgaard M, Hansen PV, von der Maase H. Some factors of importance in the radiation treatment for malignant melanoma. Radiother Oncol. 1986;5:183-192.
  17. Spitler LE, Grossbard ML, Ernstoff MS, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor (GM-CSF). J Clin Oncol 18:1614-1621, 2000
  18. Tanis PJ, Nieweg OE, van den Brekel MWM, and Balm AJM: Dilemma of Clinically Node-Negative Head and Neck Melanoma: Outcome of "Watch and Wait" Policy, Elective Lymph Node Dissection, and Sentinel Node Biopsy - A Systematic Review. Head Neck 30:380-389, 2008
  19. Urist M, Medine JE. Head and neck cutaneous melanoma. In: Clinical Practice Guidelines of the Diagnosis and Management of Cancer of the Head and Neck. Pittsburgh, PA: The American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons; 1996:81-83.
  20. Veronesi U, Cascinelli N. Narrow excision (1-cm margin ). Arch Surg. 1991;126:438-441.
  21. Veronesi U, Cascinelli N, Adamus J, et al. Thin Stage I primary cutaneous malignant melanoma: comparison of excision with margins of 1 or 3 cm. N Engl J Med. 1988;318:1159-1162.
  22. Deichmann M, Kahle B, Moser K, et al. Diagnosing melanoma patients entering American Joint Committee on Cancer state IV, C-reactive protein in serum is superior to lactate dehydrogenase. Br J Cancer. 2004;91(4):699-702
  23. Edge S et al (editors)  AJCC Cancer Staging Manual Seventh Edition: "Melanoma of Skin" pp325 to 344 in Springer New York  2010
  24. Coit DG et al  NCCN Clincal Practice Guidelines in Oncology: "Melanoma" v.2.2010 accessed 4-14-10 www.nccn.org
  25. Schmalbach C: The Management of Head and Neck Melanoma pp 781-835 in Curr Probl Surg, November 2006 (excellent overall review and presentation of the U of Michigan protocols)
  26. Eppsteiner RW, Swick BL, Milhem MM, Hoffman HT, Pagedar NA. Sentinel node biopsy for head and neck desmoplastic melanoma: not a given.Otolaryngol Head Neck Surg. 2012 Aug;147(2):271-4. PMID: 22399279