melanoma skin cancer

Melanoma  (lat. melanoma; ICD-10: C34) is a malignant tumor that develops due to melanocyte skin cells’ malignant transformation. These cells are of the embryonic origin of the neural crest. Melanomas, in most cases, occur on the skin but can occur anywhere else where neural crest cells migrate during embryonic development, such as the gastrointestinal tract or the brain.

Melanoma predominantly affects adults, with a peak incidence in the fourth decade of life, and there is no significant difference in prevalence between the sexes. The risk of developing the second primary melanoma after the first diagnosis is 3-5%.

Melanoma is a growing problem as more and more people are affected. The incidence is estimated to grow by almost 6% per year.

Melanoma is less common than other types of skin cancer. However, it is much more dangerous if it is not found early. It causes the majority (75%) deaths associated with skin tumors (48,000 deaths per year). Worldwide, 160,000 new cases of melanoma are diagnosed annually. Currently, for example, in the U.S., 1 in 50 whites, 1 in 1,000 blacks, and 1 in 200 Hispanics develop melanoma at some point in their lives.

Similarly, international white populations in Australia, New Zealand, and South Africa have the highest incidences, while Asian populations in Hong Kong, Singapore, China, India, and Japan have low incidence rates. This all together suggests that whites in sunny areas have a higher risk of developing melanoma.

Melanoma risk factors

melanoma malignant tumor

A positive family history exists in 5-10% of patients; in cases where one relative suffers from melanoma, the risk increases 2.2-fold.

Blue eyes, red hair, pale complexion; skin reaction to the sun (easily gets sunburns); benign and/or dysplastic melanocyte nevi (the number has a better correlation than size); immunosuppressive conditions (transplant patients, hematological malignancies) – all these personal characteristics carry a higher risk.

Also,  sun exposure throughout life – often exposure to UVB and UVA radiation also carries a higher risk (recent evidence suggests that the risk of melanoma is higher in people who use sunscreen – since it blocks UVB radiation more, people who use sunscreen may be more exposed to UVA radiation than the general population, with the proviso that these people must be exposed to the sun more than the general population); small latitude, number of burns; use of solarium.

Atypical mole syndrome (formerly called BK mole syndrome, dysplastic nevus syndrome, familial atypical multiple melanoma mole) – over 10 years, the risk of developing melanoma is 10.7% compared to 0.62% of control; higher risk of melanoma depending on the number of affected family members (almost 100% risk if 2 or more relatives have dysplastic nevi and melanoma).

Pathophysiology of melanoma

Some scientists suggest that benign melanocyte nevi markers of melanoma risk are not direct precursors; however, dysplastic nevi are believed to degenerate over time into melanoma. Lentigo maligna is believed to be a preinvasive precursor of lentigo malignant melanoma, and that at least 5% of lentigo maligna progresses to malignancy.

Classification of melanoma

Melanoma is classified into 4 main types according to the growth pattern. These are superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma. Other more unusual types include mucosal lentiginous melanoma, desmoplastic melanoma, and verrucous melanoma.

Superficially spreading melanoma

 Superficially spreading melanoma
Superficially spreading melanoma

Superficially spreading melanoma makes up about 70% of all melanoma. Histologically, characteristic cells are present in nests along the dermo-epidermal junction and migrate to the stratum granulosum or stratum corneum. These cells can invade the papillary dermis with inflammatory lymphocytic infiltrate.

Clinically, these superficially spreading melanomas develop from pre-existing dysplastic nevi. Typically, the lesion changes slowly over several months to years. They are usually flat but can become irregular and elevated at later stages. The lesions are average 2 cm in diameter, with zones of different colors and peripheral protrusions, indentations, or both.

Nodular melanoma

Nodular melanoma cancer
Nodular melanoma

Nodular melanoma is characterized by extensive vertical growth into the dermis with a minimal radial component. They make up approximately 15-30% of melanoma diagnoses. These are tumors typically blue-black but may lack pigment in some circumstances. They can occur de novo without pre-existing lesions.

Lentigo malignant melanoma

Lentigo malignant melanoma

Lentigo malignant melanoma represents 4-10% of all melanomas. At the cellular level, dermal and epidermal changes from sun exposure must be present. Histologically, we find irregularly shaped hyperchromatic cells that form spindle formations. The epidermis is atrophic, while the dermis contains solar elastosis with chronic inflammatory infiltrates. From a clinical standpoint, lentigo malignant melanomas are usually larger than 3 cm, flat, darkened, and begin as small mottled lesions.

