Introduction to Melanoma

Welcome to First Incision, the podcast about preparing for the General Surgery Fellowship exam. I'm your host, Amanda Nikolic. Let's get started with our team timeout. Our patient today is both the skin and soft tissue as well as the surgical oncology modules from the general surgical curriculum. And the topic we'll be covering today is everything you need to know about melanoma up until talking about the management of melanoma. We'll cover that in another podcast episode.

So what is a melanoma? A melanoma is a malignant tumor of melanocytes. And melanocytes usually reside in the basal layer of the skin. It's interesting to note that melanocytes are actually of the neural crest origin from an embryological point of view. Melanomas constitute 5% of all skin cancers. Because melanomas arise from melanocytes, they can actually develop in a number of different areas wherever melanocytes exist. So this includes both the skin, the retina, and even the leptomeninges.

So what are the risk factors for development of melanoma? So in terms of modifiable risk factors, the only modifiable risk factor is sun exposure. The types of sun exposure that increase your risk of developing a melanoma are intense intermittent sun exposure, so a history of severe blistering sunburn. Chronic sun exposure also does increase your risk and we know that UVB rays are the ones that are most associated with carcinogenesis.

And people that live closer to the equator or use tanning beds are also at higher risk. So in terms of the non-modifiable risk factors for the development of melanoma, men are more likely to get melanoma than women, and it's much more common with increasing age. The median age of diagnosis of a melanoma is in the late 40s and it's pretty rare before puberty. Other risk factors include immunosuppression.

and genetic risk factors. So about 5% to 10% of patients who have a melanoma have a family history of somebody who's had a melanoma. Skin type, which is also determined by genetics, also has a relationship with the development of melanoma. So patients who have Fitzpatrick type 1. two and three have a much higher risk of developing melanoma than four, five and six. It's worth having a little look at what the Fitzpatrick

scale is in regards to skin colour but type 1 basically always burns and never tans and has quite pale skin with freckles. Type 2 usually burns and minimally tans and has light coloured skin but darker than the really fair type 1. Type three, people sometimes have a mild burn and tan uniformly. And type four, rarely burn but always tan well. So that's sort of moderate brown colored skin.

Type 5 very rarely burns and has dark brown skin and type 6 never burns and has deeply pigmented dark brown to the darkest brown color skin. There are some genetic conditions that are associated with melanoma. The most common of these is called dysplastic nevus syndrome. And this used to be called familial atypical multiple mole melanoma, but the name has changed to dysplastic nevus syndrome.

And this is a condition associated with mutations in the CDKN2A gene and is an autosomally dominantly inherited condition where there are more than 100 moles and these increase your risk factors for developing. melanomas. The other is xeroderma pigmentosum, which is an autosomally recessive inherited condition associated with a defective nucleotide excision repair gene. So taking a thorough history of patients.

Family history is really important when looking at melanoma risk. The last thing to mention when talking about melanoma risk is potential development of melanoma from a pre-existing nevi. There's three main types of nevi, congenital nevi, benign nevi, and dysplastic nevi. Congenital nevi are those that patients are born with. And patients who have small congenital nevi are at very low risk of these developing into a melanoma over their lifetime.

However, there is a risk if patients have really giant congenital nevi, so more than 20 centimetres in size, and these are associated with a 5% to 8% lifetime risk of developing into a melanoma. and the management of these is either close observation or excision. In terms of benign nevi, These are what we would usually describe as a normal mole. So a circumscribed chronic lesion, usually with a darker color on the skin or mucosa.

These can be present at birth, as we've just talked about, or they can develop later on in life. don't have a significant risk of developing into a melanoma. But if patients have more than 200 benign nevi, then they're at high risk of developing a melanoma. And if they have more than 10... that are raised or more than 20 total nevi on the arms, then this increases the risk of developing a melanoma compared to the normal population by about 10 times. The last type of nevi is a dysplastic nevi.

And these are moles that look different than a normal mole. So they're usually more than five millimeters in size and they can have different colors and have an irregular border. About 10 to 20% of the population will have a dysplastic nevus somewhere on their body. Dysplastic nevis can turn into melanomas and the risk for developing a melanoma if you have more than five dysplastic nevis is about 10 times greater than the general population.

