Skin Cancer: Symptoms, Types & Treatment

Skin Tumours Introduction

The skin, the outermost coat of the human body, functions as a protective cover against various insulting agents, such as ultraviolet radiation, excessive heat, and various chemical agents.

Read And Learn More: General Surgery Notes

• Hence, it is one of the most common cancers in elderly patients. However, more than 90% of skin tumours are curable because they are diagnosed early and easily (unlike intra-abdominal malignancies). Many of them are low-grade cancers.
• Among skin cancers, about 70% are basal cell carcinomas, 20% are squamous cell carcinomas, and 5% are melanocarcinomas.
• Other rare skin cancers are sebaceous carcinomas, dermato fibrosarcomas, etc. In this chapter, only common malignant skin tumours and some common skin lesions, such as corn and warts, are discussed.

Classification Of Skin Tumours

Epidermal Tumours

1. Benign

• Papilloma
• Seborrhoeic keratosis
• Verrucous naevus

2. Malignant

• Basal cell carcinoma
• Epithelioma and Marjolin ulcer

Melanocytic Tumours

1. Benign

• Junctional naevus
• Compound naevus
• Intradermal naevus
• Hutchinson’s freckle
• Hairy and blue naevus

2. Malignant

• Superficial spreading melanoma
• Nodular melanoma
• Lentigo maligna melanoma
• Amelanotic melanoma
• Acral lentiginous melanoma
• Desmoplastic melanoma

Sweat Gland Tumours (Malignant)

• Hidradenocarcinoma
• Adenoid cystic carcinoma

Sebaceous Gland Tumours

• Sebaceous adenoma
• Sebaceous carcinoma

Other Tumours

• Dermatofibrosarcoma protuberans
• Trichofolliculoma (hair follicle tumour)

Premalignant Lesions Of The Skin And Risk Factors

1. Chronic irritation to the skin may occur due to various carcinogenic chemicals, such as dyes, tar and inorganic arsenic. Coal tar contains polycyclic aromatic hydrocarbons, such as benzopyrenes which are carcinogenic, arsenic, soot, and mineral oil.

• Chimney Sweeps’ carcinoma, is a scrotal skin cancer caused by an environmental carcinogensoot.
• This was observed and brought to the notice of the British Parliament, and the Chimney Sweepers Act was introduced due to the work of Sir Percivall Pott.

2. Solar keratosis (actinic keratosis): Prolonged exposure to sun rays may cause hyperkeratosis of the skin (solar keratosis). Skin changes occur due to the accumulated effect of ultraviolet rays over a period of many years. Ultraviolet rays are also present in phototherapy used to treat psoriasis (PUVA therapy—Psoralen Ultra Violet-A).

• Common sites: Back of hands, face, rim of ears.
• Age group: Middle age, more than 50 years.
• Clinically, the lesion is an irregular, firm, and irritating patch which is flat or raised and is better felt than seen.
• Malignancy should be suspected when the lesion becomes indurated, when a nonhealing ulcer develops, when the central crust sheds, or when regional lymph nodes are palpable.

3. Chronic scar: Squamous cell carcinoma that develops in scar tissue is called Marjolin ulcer.

• Burns scar is the most common cause, followed by a varicose ulcer scar, snakebite scar, chronic osteomyelitis scar, and lupus vulgaris (tuberculosis of face) scar.
• Marjolin ulcer differs from squamous cell carcinoma by its characteristics.

Comparison of majolin ulcer and squamous cell carcinoma

4. Radiodermatitis: An increased incidence of skin cancer was initially found in persons who worked in the radiology department. Now, the incidence is less due to the usage of protective gear. Radiation changes in the skin may vary from simple erythema to atrophy or hyperpigmentation. Later, this lesion develops into squamous cell carcinoma.

5. Bowen’s disease is an intraepidermal carcinoma. Chronic solar damage, inorganic compounds, and human papillomavirus (HPV)-16 are possible aetiological factors. It is rare and occurs in middle-aged patients.

• It occurs on the skin of the trunk as scaly, erythematous plaques, which are often multiple.
• They are brownish patches with raised margins. Microscopically, large clear cells are found (these cells are also found in Paget’s disease of the nipple). Topical application of 5-FU and/or imiquimod is an effective treatment.

6. Leukoplakia.

7. Autosomal recessive disorders: In this group, one or more of the DNA repair enzymes are defective or deficient. As a result, sites exposed to the sun are vulnerable to the development of various skin cancers.

