The prognostic significance of the pathologic status of the sentinel lymph node (SLN):
Has been convincingly demonstrated
Data from MD Anderson demonstrated that SLN status was:
The most significant clinicopathologic prognostic factor with respect to survival in patients with melanoma
In an analysis of 1,487 patients who underwent SLNB (median tumor thickness, 1.5 mm):
The 5-year survival rate for patients with:
Positive SLNs was 73.3%:
Compared to 96.8% for patients with negative SLNs
Several other multivariate regression analyses:
Have shown that regional lymph node status is the most powerful predictor of recurrence (both regional and distant) and survival:
Even among patients with thick melanomas
Taken together with patients who have clinical regional disease, according to analysis done by the International Melanoma Database and Discovery Platform (IMDDP) that provided revisions to the 8th edition AJCC melanoma staging system:
5-year melanoma-specific survival rates for patients with:
Stage III disease range from 93% for patients with IIIA disease to 32% for patients with IIID disease
The prognostic importance of distinguishing between:
Clinically occult and clinically detected lymph nodes:
Has been emphasized by incorporation of this criterion into the 8th edition AJCC melanoma staging system
The concept of tumor burden has become important in the era of SLNB:
As accurate microscopic staging of SLNs allows patients to be better stratified into similar risk subgroups
Several studies have shown that the diameter of the largest SLN tumor nodule and the total SLN tumor volume:
Are significant predictors of recurrence and survival
The prognostic significance of sentinel node tumor burden continues to be an active area of investigation worldwide
The landmark prospective Multicenter Selective Lymphadenectomy Trial-I (MSLT-I):
Was designed in 1994 to assess whether a selective approach to regional lymphadenectomy limiting completion lymph node dissection:
To patients with microscopic disease in SLNs:
Confers a survival benefit compared to wide excision of the primary melanoma and observation of the regional nodal basin
Patients with primary cutaneous melanomas at least 1 mm thick or with Clark level IV or V tumors with any Breslow thickness were eligible for the trial
Two thousand and one patients were randomly assigned to:
Wide excision alone and observation of the regional nodal basin(s) (40%) or wide excision and lymphatic mapping and SLNB (60%), with subsequent CLND if any SLNs were positive
In 2014, the final trial report was published with 10 years of follow-up data:
Ten-year disease-free survival rates were significantly higher in the SLNB group than in the observation group among patients with intermediate-thickness melanomas:
71.3 Ā± 1.8% in the SLNB group compared to 64.7 Ā± 2.3% in the observation group (hazard ratio for recurrence or metastasis, 0.76; 95% CI 0.62 to 0.94; P =.01)
When the SLNB group was further explored:
It was noted that patients who had evidence of microscopic SLN involvement did worse than patients with a negative SLNB
For patients with intermediate-thickness primary melanoma (defined in MSLT-I as 1.2 to 3.5 mm):
The melanoma-specific survival at 10 years was significantly worse in patients with a positive SLNB compared to those who had a negative SLNB:
62% vs. 85%, HR 3.09, 95% CI 2.12 to 4.49
For patients with thick melanoma (defined in MSLT-I as > 3.50 mm):
The melanoma-specific survival rate at 10 years was again significantly worse in patients with lymph node involvement compared to those who had a negative lymph node biopsy (48.0% vs. 64.6%, HR 1.75, 95% CI 1.07 to 2.87)
Interestingly, when applied to the study cohort, a statistical approach called latent-subgroup analysis (a technique that accounts for the observation that nodal status was initially only known in the SLNB group):
Showed a clear benefit of SLNB
Among patients who had SLNB and a positive SLN compared to those who developed clinical regional melanoma metastasis after wide excision alone:
There was doubling of melanoma-specific and distant diseaseāfree survival and a tripling of disease-free survival
Sentinel Lymph Node Biopsy (SLNB):
Purpose:
Identifies microscopic nodal metastases in patients with clinically node-negative melanoma
Provides accurate staging (AJCC 8th edition) and guides adjuvant therapy decisions
Prognostic Significance:
SLN-positive status is the strongest independent prognostic factor for recurrence and survival:
In intermediate-thickness melanomas
5-year melanoma-specific survival (MSS):
SLN-negative: ~ 90% to 95%
SLN-positive: ~ 60% to 70%
References:
Morton DL, Thompson JF, Cochran AJ, et al. N Engl J Med. 2006;355(13):1307ā1317. doi:10.1056/NEJMoa060903 Balch CM, Gershenwald JE, Soong SJ, et al. J Clin Oncol. 2009;27(36):6199ā6206.
van der Ploeg AP, van Akkooi AC, Rutkowski P, et al. Ann Surg Oncol. 2011;18(2):519ā528.