They occur in areas exposed to the sun (e.g., the face and neck of the elderly). Significant edge irregularities are present. Lentigo malignant melanoma usually develops within the Hutchinson melanocyte spot (lentigo maligna). When tumor thickness and location are taken into account, the prognosis for these melanomas is probably not worse than for other subtypes.

Acral lentiginous melanoma

Acral lentiginous melanoma
Acral lentiginous melanoma

Acral lentiginous melanoma makes up 2-8% of all melanoma in whites and 35-60% of all melanoma in dark-skinned individuals. Cellular proliferation is present along the dermal-epidermal border with microinvasion into the papillary dermis. The cells have increased melanin granules production, which fills their dendritic extensions.

Acral lentiginous melanoma occurs on the palms of the hands, under the nail bed, and on the feet’ soles. They can appear on the palms and soles of the feet as flat, ocher, or brown spots with irregular edges. Sublingual lesions may be brown or black, with ulcerations in later stages. There is no correlation with a worse prognosis for these lesions when tumor thickness is considered.

Desmoplastic melanomas

 Desmoplastic melanomas
Desmoplastic melanoma

Desmoplastic melanomas makeup approximately 1% of melanoma cases and tend to perineural invasion, especially in the head and neck. They are more prone to local recurrence but have a lower incidence of regional metastases.

Symptoms of melanoma

Typically, melanoma lesions are irregular contours and pigmentation. Macular areas correlate with the radial growth phase, while elevated areas usually correspond to nodular aggregates of malignant cells in the vertical growth phase.

Patients usually present with skin lesions that have changed in size, color, contour, or configuration. The acronym “ABCDE” is a feature of the international awareness campaign and can be used to remember characteristics that suggest malignant melanoma.

Lesions may itch, bleed, ulcerate, or develop satellites.

An excisional biopsy of such suggestive lesions should be performed so that the pathologist can confirm the diagnosis – full skin thickness is essential for proper histological diagnosis and classification. The most important prognostic indicator for stage I and II tumors is obesity. The biopsy also determines the margins of resection and which patients are candidates for sentinel lymph node biopsy and other additional therapy.

Patients with metastatic disease or melanoma are primarily on other systems (not the skin) have signs and symptoms associated with the affected organ system.

Clinical classification of melanoma

Two classification schemes have been developed, one based on the lesion’s vertical thickness and the other on the anatomical level of invasion of the skin layers. The Clarke classification is only used today for thin (T1) melanoma. The Breslow classification more accurately predicts tumor behavior, so it is often used.

Breslow classification:

  1. thickness 0.75 mm or less,
  2. thickness 0.76 – 1.5 mm,
  3. thickness 1.51-4 mm,
  4. thickness greater than 4 mm.

Clark classification:

  • level I – affects only the epidermis (melanoma in situ); no invasion,
  • level II – invades the papillary dermis but not the papillary-reticular dermal border,
  • level III – invades and expands the papillary dermis, but is not present in the reticular dermis,
  • level IV – invades the reticular dermis but not the subcutaneous tissue,
  • level V – invades subcutaneous tissue.

TNM classification of melanoma

Primary tumor
 
pTX – primary tumor cannot be assessed,
PTO – no evidence of primary tumor,
pTis – melanoma in situ; affects only the epidermis (CL I),
pT1 – tumor 1 mm or less thick, affecting the papillary dermis (CL II) (or to the papillary reticular margin – CL III); pT1b may mean either that the melanoma is less than 1 mm with ulceration or is less than 1 mm but according to Clarke is IV or V),
pT2 – the tumor is 1.01 – 2 mm thick,
pT3 – the tumor is 2.01-4 mm thick,
pT4 – tumor thicker than 4 mm and/or invades subcutaneous tissue (CLV) and/or satellites within 2 cm from the primary tumor,
pT4a – tumor thicker than 4 mm with or without ulceration,
any Ta – is not ulcerated.
Any Tb – ulcerated.
 
Regional lymph nodes:
 
NX – it is not possible to assess whether the lymph nodes are affected,
N0 – no metastases in regional lymph nodes,
N1 – metastasis in one lymph node,
N2 – metastases in 2-3 lymph nodes or spread of melanoma to the skin towards a nearby lymph node,
N3 – metastases in 4 or more lymph nodes or spread of melanoma into the skin towards the area of lymph nodes and lymph nodes,
any Na – melanoma can only be seen under a microscope,
any Nb – melanoma in the lymph node visible to the naked eye.
 
Distant metastases
 
MX – distant metastases cannot be assessed,
M0 – no distant metastases,
M1 – distant metastases,
M1a – metastases to the skin or subcutaneous tissue or distant lymph nodes,
M1b – lung metastases,
M1c – metastases to other organs.