But in general, you don't need to excise these to prevent it because the risk is small, but you do need to monitor to make sure that there's no changes. And if a patient comes in noticing a change, then that would be an indication to do more investigation.

So let's move on to talk about how melanoma presents. And this also ties in with the different types of melanoma because each different type has its own macroscopic and microscopic appearance. So starting with the basics of what a melanoma might look like. What we get taught in med school is the ABCD of looking at pigmented lesions on the skin. And this is helpful if you're going to describe a photograph of a lesion in the exam.

So A stands for asymmetry, and this is where one half of the melanoma doesn't look like the other half of the melanoma. B stands for border irregularity. So if the border looks scalloped or poorly circumscribed or irregular, then that would be a sign of a melanoma. C stands for color. So melanomas will typically have multiple different colors within the melanoma, so quite heterogeneous appearance. And they can be shades of tan and brown, black, white.

red or blue sometimes. So this is a sign that maybe this is a melanoma. D is for diameter. So a lesion that's over six millimeters is increasing your suspicion that this is a melanoma. We can continue the ABCD to talk about EF and G, which mostly relates to if it's looking like a nodular melanoma. So signs that you would be more suspicious of a nodular melanoma. have to do with E. So if you have an elevated or raised lesion.

F, if you have a nodule that's quite firm to the touch, and G for growth. So rapidly growing lesion is also a pretty suspicious sign that this is a melanoma. So the different types of melanoma include melanoma in situ, which is called lentigo maligna, and then the different types of invasive melanomas. So this is superficial spreading, nodular. lentigo maligna melanoma, acral lentiginous melanoma, and desmoplastic melanoma. So let's talk about each of these in turn. The first is...

lentigo maligna which is in situ disease. This has previously been called Hutchinson's melanotic freckle as well in case you hear that term. In our curriculum, it talks about describing the pathology and clinical features of the pre-malignant lesions. And I think in this case, they're talking about lentigo maligna.

So a lentigo maligna is a slow-growing lesion. It grows over a number of years, and it often occurs in sun-exposed areas such as the face, the neck, and the hands, and often happens in elderly patients. Macroscopically, it will look like an asymmetrical pigmented lesion, but it's important to note that it can also be amelanotic or a pink color. It can be a difficult lesion to pick up.

Microscopically, lentigo maligna is a propagation of malignant melanocytes along the base of the epidermis, and they can extend superficially into the stratum corneum, kind of like Paget's disease. And because of its slow-growing nature, it can progress to lentigo maligna melanoma, which is when invasive disease develops, but it may continue to be in situ disease for quite a long time.

Moving on to the invasive types of melanoma. The first one is superficial spreading melanoma. And this is the most common subtype accounting for about 60%. It's often found in the lower limb in women and on the back in men and has a strong relationship with that intermittent extreme sun exposure we talked about earlier. This is the one that has the most sort of characteristic

If you Google melanoma, you'll see a lesion that is most likely going to be a superficial spreading melanoma. And so you'll see an asymmetrical pigmented lesion with irregular borders. color variation and it'll be more than six millimeters in size. The typical growth pattern of a superficial spreading melanoma has to do with its name. So typically there'll be a radial growth phase where it spreads superficially before it then becomes invasive and invades deeper.

The next subtype is the nodular melanoma. Nodular melanoma accounts for about 15% of melanomas and is more common in men than women. It's common that this is amelanotic, so it's usually a pink lesion, and it can be really difficult to pick up because it doesn't have that pigmentation that is classically associated with a melanoma.

It's typically rapidly growing and elevated. That's why it's called a nodule, nodular melanoma. And it's much more aggressive than superficial spreading melanoma and accounts for a lot of the deaths associated with melanoma. The EFR rule is relating pretty much to the nodular melanoma. So you're going to see an elevated and evolving lesion, which is firm and grows quickly. And it can be mistaken for a BCC or SCC because it's usually a melanotic nodular lesion. So that's something to be aware of.

The next type is the lentigo maligna melanoma. So this is a melanoma that arises in a patch of lentigo maligna. So typically happens in that same age group we were talking about with the melanoma in situ. So elderly. on the face, neck and hand, so areas of UV damage. And it accounts for about 10 to 15% of melanoma.