Impact on Treatment Decisions:
SLN status determines eligibility for:
Adjuvant immunotherapy:
Nivolumab, pembrolizumab
Targeted therapy in BRAF-mutant patients:
Dabrafenib + trametinib
Surveillance protocols
Reference:
Weber J, Mandala M, Del Vecchio M, et al. N Engl J Med. 2017;377(19):1824ā1835.
Eggermont AMM, Blank CU, Mandala M, et al. N Engl J Med. 2018;378(19):1789ā1801.
Supporting Trials:
MSLT-I:
SLN status is prognostic for recurrence-free and melanoma-specific survival
MSLT-II and DeCOG-SLT:
No survival benefit with completion lymph node dissection (CLND)
References:
Morton DL, Thompson JF, Cochran AJ, et al. N Engl J Med. 2006;355(13):1307ā1317.
Faries MB, Thompson JF, Cochran AJ, et al. N Engl J Med. 2017;376(23):2211ā2222.
Leiter U, Stadler R, Mauch C, et al. Lancet Oncol. 2016;17(6):757ā767.
AJCC Staging Integration:
SLN status incorporated in Stage III classification:
Stage IIIA:
Micrometastases + no ulceration = best prognosis
Higher sub-stages = greater tumor burden or ulceration
Reference:
Gershenwald JE, Scolyer RA, Hess KR, et al. CA Cancer J Clin. 2017;67(6):472ā492.
Guidelines:
SLNB recommended for:
Breslow depth ā„ 1 mm
0.8mm to 1.0 mm with high-risk features:
Ulceration, high mitotic index
Reference:
NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesĀ®) for Melanoma, Version 2.2024.
Conclusion:
Sentinel lymph node status is a powerful prognostic marker in cutaneous melanoma and has direct implications for staging, risk stratification, treatment planning, and surveillance
Knowledge of the factors predictive of a positive sentinel lymph node (SLN):
Is useful for counseling patients regarding treatment options
The incidence of positive SLN in patients with cutaneous melanoma varies by:
Tumor thickness
Histologic subtype
Anatomic site
In most studies, the overall incidence of a positive SLN among patients undergoing SLNB ranges from 15% to 20%
Multivariable analyses have revealed several factors associated with an increased risk of positive SLNs:
Increasing tumor thickness, ulceration, lymphovascular invasion, high mitotic rate, young age, and melanoma subtype
The overall incidence of SLN metastases by AJCC clinical substage among patients who had SLNB from one institutional study:
For stages IA, IB, IIA, IIB, and IIC was 2%, 9%, 24%, 34%, and 53%, respectively
Based on a published risk prediction model, investigators at Melanoma Institute Australia recently developed an SLN metastasis risk prediction tool that was validated with data from The University of Texas MD Anderson Cancer Center (MD Anderson) to serve as a general guide to estimate individual risk of harboring a tumor involved SLN:
18% to 40% for acral lentiginous melanoma (ALM) of the fingers, toes, and sole at stage IB to II:
In particular, ALM common on the digits and soles:
Has a higher risk of SLN positivity compared to other subtypes, with rates of 18.4% for stage IB and 39.5% for stage II
Predictors of positive SLN include:
Breslow thickness:
Risk increases with thickness:
ā„ 0.8 mm is a key threshold
Ulceration:
Independently increases risk
High mitotic rate:
Specially > 1/mmĀ²
Younger age:
Patient < 60 years have a higher risk
Lymphovascular invasion, microsatellitosis, and vertical growth phase:
All increase risk
Acral lentiginous histology:
ALM subtype is an independent predictor
Location on the sole, fingers, or toes:
ALM and subungual melanomas have higher SLN positivity than other sites
The American Society of Clinical Oncology and Society of Surgical Oncology recommend:
SLN biopsy for melanomas ā„ 0.8 mm or with high-risk features, and specifically highlight the higher risk in ALM and distal extremity sites.