• Xeroderma pigmentosum and albinism increase the risk of skin cancer. Muir-Torre syndrome, dystrophic epidermolysis bullosa, Werner syndrome.
• Nevoid basal cell carcinoma and Li-Fraumeni syndrome are the other genetic syndromes with skin cancers.

8. Immunosuppression:

• Squamous cell carcinoma develops in 50% of patients within 20 years of organ transplantation due to immunosuppression. Skin cancer is the most common neoplasm after solid organ transplantation.
• Patients with lymphoma, leukaemia, and autoimmune diseases on treatment may also develop skin cancers.
• 30% may be aggressive

Basal Cell Carcinoma (Bcc) Or Rodent Ulcer

It is the most common malignant skin tumour. It arises from basal cells of the pilosebaceous adnexa and occurs only on the skin. Generally, it is a slow-growing neoplasm which may present as an ulcer of a chronic (many years) duration.

• Metastasis and death from this disease are extremely rare. In some cases, it may present as a locally penetrating, ulcerative, and destructive lesion.
• The majority of lesions are found on the face, above a line from the lobule of the ear to the angle of the mouth.

Basal Cell Carcinoma Common Sites

• Inner canthus of the eye, outer canthus of the eye, eyelids, bridge of the nose.
• Around the nasolabial fold. These sites are the areas where tears roll down. Hence, BCC is also known as tear cancer cell carcinoma.
• Naevoid basal cell carcinoma syndrome (NBCCS): Gorlin syndrome is an inherited medical condition with multiple body systems which are defective, such as the skin, nervous system, endocrine system, eyes, and bones.
• Inborn kyphoscoliosis and anomalies in the ribs may be present. Other lesions are ovarian fibroma and odontogenic tumours.

A brother and sister with xeroderma pigmentosum developed 33 and 26 skin malignancies respectively which included basal cell carcinoma, squamous cell carcinoma and malignant melanoma, from the age of 5 to 22 years.

• Eventually, the boy died at 22 years of age. This is the sad part of this distressing and frustrating disease.
• I have not seen this girl for 20 years now.

Basal Cell Carcinoma Precipitating Factors

• Ultraviolet (UV) rays: Broad-spectrum short-wavelength UVB radiation (290–320 nm) also called sunburn rays are probably responsible for basal cell carcinoma. Basal cell carcinoma is common in Australia1 and New Zealand because of this reason. The latent period between skin damage and to development of BCC is about 20 years.
• Fair skin is vulnerable to the development of basal cell carcinoma.
• Arsenic, which was once used in skin ointments, also increases the risk of basal cell carcinoma.

Basal Cell Carcinoma Clinical Features

• The most common clinical presentation is an ulcer that never heals. Sometimes, healing takes place with scabbing, which later breaks down and forms an ulcer again. The ulcer has a raised and beaded edge, maybe indurated, and bleeds on the touch.
• The base may be subcutaneous fat or deeper structures, like muscle or bone, depending on the level of invasion.

When the lesion is big, it is called a rodent ulcer.

It may also present as a painless, firm, nodule, which is pigmented with fine blood vessels on its surface.

• Basal Cell Carcinoma: Types
• • Nodular: Nodulocystic or noduloulcerative—70%
  • Pigmented
  • Superficial: Occurs on the trunk
  • Cystic
  • Infiltrative
  • Basosquamous: Rare
• It may be present in a noduloulcerative form.
• Rarely, it may be a nodulocystic variety, which does not show fluctuation.
• Field fire rodent ulcer is a rapidly growing rodent ulcer, with destruction and disfigurement of the facial skin. It has an advancing edge with a healed, central scar.
• The more aggressive, infiltrative form is the morphea form, and the more common form is the noduloulcerative form. Less aggressive: Nodular, superficial and micronodular, basosquamous.

Basal Cell Carcinoma Differential Diagnosis

• Keratoacanthoma: It occurs only over the face. The edge may be raised with ulceration, resembling basal cell carcinoma.
• Sclerosing angioma
• Malignant melanoma: Pigmented basal cell carcinoma may be mistaken for malignant melanoma.
• Squamous cell carcinoma

Basal Cell Carcinoma Spread

• It spreads by local invasion. Even though it is slow growing, it slowly penetrates and destroys the deeper underlying tissues, such as bone, cartilage, or even the eyeball (hence, the name rodent ulcer). It does not spread by lymphatics because of its large tumour emboli. Blood spread is extremely rare.
• Morpheaform BCC synthesises type 4 collagenase and, therefore, spreads rapidly. A white scar-like growth pattern is seen in the morphea form variety.