It typically, as I've mentioned, will arise in that precursor lesion. So any nodule in an area of in situ disease or any changing pigmented lesion on the face or neck or hands should be had an excisional bile. done on it. The recurrence rate following excision is pretty high, 8% to 20%, and it's thought to be because there's sort of a field change with the in situ component, and assessing the margins as a pathologist can be very difficult.

The next one to talk about is the acral lentiginous melanoma. And these are melanomas that arise on the soles of the feet or the palms of the hands and clued under the nail bed. These account for about 5% to 10% of melanomas, and they're the most common melanomas that occur in really dark-skinned patients. They can arise de novo, or they can arise in a pre-existing nevus on the hands or feet.

Typically, acral indigenous melanoma will have a similar sort of process to the superficial spreading melanoma where they have a radial growth phase, so where they grow along the skin before they become invasive. The last type of melanoma is a desmoplastic melanoma. And this is quite rare. It's about 1% to 4% of melanomas and typically occurs in sun-damaged skin of the head and neck in older patients.

It is characterized by malignant spindle-celled melanocytes with a surrounding fibrous stroma, which is why it's called desmoplastic. And the appearance is that 50% of the time they'll be amelanotic, so they may be... a pigmented or a non-pigmented lesion, and they often present as a flat nodule with quite an abnormal appearance, almost like a thickened plaque.

And the different types include a mixed type, which can be mixed with the other type of melanoma or a pure desmoplastic type. And a mixed type has a poorer survival. The other interesting thing about desmoplastic melanoma is that it has a high risk of local recurrence, up to 20%. So some people suggest taking a wider margin than what we're going to talk about later with the guidelines for margins. for removing a melanoma.

And the other interesting thing is that it has a much higher tumor mutation burden, but this also means that it has a higher response to anti-PD-1 immunotherapy, up to double what all of the other subtypes get due to its high. a DNA damage load. So that's quite interesting as well.

Just briefly, the histopathology of a melanoma is a proliferation of atypical melanocytes in the basal layer of the skin. In the radial growth phase, which we talked about in the superficial spreading melanoma, usually the atypical melanocytes will remain largely confined to the epidermis. And these are basically still dependent on exogenous growth factors from the surrounding keratinocytes.

In the vertical growth phase, the atypical melanocytes invade the upper layer of epidermis and beyond and penetrates the underlying dermis and subcutaneous tissues going through the basement layer. And this is where the... keratinocytic and fibroblast control and communication with the melanocytes is lost. They have acquired their own growth factors and are highly metastatic once they have gone into this vertical growth phase.

The immunohistochemistry for melanoma is typically positive for S100, melan A, SOX10, and HMB45. In terms of the driver mutations for melanoma, the most common mutation is a BRAF mutation. And BRAF is an oncogene. So a mutation means that you get a proto-oncogene with a BRAF mutation. And these are most common in melanomas that are related to chronic sun damage and often present in younger patients.

And a V600E BRAF mutant is important because there is a targeted therapy for patients who have a V600E BRAF mutation. Some other potential mutations include a germline mutation in the CDKN2A gene, which we talked about when we mentioned the dysplastic nevus syndrome. And the other interesting mutation to be aware of is that a CKIT mutation is common in the acral lentiginous melanoma group.

So we've talked about how melanomas present and the different ways that they can look. But how do you actually work up a patient who you think might have a melanoma? The first thing is a thorough history. You want to take a detailed history of the presenting symptoms and history of the lesion. And interestingly, the most sensitive person to pick up a melanoma is actually the patient themselves.

You want to take a history about the risk factors for melanoma, such as a family or personal history of melanoma, sun exposure history, skin type, and any medical comorbidities, including immunosuppression. You want to also know if there's been a previous excision or shave or punch biopsy performed on the lesion. You also want to ask them about systemic symptoms such as weight loss.

anaemia, neurological symptoms or respiratory symptoms that may indicate metastatic disease or whether they've noticed any lumps in the lymph node basins. The next step is an examination and it needs to be a thorough examination of the whole body. On general inspection, you want to have a look at the general features of their skin color and any evidence of...

sun damage or skin damage. You want to have a look for any previous surgical scars or other suspicious lesions. You also then want to examine the lesion and document the A to F. as well as look at the local regional nodal basins and palpate for any masses. You also want to examine for systemic disease. This may include percussion and auscultation of the chest.