Additionally, unique lymphatic drainage patterns in the fingers, toes, and sole may require careful mapping, as drainage to popliteal or epitrochlear nodes is not uncommon
In summary:
ALM of the fingers, toes, and sole has a higher incidence of SLN positivity than other cutaneous melanomas, with Breslow thickness, ulceration, mitotic rate, and younger age being the most important predictors
Detected by sentinel lymph node mapping (SLNM) and sentinel lymph biopsy (SLNB)
Clinically detected:
Palpable and / or radiographically detected nodes
Fine-needle aspiration or core biopsy:
Can usually yield a diagnosis in patients who develop clinically enlarged regional nodes
Incisional or excisional biopsy:
Is rarely indicated for diagnostic purposes
Intraoperative Lymphatic Mapping and Sentinel Lymph Node Biopsy:
Beginning in the 1990s after its introduction by Morton and colleagues:
Several investigators proposed intraoperative lymphatic mapping and SLNB as a minimally invasive procedure for identifying approximately 15% to 20% of patients offered the procedure who harbor occult microscopic disease
This approach is sometimes termed selective lymphadenectomy
From a historical standpoint as initially proposed by Morton:
The SLNB approach facilitates identification of patients for whom completion lymph node dissection would be recommended
Several studies have demonstrated that the SLNs are the first nodes to contain metastases, if metastases are present, and thus the pathologic status of the SLNs reflects that of the entire regional nodal basin
If the SLN lacks metastasis, the rest of the regional lymph nodes are unlikely to contain disease, and a completion lymphadenectomy (CLND) would therefore be unnecessary
Multiple studies have demonstrated that the immediate false-negative rate for SLNB is less than 5%
Other studies have confirmed the validity of the SLN concept and the accuracy of SLNB as a staging procedure
It is imperative, however, that the surgeon employing SLNB has adequate pathology and nuclear medicine support
Sentinel Lymph Node Biopsy Technique:
It is strongly preferred that lymphatic mapping and SLNB be performed at the time of wide excision of the primary melanoma
If a wide excision has already been performed, SLNB can still generally be performed with equivalent accuracy:
However, prior extensive reconstruction of the primary melanoma wide excision site (e.g., by extensive rotational flap reconstruction) that alters lymphatic pathways in the region:
May significantly reduce the accuracy of this technique if performed after wide excision in such patients
Since the introduction of lymphatic mapping and SLNB, the technique has undergone several refinements that have resulted in improved detection of SLNs:
Use of a vital blue dye to identify SLNs has been part of the technique since its introduction:
I typically use isosulfan blue 1% or Lymphazurin at our institution
If a patient is noted to have a significant history of allergic reactions:
You may substitute methylene blue and anecdotally note overall similar results and a favorable side effect profile
Some surgeons prefer to give prophylaxis to prevent allergic reactions:
Using a cocktail of I.V. diphenhydramine, I.V. hydrocortisone, and I.V. famotidine administered prior to injection of isosulfan blue
The blue dye is injected intradermally:
Around the residual intact tumor or biopsy site:
It is taken up by the lymphatic system and carried via afferent lymphatics to the SLN(s)
The draining nodal basin is explored, and the afferent lymphatic channels and first draining lymph nodes (the SLNs) are identified by the uptake of the blue dye
With the use of blue dye alone, an approach utilized mostly in the early 1990s:
An SLN was identified in approximately 85% of cases:
Although this initial approach was promising, 15% of patients were unable to benefit from the procedure because no SLN was identified
Subsequently, additional techniques were incorporated that have significantly improved SLN localization:
Preoperative lymphoscintigraphy
Intradermal injection of technetium-99 (99Tc)-labeled sulfur colloid accompanied by intraoperative use of a handheld gamma probe
Preoperative lymphoscintigraphy using 99Tc-labeled sulfur colloid:
Facilitates the identification of patients with multiple draining nodal basins and patients with lymphatic drainage to SLNs located outside standard nodal basins, including:
Epitrochlear, popliteal, and ectopic /interval / in-transit sites
In 2013, Tc 99m tilmanocept (Lymphoseek):
Was approved by the FDA as a receptor-targeted lymphatic mapping agent:
Whose mechanism of action is to bind to mannose receptors on lymphatic tissue
It accumulates in lymphatic tissue within minutes and facilitates localization of SLNs:
It can be used in place of 99Tc-labeled sulfur colloid for both lymphoscintigraphic imaging as well as for intraoperative management
In patients with melanomas that drain to multiple regional nodal basins:
The histologic status of one draining basin does not predict the status of other basins:
Therefore, it is particularly important to identify and assess all at-risk regional nodal basins to properly stage the patient
An advance from traditional nuclear imaging is the use of single-photon emission computed tomography (SPECT) imaging merged with CT:
SPECT / CT facilitates localization of SLNs by overlaying radiotracer uptake activity onto the noncontrast CT image and is particularly helpful in the head and neck region:
In one study, the surgical approach was revised because of SPECT / CT imaging in up to 30% of cases
Preoperative lymphoscintigraphy. After injection of 99Tc-labeled sulfur colloid at the primary cutaneous melanoma site (upper midline back), preoperative lymphoscintigraphy revealed (A) drainage to multiple nodal basins (bilateral neck and left axilla), (B) āin-transitā/ectopic sentinel lymph nodes (SLNs) in the right flank region and right axilla from a primary tumor of the right lateral back, and (C) SLNs in a right lower-extremity popliteal fossa lymph node basin and a right inguinal lymph node basin from a primary tumor of the heel. (Photos courtesy of Gershenwald JE. Copyright retained by Gershenwald and the University of Texas MD Anderson Cancer Center.)Preoperative lymphoscintigraphy. After injection of 99Tc-labeled sulfur colloid at the primary cutaneous melanoma site (upper midline back), preoperative lymphoscintigraphy revealed (A) drainage to multiple nodal basins (bilateral neck and left axilla), (B) āin-transitā/ectopic sentinel lymph nodes (SLNs) in the right flank region and right axilla from a primary tumor of the right lateral back, and (C) SLNs in a right lower-extremity popliteal fossa lymph node basin and a right inguinal lymph node basin from a primary tumor of the heel. (Photos courtesy of Gershenwald JE. Copyright retained by Gershenwald and the University of Texas MD Anderson Cancer Center.)