Treatment of melanoma

Drug therapy is of questionable value, and it is used as an adjunct therapy in advanced stages. Surgical therapy for melanoma is based on predicting the risk of local recurrence and metastatic disease and the potential morbidity of the surgery. If the lesion has not spread beyond the primary site, it is potentially curable. Most of these lesions are thin (thinner than 1 mm or CL I or 2).

Treatment of melanoma by stages

For stage 0, the tumor is abundantly excised or previously biopsied. The margin is 0.5 – 1 cm for melanoma in situ. No other therapy is required.

For a T1 lesion, excision margins of 1 cm are sufficient, but lesions thicker than 1 mm requires a margin of 2 cm. Studies do not suggest an improvement in recurrence or survival with higher resection margins. For lesions thicker than 1 mm, many recommend a simultaneous biopsy of sentinel lymph nodes by wide resection.

For stage II, surgical resection with a margin of 2 cm is recommended. Recurrence or survival with margins greater than 2 cm (4-6 cm) does not improve. A complete lymphadenectomy is also performed on patients with suspected lymph node metastases – excision of all lymph nodes in the affected region. Sentinel lymph node biopsy should be considered if clinically positive lymph nodes are not present.

Using blue dye, a radioisotope, or both of these injected into the primary melanoma, the first lymph node into which the melanoma would spread can be identified and biopsied for pathological analysis. If the node is positive, then regional lymph metastases are likely, and then a complete dissection of the regional nodes must be made.

The correlation is based on the thickness of the primary tumor. If the sentinel lymph node is negative, there is a 99% chance that everyone else is negative. This procedure becomes the standard of care for tumors thicker than 1 mm.

For stage III, local excision of the primary tumor with a margin of 2 cm is required. Better survival with wider resection margins has not been demonstrated. Skin grafting may be required to close the defect. In any case, it is necessary to report the dissection of regional lymph nodes since stage III melanoma also represents metastases to lymph nodes.

Stage IV  is usually refractory to standard therapy, so it is usually only approached in clinical trials, i.e., experimental drugs. Palliative surgical resection is most often performed in the gastrointestinal tract, brain, lungs, or bones, with occasional long survival. Metastatic lymph nodes can also be palliatively removed. Radiation can provide symptomatic relief for metastases to bone, brain, or internal organs.

Complications

The inability to close the incision is not a real complication; however, wound dehiscence, skin necrosis, or both can occur from tension closure. Wound infection is a potential complication. Seromas and lymphocele occur in about 27% of cases with axillary lymph node dissection, nerve dysfunction, and/or pain in about 22% of cases, and hematoma in 1% of cases.

Lymphedema of the upper and lower extremities can complicate the axillary and inguinal lymph nodes’ dissections. These complications occur in 2-39% of cases. Complete resection should be avoided at all costs.

Prognosis

Poor prognostic factors are as follows:

  • tumor thickness (worse prognosis for thicker lesions),
  • evidence of tumors in regional lymph nodes (stage III disease),
  • more positive lymph nodes,
  • presence of distant metastases (stage IV),
  • anatomical location (lesions on the trunk and/or face have a worse prognosis than lesions on the extremities),
  • the presence of ulceration,
  • the presence of regression on histological examination (this is still debated),
  • Male sex.

We use a relative survival rate to express the prognosis, where anyone who dies from other (non-melanoma) causes does not count. This has proven to be a more accurate way of describing the prognosis for people with certain types and cancer stages. Of course, these prognoses are based on five years of survival from diagnosis and the start of treatment.

  • Stage 0: five-year survival is 97%,
  • stage 1: five-year survival is 90-95%. If biopsy sentinel node shows the finding of melanoma in the lymph node, five-year survival drops to 75%.
  • Stage IIA: Five-year survival is approximately 85%. If a sentinel node biopsy finds melanoma in the lymph node, the five-year survival drops to 65%.
  • Stage IIB: Five-year survival is 72-75%. If a sentinel node biopsy shows melanoma in the lymph nodes, the five-year survival drops to 50-60%.
  • Stage IIC: Five-year survival is approximately 53%. If a sentinel node biopsy shows melanoma in the lymph nodes, the five-year survival drops to 44%.
  • Stage III: Five-year survival is approximately 45%. It is higher if the melanoma has spread to only one node and lower if it has spread to more than 3 nodes. It is more if the spread can only be seen microscopically. It is lower if the melanoma is ulcerated.
  • Stage IV: Five-year survival is approximately 10%. It is more if it has spread to the skin or distant lymph nodes. At this stage with distant metastases, if there is only one metastatic site, the one-year survival is 36% but drops to 13% with 2 metastatic sites. Patients with 3 or more metastatic sites essentially have 0% survival in the first year.
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