Basal Cell Carcinoma TNM Staging

Skin cancer other than melanoma

• T1 – Tumour <2 cm in greatest dimension with less than 2 high-risk features
• T2 – Tumour >2 cm in greatest dimension (or) tumour of any size with 2 or more high-risk features.
• T3 – Tumour invasion of the maxilla, mandible orbit or temporal bone.
• T4 – Tumour with invasion of skeleton or perineural invasion of skull base
• N0 – No regional lymph nodes
• N1 – Metastasis in a single ipsilateral lymph node <3 cm
• N2 – Metastasis in a single ipsilateral lymph node >3 cm but <6 cm; or B/L or contralateral lymph nodes none >6 cm in greatest dimension
• N3 – Metastasis to lymph node >6 cm in greatest dimension
• M0 – No metastases
• M1 – Distant metastases

Basal Cell Carcinoma Investigations

Wedge biopsy from the edge of the ulcer. The edge is selected for the following reasons:

• The edge is the growing part, so malignant cells are numerous
• The centre has slough or scabs, which may not reveal malignancy
• Comparison with normal skin is possible

Basal Cell Carcinoma Histology 

Histology  Types:

1. Basosquamous,
2. Morpheaform,
3. Adenoid,
4. Infiltrative.

• Microscopic Picture
• • The central mass of polyhedral cells
  • Cells are darkly stained
  • With peripheral palisade layer of columnar cells. Cell nests, keratinisation and mitotic figures are absent.

Basal Cell Carcinoma Treatment

Surgery followed by reconstruction is the main line of treatment.

1. Surgery is indicated when the lesion is very close to the eye, adherent to cartilage or bone, in easily accessible sites, such as the neck or hand and in radiation failure cases. Wide excision is done in all cases:

• This means excision of the growth with at least 3–4 mm of healthy margin all around, including at the base.
• The resulting defect is closed by:
• • Primary suturing of the defect if the lesion is small.
  • Skin grafting if the defect is big, as in the neck or the dorsum of the hand.
  • Rotation flaps in the face for a better cosmetic effect.

Mohs’ micrographic surgery: It is a special surgical technique which involves the excision of skin cancer under microscopic control. It minimises the chance of recurrence and maximises the conservation of the surrounding normal tissue.

• The technique offers a complete evaluation of the lateral and deep margins of the tumour site.
• This procedure gives better cosmetic results since only a minimal amount of normal tissue is removed.
• Indications for Mohs’ procedure are:
• • Centrofacially located tumours
  • Large tumours, poorly defined tumour margins
  • Lesions with perineural/perivascular involvement
  • Tumours at the site of prior radiation therapy
  • Tumours in the setting of immunosuppression
  • High-risk histological subtype of BCC
  • Recurrent lesions

2. Radiation is indicated in elderly patients who have an extensive lesion requiring a complicated plastic reconstruction. Dosage: 4000–6000 cGy units. Radiation chondritis and osteitis are the complications.

3. Other forms of treatment

• Small and superficial: Curettage with electrodesiccation.
• Liquid nitrogen for tumours <1 cm in diameter.
• CO₂ Laser in Basal Cell Carcinoma
  • Useful in superficial BCC that are confined to the epidermis and papillary dermis.
  • At least 4 mm surrounding healthy skin should be removed.
  • For patients with multiple tumours or with hereditary Gorlin’s syndrome—laser is very useful.
  • Acts by superficial vaporisation.
  • Pathological margins cannot be examined.
  • Indication in high-risk BCC—large (>2 cm), located near the eye, nose, and ear.
  • Precancerous or low-grade BCC.

Flaps and Reconstruction Following Tumour Excision

1. Healing by secondary intention: Simplest method: Suitable only if the defect is <1 cm, superficial, and located in a cosmetically inconspicuous site.

• Disadvantage: Not always cosmetically acceptable; may result in contour irregularity, distortion of surrounding structure, and unstable coverage.

2. Primary closure: In the majority of cases, this is possible. Simple, but the defect needs to be small. Possible only if excessive tension and distortion can be avoided.

3. Skin graft:

• A skin graft does not look like normal skin but provides a good skin cover.
• Cannot be used across a joint. Cosmetically acceptable, but does not give colour and contour match. Preferred if the patient has a high risk of local recurrence, such as in malignant melanoma. Two types of skin grafts: Split and full-thickness grafts.
• Skin grafts will not take on in the following situations: Cortical bone without periosteum, Cartilage without perichondrium, tendon without paratenon and in irradiated tissues.