Perhaps the most important development in the SLNB technique:
Has been the introduction of intraoperative lymphatic mapping:
Using a handheld gamma probe
In this approach, 0.5-mCi 99Tc-labeled sulfur colloid, or Lymphoseek is injected intradermally prior to surgery, either in nuclear medicine prior to arrival in the operating room (sometimes in concert with preoperative lymphoscintigraphy) or after induction of general anesthesia
During surgery, a handheld gamma probe is used to transcutaneously identify SLNs to facilitate their removal
The use of both blue dye and radiotracer increases the surgeonās ability to identify the SLN (> 96% to 99% sensitivity) compared to the use of blue dye alone (ā 84% sensitivity)
Although most clinicians use a combined modality approach, some favor the single-agent strategy of radiotracer alone, and some have reported similarly excellent sensitivity compared to a combination strategy
Epidemiology and Clinical Presentation of Plantar Melanoma:
Melanomas of the sole are predominantly acral lentiginous melanoma (ALM):
Which is the most common melanoma subtype in patients of African and Asian descent:
It is associated with a poorer prognosis due to frequent late-stage diagnosis
Acral lentiginous melanomas occur:
On the palms (palmar), soles (plantar), or beneath the nail beds (subungual):
Although not all palmar, plantar, and subungual melanomas are acral lentiginous melanomas
These melanomas account for only 2% to 8% of melanomas in white patients:
But for a substantially higher proportion of melanomas (35% to 60%) diagnosed in darker-skinned patients:
Their clinical extent at the primary site may be difficult to define, and scouting biopsies are sometimes employed to facilitate clinical assessment of the extent of disease
ALM on the sole often presents as an irregularly pigmented, asymmetric lesion with a parallel-ridge dermoscopic pattern:
Diagnosis requires a full-thickness excisional biopsy for histopathologic confirmation
Unique Anatomic and Surgical Challenges of the Sole:
The sole is characterized by thick, glabrous skin, minimal subcutaneous tissue, and a weight-bearing function:
All of which complicate surgical management
Achieving recommended excision margins:
Is often difficult due to the risk of exposing or injuring underlying structures and the challenge of primary closure
The need for wide excision can result in large defects that are difficult to reconstruct:
With a high risk of surgical complications such as delayed healing, infection, and impaired ambulation
These factors necessitate complex reconstructive approaches, including:
Local flaps or skin grafts, to restore both form and function and to preserve quality of life
Surgical Management and Margin Recommendations:
The standard of care is surgical excision with histologically negative margins
The American Academy of Dermatology and the National Comprehensive Cancer Network recommend margin width based on Breslow thickness:
1 cm for melanomas ā¤ 1 mm thick, and up to 2 cm for thicker lesions:
With excision to but not including the fascia
However, in the sole, these margins may need to be modified to preserve function and accommodate anatomic constraints:
Though sub-1-cm margins for invasive melanoma are generally not recommended unless absolutely necessary
Sentinel lymph node biopsy is indicated for invasive lesions (generally ā„ 0.8 mm or with other high-risk features) and should be performed prior to or at the time of wide excision
Closure of surgical defects often requires skin grafts or local flaps, such as medial plantar or sural neurocutaneous flaps, to achieve durable coverage and maintain ambulation
Special Considerations for Margin Assessment and Recurrence:
Melanomas of the sole, like other specialty sites, have higher rates of positive margins, local recurrence, and upstaging compared to trunk and proximal extremity melanomas
This is attributed to both the anatomic complexity and the frequent subclinical extension of ALM
Staged excision with comprehensive margin assessment (e.g., slow Mohs or complete circumferential peripheral and deep margin assessment [CCPDMA]) may be considered for melanoma in situ or thin ALM in anatomically constrained areas to maximize tissue conservation and ensure complete tumor removal, though prospective data are lacking