and palpating the abdomen for intra-abdominal masses, and maybe a neurological exam if their history suggests neurological symptoms. The next step is a biopsy. And when we're talking about melanoma, for any pigmented lesion or lesion you're suspicious is a melanoma, an excisional biopsy is required. And an excisional biopsy is a...

excision of the lesion with a minimal margin, so just one to two millimeters, including a cuff of subdermal fat. And this is really important so that you can stage the depth of the tumor. And you want to primarily close this area. You don't want to do flaps because if you have to come back and take wider margins, it makes it much more complicated. You also don't want to take wide margins as this can influence.

if the patient needs a sentinel lymph node biopsy, depending on the pathology that you get back. You want to avoid a punch. shave or incisional biopsy. But sometimes that might be required if you have a very, very large lesion, such as a large lentigo maligna. In those situations, you may have to do an incisional biopsy to remove the most malignant or nodular area of the tumor.

However, I'd probably avoid talking about that in the exam if you can avoid it. I think the answer really should be an excisional biopsy is the first step for workup of a melanoma.

So once you have done your excisional biopsy, you're going to get a pathology report. And there are some features that you are always going to get on a synaptic report for a melanoma. The first one is the Breslow thickness or the thickness of the tumour. This is a little different from other cancers in other areas where the widest size of the tumor is what we're interested in. For melanoma, it's specifically the thickness or depth from the superficial aspect of the skin to deep, not the...

width of the tumor that we're looking at. The old measurement was Clark levels, but we don't really use that anymore. So in terms of Breslow thickness, a thin melanoma is considered less than one millimeter thick. An intermediate melanoma is one to four millimeters thick. And a thick melanoma is more than four millimeters thick. And this has prognostic implications. So a thin melanoma less than one millimeter has a five-year survival of more than 95%.

A thick melanoma, more than 4mm thick, has a 5 year survival of only 50%. Some other prognostic factors that you might see on the histological diagnosis include whether the tumor is ulcerated or not. You'll also receive the mitotic count per millimeter squared. evidence of any satellite lesions around the primary melanoma, whether there's any lymphovascular invasion, whether there are any tumor infiltrating lymphocytes.

Whether there's a desmoplastic melanoma component, remember we talked about that being a type of melanoma and you can get a mixed desmoplastic melanoma. Whether there's any neurotropism, which is just another term for perineural invasion. And they'll also tell you the melanoma subtype and all of the excision margins for both the invasive and in situ component. And they should give you both radial margins as well as a deep margin.

All of these factors are also the factors that will influence the prognostic outcome of the patient. So tumors that are thicker, that are ulcerated, that have a high mitotic rate. evidence of perineural or lymphovascular invasion. And if they don't have any tumor infiltrating lymphocytes, because that's a sign that the immune system is fighting off the tumor, then all of those things are worse prognostic factors and are associated with a higher risk of both local recurrence as well as distance.

So let's talk about staging of melanoma. There is a AJCC 8th edition TNM staging system for melanoma. This staging system basically has T-stage split up into thicknesses. And within each of those T stages, an A designation means that there's no ulceration and a B designation means that there is ulceration. So T1 tumors are those that are less than one millimeter thick. T1A is less than 0.8 of a millimeter with no ulceration.

And T1B is either less than 0.8 of a millimetre with ulceration or 0.8 to 1 millimetre with or without ulceration. T2 is 1 to 2 millimetres thick. T2A is 1-2mm thick without ulceration and T2B is 1-2mm thick with ulceration. T3 is 2-4mm thick and T3a is 2-4mm thick without ulceration. T3b is 2-4mm thick with ulceration. And T4 is more than 4 millimetres. And T4A is more than 4 millimetres without ulceration. And T4B is more than 4 millimetres with ulceration. For the nodal staging,

It has to do with the number of nodes involved. But the A and B designates whether or not the node was clinically occult or whether the node was clinically detected. So for example, N1 is one tumor-involved node. With N1a being it's clinically occult, so it's only detected by a sentinel lymph node biopsy. And N1b, where it's clinically detected. So it was seen by ultrasound or biopsy preoperatively and was clinically detectable pre-Sentinel lymph node or pre-clearance.