4. Commonly used skin flaps:

• Rotation flap: It is a semicircular flap of skin and subcutaneous tissues which rotates about a pivot point into the defect to be closed. A small triangle of skin may be removed to facilitate rotation.
• Advancement flap: The defect is closed by stretching the skin. It may be a single, double, or V-Y advancement flap. V-Y flap is an example: Good for defects on the medial cheek and ala of the nose. The V-shaped incision is made and then advanced to cover the defect, which is later sutured in a ‘Y’ shape.
• Transposition flap: Bilobed and rhomboid flaps are a few examples. A rectangular piece of skin and subcutaneous tissue is rotated. Types of transposition flap are:

1. Banner flap: Provides excellent contour and a reasonable colour match. It can only be used for small defects.
2. Bilobed flap: The banner flap uses a single lobe. In this flap, however, two lobes are created and then rotated. It is used when the defect is too large enough to be closed with a banner flap, especially useful in the area around the nose. It produces a conspicuous scar and is less desirable than a banner flap.
3. Rhomboid flap: Geometric modification of the banner flap. It may be used for medium-sized defects.

5. Complex flaps: Pectoralis major myocutaneous flaps and radial artery-free flaps are complex flaps used for reconstruction.

Reconstruction Options For Lips

The most important factor that dictates reconstruction is the amount of remaining lip vermilion.

• Primary closure for small defects
• Vermilion advancement flap
• Abbe flap: Mainly used for the upper lip. It is harvested based on the labial artery. It provides a good cosmetic effect. It causes minimal loss of function in the lower lip. Modification of the Abbe flap, like the reverse Abbe flap, may also be used for lower lip defects.
• Estlander flap: It is a type of rotational flap from the upper lip to the lower lip. It produces a round commissure and loss of the normal taper of vermilion.
• ebster-Bernard flap: It is a medial advancement of cheek tissue to create a new lower lip. It gives a good result. Disadvantage: Results in significant facial scarring.
• Very large lower lip defects may also be closed with a ‘double central severe Abbe’s flap’ or bilateral Karapandzic flap.

Squamous Cell Carcinoma (Scc) Or Epithelioma

It is the second most common malignant skin tumour, after basal cell carcinoma. It arises from the prickle cell layer of the Malpighian layer of the skin. It usually affects elderly males. All the premalignant conditions listed earlier apply to this condition as well. It may also occur de novo.

• Basosquamous carcinoma is the term applied to squamous cell carcinoma arising in a preexisting basal cell carcinoma. It is interesting to note that a variety of names have been given to squamous cell carcinoma, based on its site.
• Also summarizes the typical sites of SCC, in terms of skin, mucous membrane, and junction involvement.

Sites of squamous cell carcinoma

Typical sites of squamous cell carcinoma

Squamous Cell Carcinoma Pathological Types

• Ulcerative variety—most common
• Proliferative growth—cauliflower-like
• Ulcero-proliferative

Squamous Cell Carcinoma Clinical Features

• Most lesions are preceded by actinic keratosis. Such lesions grow slowly and are locally invasive without metastasis. If not from keratosis, the lesion is aggressive and metastatic.
• Typically, it is an ulcerative or cauliflower-like lesion.
• The edge is everted and the base is indurated and it may be subcutaneous tissue, muscle or bone. The floor contains cancerous tissue which looks like granulation tissue. It is pale, friable, and bleeds easily on the touch.
• The surrounding area is also indurated.
• Mobility is usually restricted, due to infiltration of the underlying structures. In very early cases, the ulcer can be moved along with the skin over the underlying structures.
• Regional lymph nodes, such as inguinal lymph nodes (both vertical and horizontal groups), may get enlarged when squamous cell carcinoma affects the lower limb or abdominal wall. Hard lymph nodes are suggestive of secondaries.

Squamous Cell Carcinoma Spread

1. Local spread occurs by infiltration into the surrounding tissues. Depending on the site, various structures may be involved. Some examples are:

• Tendon involvement in the dorsum of the hand.
• Muscle involvement in the abdominal wall.
• Bone involvement (for example. the tibia is involved in carcinoma developing in a varicose ulcer or mandible in carcinoma cheek).

2. Lymphatic spread is the chief mode of spread, though it occurs relatively late. Regional nodes are involved first.

• Nodes which are soft to firm and tender are due to secondary infection.
• Nodes which are hard, non-tender, with or without fixity are due to secondary deposits.
• In untreated cases, nodes start ulcerating through the skin and result in bleeding and pain.
• As already stated, nodes are not involved in Marjolin ulcer.

3. Blood spread is rare and late.

Squamous Cell Carcinoma Differential Diagnoses

Various benign skin lesions may look like squamous cell carcinoma in early cases.