Mohs micrographic surgery is not recommended for invasive melanoma but may be selectively considered for melanoma in situ or minimally invasive lesions in specialty sites
Gaps in Evidence and Areas for Further Study:
There is a paucity of prospective, site-specific trials for plantar melanoma
Most recommendations are extrapolated from studies of melanomas at other sites, and further research is needed to define optimal surgical margins, reconstructive techniques, and long-term outcomes for melanomas of the sole
In summary:
The surgical management of melanomas on the sole requires careful consideration of the unique anatomic and functional challenges, with a focus on achieving negative margins, minimizing morbidity, and optimizing reconstruction to preserve ambulation and quality of life
Margin width should be tailored to tumor thickness and anatomic constraints, with a preference for standard margins when feasible, and the use of advanced margin assessment techniques in select cases
The special anatomic considerations for the surgical management of melanomas of the fingers and toes include:
The limited soft tissue between the skin and underlying structures, particularly in the nail apparatus, and the need to balance oncologic control with preservation of function
The American Academy of Dermatology recommends:
That wide excision of cutaneous melanoma on the digits should be performed with histologically negative margins:
But acknowledges that margins may need to be narrower than standard recommendations to preserve function and accommodate the unique anatomy of the fingers and toes
For subungual melanoma:
Partial amputation at the distal interphalangeal joint has traditionally been performed to avoid complications from degloving the distal digit:
But there is no evidence that this improves prognosis or survival compared to more conservative, digit-sparing approaches, especially for thin (ā¤ 0.8 mm) or in situ lesions
Digit-sparing surgery with narrower margins may be considered in select cases to maximize function:
But this approach warrants further investigation
The depth of excision:
Is generally recommended to the level of, but not including, the fascia
These recommendations are based on expert consensus and the anatomic constraints of the digits, as high-level evidence is lacking for these specific sites
In addition to the anatomic and functional constraints previously discussed:
Several further considerations are critical for the surgical management of melanomas of the fingers and toes
The limited subcutaneous tissue and proximity to bone, tendon, and neurovascular structures:
Often necessitate tailored excision techniques and may preclude standard wide excision margins, especially in the nail apparatus and subungual region
For subungual melanoma:
Studies have shown that amputation at the level of the distal interphalangeal joint for fingers and at the proximal phalanx or metatarsophalangeal joint for toes achieves local control:
But more conservative, digit-sparing resections with histologically negative margins are increasingly favored to preserve function:
As the level of resection does not significantly impact survival when margins are clear
Acral lentiginous melanomas:
Which predominate in these locations, are frequently diagnosed at a greater thickness and are associated with higher rates of nodal and systemic metastasis:
Underscoring the importance of accurate staging and consideration of sentinel lymph node biopsy for invasive lesions
The unique anatomy also complicates reconstruction:
Often requiring:
Skin grafts or local flaps to maintain function and cosmesis
In anatomically complex sites where standard margins are not feasible:
Staged excision or slow Mohs micrographic surgery may be considered to maximize tissue conservation while ensuring complete tumor removal:
With retrospective data supporting comparable local control to conventional excision
Finally, the risk of surgical complications including:
Positive margins, local recurrence, and need for complex reconstruction:
Is higher in these specialty sites compared to trunk or proximal extremity melanomas:
Necessitating multidisciplinary planning and patient counseling regarding both oncologic and functional outcomes
Current Controversies in Melanoma Treatment. Temple-Oberle C, Nicholas C, Rojas-Garcia P. Plastic and Reconstructive Surgery. 2023;151(3):495e-505e. doi:10.1097/PRS.0000000000009936.