For N1 there is also a C which is where there's no regional lymph node disease but there is the presence of satellite or microsatellite lesions. For N2, it's two or three tumor-involved nodes. So N2A is where it's clinically occult, so it's only detected by a sentinel node. And N2B is where there's two or three nodes and at least one of them was clinically detected.

And N2C is where there's one clinically occult or clinically detected node, but also the presence of satellite or microsatellite or in-transit metastases. N3 is where there's... greater than or equal to four tumor-involved nodes. So N3a is where there's greater than or equal to four clinically occult nodes detected by sentinel node. N3B is where there's greater than or equal to four nodes, at least one of which was detected clinically, and any number or presence of any number of matted nodes.

And N3C is where there's greater than or equal to two clinically occult or clinically detected nodes, but there's also presence of in-transit satellite or microsatellite metastases. And so the last group to talk about is the M staging or metastatic staging. This is a little complex as well. So M1 is where there's evidence of distant metastases.

M1A is where there's distant metastases to skin, soft tissue including muscles and or non-regional lymph nodes. And then there's another group here where if it's... M1A and then in brackets one, there's also an elevated LDH level because the LDH level is correlated with prognosis and survival. So that's why I think it's factored into the M staging here. M1B is where there's distant metastases to the lung with or without M1A sites of disease. And again, M1B...

And then in brackets one is where there's also an elevated LDH level. And then M1C is where there's distant metastases to non... central nervous system visceral sites with or without M1A or M1B sites as well. And same deal, M1C bracket one is where the LDH is also elevated. And then there's an M1D where there's distant metastases to the central nervous system, with or without those other sites. And again, M1D with a bracket one is where the LDH is also elevated.

The staging of melanoma is also a bit complicated. I like to think of it as stage one and two being the different thicknesses of melanoma with no nodal disease. Stage three is any T-stage but nodes involved. And stage four is metastatic disease. So stage one is split into 1A and 1B. And so 1A is... T1A thickness and no nodes or metastases. So all of the 1s and 2s have no nodes or metastases. Stage 1B is either T1B or T2A disease.

Stage 2A is T2B or T3A disease. And stage 2B is T3B or T4A disease, with 2C being T4B disease. Stage three is split up into three A, B, C and D and it's worth having a look at the AJCC 8th edition stage three subgroups. because they're split up with this sort of color-coded table that's quite difficult to describe. The reason splitting stage three into these different subgroups is important is because the five-year overall survival is very different depending on if you're a 3A or a 3D.

So for example, stage 3A disease has a 93% five-year survival, but stage 3D disease has a 32% five-year survival. And this staging is going to guide your treatment. So for patients who have stage 3B onwards disease, even if their melanoma and their nodes have been resected, they'll now be offered adjuvant treatment. So that's why this... particular staging breakdown is important.

So the last thing to mention in terms of staging for melanoma is what further investigations you should do for patients. In general, systemic staging isn't indicated in stage 1 and stage 2 melanomas in asymptomatic patients, so as long as they don't have any history or examination findings that make you suspicious for disseminated disease. Sentinel lymph node biopsy should be performed if the melanoma is more than one millimeter thick.

in clinically negative nodes. But any patients with more than 0.8 millimeter thick melanoma that has high risk features, such as ulceration, lymphovascular invasion or a high mitotic count also require a sentinel lymph node biopsy. If a patient has any palpable lymphadenopathy, then this should be investigated with an ultrasound guided FNA. And we'll talk a little bit in the next episode about what to do in those patients. In terms of systemic staging, staging for melanoma is usually a PET-CT.

and either a CT or an MRI brain to screen for metastatic disease. My understanding is, and what the... Cancer Council guidelines say is that systemic staging should be considered in stage 3B or above. So that means that patients who have a really thick melanoma but lymph node negative, so stage 2B or 2C, And patients with 3A disease, so they have an early thickness melanoma, but a clinically negative but central node positive metastases.

also aren't recommended to have systemic staging. So only stage 3B and above.

So because this is such a big topic, I'll split it up over two episodes. Our next episode will go into the management of melanoma. We'll talk about operations, lymph nodes, and all of the different... medical treatments for melanoma. Once again, please remember to rate, review and subscribe to the podcast. It helps other people find it. And also I love reading your reviews.

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