If there is concern regarding the ability to achieve suitable wound closure:
A plastic or reconstructive surgeon may be consulted:
Ideally in the preoperative setting
Options for closure include:
Primary closure
Skin grafting
Local and distant flaps
Primary closure:
Is the method of choice for most lesions:
But it should be avoided when it will distort the appearance of a mobile facial feature or interfere with function
Many defects can be closed using an advancement flap, undermining the skin and subcutaneous tissues to permit primary closure
Primary closure may be facilitated with the longitudinal axis of an elliptical incision to be approximately three times the length of the short axis:
Lesser extension of the longitudinal axis can also sometimes be employed
The skin and subcutaneous tissue are removed down to, but generally not including the underlying muscular fascia
Closure of the wound edges is usually performed in two layers:
A dermal layer of 3-0 undyed absorbable sutures and either interrupted skin closure using 2-0, 3-0, or 4-0 nonabsorbable sutures and / or a running subcuticular skin closure using 4-0 monofilament absorbable sutures
Three layers are sometimes used:
Particularly for primary melanomas of the back:
With approximation of Scarpaās fascia
After excision:
The specimen should be oriented for permanent assessment of histologic margins
Application of a skin graft is one of the simplest reconstructive methods used for wound closure:
Split-thickness skin grafts are most commonly used:
For lower extremity primary lesions:
Split-thickness grafts can be harvested from the contralateral extremity
In general, skin grafts should be harvested from an area remote from the primary melanoma and outside the zone of potential in-transit metastasis
A full-thickness skin graft:
Can provide a result that is both more durable and of higher aesthetic quality than a split-thickness graft
Full-thickness grafts have most commonly been used on the face:
Where aesthetic considerations are most significant, but can also be used elsewhere
Donor sites for full-thickness skin graft to the face:
Should be chosen from locations that are likely to match the color of the face:
Such as the postauricular or preauricular skin or the supraclavicular portion of the neck
Local flaps:
Offer numerous advantages for repair of defects that cannot be closed primarily:
Especially on the distal extremities and on the head and neck
Color match is excellent, durability of the skin is essentially normal, and normal sensation is usually preserved
Transposition flaps and rotation flaps of many varieties have been used:
Although for patients with high risk of in-transit metastasis, extensive flap reconstruction may significantly alter regional lymphatics
Distant flaps may be considered when sufficient tissue for a local flap is not available and when a skin graft would not provide adequate wound coverage
Use of a wound VAC to facilitate granulation tissue:
That serves as a healthy tissue bed for subsequent skin graft can often obviate the need for complex reconstructive options (e.g., melanoma arising on the heel of the foot)
The melanoma staging system continues to evolve in parallel with our understanding of this complex disease
Some key features of the 8th Edition staging system include:
Modifications to the T1 subcategory
More granular incorporation of:
Satellite, in-transit, and microsatellite disease into the N category
Refinement and expansion of the M1 subcategories
T Category:
Breslow tumor thickness and tumor ulceration:
Remain the dominant prognostic factors in the T category
Breslow tumor thickness:
Measured in millimeters and reported to the nearest tenth of a millimeter in the 8th Edition:
Is determined by using an ocular micrometer to measure the total vertical height of the melanoma:
From the granular layer to the area of deepest penetration
Historically, Clark level of invasion:
Was determined by assessing the extent of penetration into the dermis
Prospective data support that measurement of Breslow tumor thickness:
Is more reproducible than measurement of Clark level and that Breslow tumor thickness is the more accurate predictor of outcome
The AJCC Melanoma Expert Panel:
Continues to use Breslow tumor thickness cut-points of:
1 mm for the T categories
2 mm for the T categories
4 mm for the T categories
However, in the 8th Edition of the AJCC staging system:
A tumor thickness stratum of 0.8 mm plays a key prognostic role:
In subcategorizing T1 tumors:
In contrast to previous incorporation of mitoses (as a dichotomous variable only:
i.e., < 1 mitosis/mm2 vs. at least 1 mitosis/mm2:
Contributed to the definition of T1a and T1b, respectively in the 7th Edition
Specifically, in the 8th Edition, primary melanomas:
With a tumor thickness < 0.8 mm without ulceration are:
Designated T1a
Whereas primary melanomas 0.8 to 1.0 mm or those < 0.8 mm with ulceration are:
Categorized as T1b
Despite its removal from the T category for thin melanomas:
The AJCC recognizes the prognostic importance of mitotic rate in all T1 to T4 lesions:
Notes that this important covariate should be recorded (as number of mitoses/mm2), as it will likely be included in the development of clinical tools and contemporary prognostic models
Melanoma may also present as metastasis to a regional nodal basin, or even with distant metastatic disease:
Yet without evidence of a primary lesion:
When there is no evidence of a primary tumor (i.e., unknown primary or completely regressed melanoma) or when thickness cannot be assessed:
The AJCC (8th Ed.) categorizes these as T0 and TX, respectively
Primary tumor ulceration:
Is histopathologically defined:
As the absence of an intact epidermisoverlying a portion of the primary tumor
Importantly, ulcerated melanomas are associated with a:
Significantly worse prognosis than nonulcerated melanomas of the same thickness
In the T category of the AJCC staging system, ulcerated tumors are designated by bfollowing the numerical T:
An exception to this rule is for a nonulcerated primary melanoma with a tumor thickness 0.8 to 1 mm:
It is also designated by a ābā (T1b)
N Category:
The N category refers to melanoma metastases to:
Regional lymph node basins and other intralymphatic manifestations of melanoma metastasis (e.g., in-transit, satellite, and microsatellite disease)
Regional nodal tumor burden:
Is the most important predictor of survival in patients without distant disease
Overall, there is significant heterogeneity in prognosis among patients with regional disease
Multiple studies have demonstrated that the number of pathologically involved lymph nodes:
Is a dominant and independent predictor of outcome in patients with melanoma
The 8th Edition AJCC staging system N category continues to use:
1, 2 to 3, and 4 or more regional lymph nodes to generate N subcategories
The presence of primary tumor ulceration has also been shown to be an independent adverse prognostic factor:
Among patients with regional nodal disease:
Leading to its continued incorporation into the melanoma staging system
In the 8th Edition:
Both primary tumor thickness and ulceration are used to define N stage groups
Aside from the number of tumor-involved lymph nodes:
It is important to distinguish the:
Burden of nodal disease as well as the presence or absence of in-transit, satellite, and/or microsatellite disease
Previous empiric definitions such a microscopic and macroscopic regional nodal disease:
Have been replaced by āclinically occultā or āclinically detectedā regional nodal disease, respectively:
Patients who have clinically negative regional lymph nodes but pathologically documented nodal metastases (i.e., a positive sentinel node):
Are defined as having āclinically occultā nodal metastases:
Designated by the letter a in the N category
In contrast, patients with clinical evidence of regional nodal metastases that is confirmed on pathologic examination are defined as having āclinically detectedā nodal metastases:
Designated by the letter b in the N category
Overall, survival for patients with clinically detected nodal disease is worse than for patients with clinically occult nodal disease
Additional components of the N category include:
Satellite, in-transit, or microsatellite disease
Presence of at least one of these types of metastasisis coded by a suffix ācā in the 8th Edition N category and further stratified according to the number of tumor-involved regional lymph nodes:
N1c, N2c, or N3c
Satellite and in-transit metastases are classically defined:
As skin or subcutaneous lesions:
Within 2 cm of the primary tumor or more than 2 cm from the primary melanoma, respectively:
But generally not beyond the regional nodal basin, and are types of non-nodal regional metastasis
Microsatellites are defined as:
Any foci of metastatic tumor cells adjacent or deep to, and discontinuous from the primary tumor
It is important that there be an element of normal interposition tissue, that is, if only fibrosis and/or inflammation separate a suspected microsatellite from its primary, one should query where this represents regression of this intervening region
Microsatellites are also included in the N category staging system
M Category:
The M category refers to:
Melanoma distant metastasis and is classified as stage IV
Within the M category:
There is only one stage, M1
In contrast to the three M subcategories in the 7th Edition (M1a, M1b, and M1c)
There are four subcategories in the 8th Edition AJCC melanoma staging system
Distant metastases to the skin, subcutaneous tissue, or distant lymph nodes:
Are designated M1a:
They are associated with a better prognosis than metastases to other anatomical sites
Metastases to the lungs:
Are associated with an intermediate prognosis:
Are designated M1b
Visceral metastases are associated with a worse prognosis:
Are designated M1c
New to the 8th Edition is the addition of a subcategory for CNS metastasis (i.e., brain, spinal cord, and/or leptomeningeal disease):
Designated M1d
This category of disease is generally associated with worse survival compared to the other M categories
M1c now includes patients with non-CNS visceral metastasis
The subcategories reflect survival differences among patients with metastatic disease:
Depending on the anatomic sites of metastases.
Serum lactate dehydrogenase (LDH) level also continues to be included in the M category:
An elevated LDH has been shown to adversely influence survival across patients with stage IV disease
LDH level is denoted with:
The suffix (0) in patients without elevation, or (1) for those with an elevated LDH (i.e., M1a(1) ā¦M1d(1))
In patients in whom LDH level is unknown or unspecified, no suffix is added
Clinicopathologic Staging (c/pTNM)
Clinical staging includes:
Above-noted features of the primary tumor:
As well as lesions and clinical and/or radiologic studies
Pathological staging involves incorporating all variables of microstaging of the primary tumor:
As well as information from the surgical specimen, including treatment effect and margin status
Lymph node status is confirmed by both identification and quantification of sentinel and/or regional nodal basin involvement
Formal pathological staging is crucial to both proper classification and prognostication of patient outcome
EXTENT OF DISEASE EVALUATION
In addition to physical examination, several adjuncts are used to determine the extent of disease
The National Comprehensive Cancer Network (NCCN) provides guidelines to evaluate for possible metastatic melanoma with imaging
For melanoma in situ:
Imaging studies are not recommended
For stages IāII melanoma:
Imaging is recommended only if there are specific signs or symptoms that need evaluation
For stage III melanoma:
It is my general practice to obtain baseline imaging with a:
Chest x-ray, computed tomographic scan, PET/CT, and/or magnetic resonance imaging (MRI) of the brain
Ultrasonography with fine-needle aspiration of the associated lymph node basins may be useful in detecting metastatic disease in lymph nodes:
Excisional biopsy and/or formal resection of suspicious nodes solely for diagnostic purposes is discouraged
Patients who present with suspected stage IV are generally staged with:
Computed tomography (CT) of the chest, abdomen, and pelvis Ā± positron emission tomography (PET) as well as MRI of the brain:
Image-guided percutaneous biopsy of concerning lesions can be used to confirm disease
Excisional biopsy of suspected metastatic lesions is rarely indicated for diagnostic purposes
#Arrangoiz #CancerSurgeon #HeadandNeckSurgeon #SurgicalOncologist #MountSinaiMedical Center #MSMC #Melanoma #SkinCancer
The molecular classification of melanoma, considering the increasing incidence rates projected for 2025 in the United States and the associated risk factors such as ultraviolet (UV) exposure, demographic changes, and genetic predispositions:
Is primarily based on the genetic alterations and the degree of cumulative sun damage (CSD)
Low-CSD Melanomas:
These include superficial spreading melanomas and nodular melanomas:
Which are often characterized by BRAF mutations, particularly the BRAFV600E variant
These melanomas are typically associated with:
Intermittent, intense UV exposure
High-CSD Melanomas:
These include lentigo maligna melanomas and desmoplastic melanomas
They often have a high mutation burden and can harbor:
NRAS mutations, TP53 mutations, and other non-V600E BRAF mutations
These melanomas are associated with chronic, cumulative UV exposure
Non-CSD Melanomas:
These include acral lentiginous melanomas and mucosal melanomas:
Which usually do not show BRAF, NRAS, or NF1 mutations (triple wild-type)
However, they may have mutations in C-KIT, GNAQ, or GNA11 genes
These melanomas are not related to UV exposure
Familial Melanomas:
These are often associated with germline mutations in genes such as:
CDKN2A and MC1R:
Which significantly increase melanoma risk
These genetic changes are inherited and present in all body cells
The molecular classification of melanoma is crucial for guiding targeted therapies and improving patient outcomes:
For instance, BRAF inhibitors (e.g., vemurafenib, dabrafenib) and MEK inhibitors (e.g., trametinib):
Are effective in treating melanomas with BRAF mutations, while immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) have shown efficacy across various melanoma subtypes
The American Joint Committee on Cancer (AJCC) staging system (8th Edition) for thin melanomas (less than or equal to 1 mm):
Includes both tumor thickness and ulceration as distinguishing features of a stage 1a and stage 1b melanoma
The American Society of Clinical Oncology (ASCO) and the Society for Surgical Oncology (SSO) jointly developed evidence-based recommendations for the use of SLN biopsy for patients with melanoma:
The guidelines note that SLN biopsy is recommended for:
All patients with intermediate-thickness melanomas (between 1 and 4 mm):
Studies have shown that SLN biopsy is useful for identifying nodal metastases in these patients:
Who account for about one-third of all melanoma cases
SLN biopsy detects cancer in the sentinel nodes in about:
18% to 26% of patients
The majority of melanomas are thin (1 mm thick) and usually can be cured simply by wide local excision of the primary tumor:
The incidence of tumor-positive SLN biopsy among patients with thin melanomas is approximately 5%
Although SLN biopsy is not necessary in most cases:
The guideline recommendations note that it should be discussed and considered for selected patients with:
Thin melanomas (0.8mm to 1mm)
Those with melanomas < 0.8mm and possess high-risk factors:
Such as:
Ulceration
A mitotic rate of 1/ mm2
Wong et al:
Evaluated the results of SLN biopsy in 223 patients with thin melanomas and found nodal metastasis to be uncommon among patients with:
Melanomas less than 0.75 mm thick
Less than Clark level IV
References:
Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2018;36:399-413.
Wong SL, Brady MS, Busam KJ, Coit DG. Results of sentinel lymph node biopsy in patients with thin melanoma. Ann Surg Oncol.;2006;13:302-309.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 