• Differential Diagnosis
• • Basal cell carcinoma: Typical sites
  • Keratoacanthoma: Benign self-limiting
  • Papilloma : Benign lesion
  • Pyogenic granuloma: Painful, short duration
  • Tuberculous ulcer: Uncommon

Squamous Cell Carcinoma Investigations

• A wedge biopsy from the edge of the ulcer or growth is taken. The main reason is that the edge is the most proliferative area in malignancies. However, in proliferative lesions, punch biopsy may also be taken.
• Microscopic picture: 80% of these cancers are well differentiated, characterised by a central, structureless mass of keratin, surrounded by normal-looking squamous cells arranged in concentric manner like onion skin.

This appearance is known as an epithelial pearl or cell nest. In 20% of cases, cells are undifferentiated with numerous mitoses and without keratinisation.

• Broder’s Classification
  • Well-differentiated – 75% keratin pearls
  • Moderately differentiated – 50% keratin pearls
  • Poorly differentiated – 25% keratin pearls
  • Anaplastic – <25% keratin pearls

Squamous Cell Carcinoma Treatment

Treatment of the primary: Epithelioma is treated by wide excision or radiotherapy.

1. Surgery: It is indicated when the lesion is small and superficial, a lesion involving deeper tissues, such as muscles, cartilage, or bone or in radio-recurrent cases.

• Excision involves the removal of the growth along with 1 cm of normal healthy tissue from the palpable, indurated edge of the tumour in high-risk cases.
• In low-risk patients, lesions may be excised with a 4–6 mm margin. After wide excision, the defect may be closed with a split skin graft or with a flap to reconstruct the part, depending on the extent of resection.
• If the growth is fixed to the tibia, growth can be removed with the involved periosteum followed by radiotherapy. One attempt should be aimed at preserving the limb. If it recurs then below knee amputation is performed.

2. Radiotherapy: Is indicted for the following reasons

Primary

1. Patients unable or unwilling to undergo surgical treatment for the primary
   lesion
2. Clear margins cannot be obtained by surgery
3. Adjuvant treatment
4. Histologically aggressive (e.g. perineural invasion)
5. High grade
6. Bone invasion
7. Lymph nodes—adjuvant or palliative intent

Treatment of the metastasis in the lymph nodes

• In about 20% of patients, enlarged regional nodes are due to secondary infection. In all such suspected cases, ultrasound-guided FNAC is done. If found negative, treat the primary. Once the primary is treated and antibiotics are administered, lymph nodes may regress. During follow-up ‘wait and watch policy’ is observed.
• If the lymph nodes are positive for malignancy, radical block dissection is done. Thus, squamous cell carcinoma of the leg requires inguinal block dissection. If lymph nodes are hard and fixed to the femoral vessels, chemo-radiotherapy is given first.
• combinations of cisplatin with 5-fluorouracil (5-FU), doxorubicin, or bleomycin have been used. Radiotherapy dose is 3000–4000 cGy units over 3–4 weeks, 200 units/day.
• Lymph nodes may regress following chemoradiotherapy and block dissection is done.
• Even in advanced fungating lesions, the response rate to radiotherapy is reasonably good. Dose: 3000 to 4000 cGy units over 3 to 4 weeks 200 units/day.

Structures Removed in Inguinal Block Dissection.

• The superficial group of nodes consists of a horizontal chain which lies below the inguinal ligament and a vertical chain which lies along the upper 5–6 cm of the long saphenous vein (these two groups of nodes form the letter T).
• The deep glands are located along the proximal end of the femoral vein and one lies within the femoral canal.
• Fat, fascia, and lymphatics are cleared from 2 cm above the inguinal ligament up to 2 cm below the saphenofemoral junction. The medial clearance is important up to the femoral canal. Around 8–10 cm of the long saphenous vein near its termination is removed to facilitate lymph node clearance.
• The saphenous vein may be preserved if nodal tissue is removed from the vessel circumferentially; otherwise, it is sacrificed.
• Cloquet’s node is sent as a separate specimen for frozen section examination.

Complications Of Inguinal Block Dissection And Treatment

• Wound infection → Broad-spectrum antibiotics
• Lymphorrhoea → Adequate drainage
• Haemorrhage → Perfect haemostasis
• Flap necrosis → Edges to be trimmed. At surgery Avoid sharp corner
• Femoral blow-out → Dangerous complication. Sartorius muscle slide to cover femoral vessels at the end of surgery should be done.

Summary of the Treatment of Squamous Cell Carcinoma

Prognostic Factors of SCC

• • Invasion: Deeper the lesions or SCC less than 2 mm, metastasis is unlikely. If it is greater than 6 mm—15% SCC may have metastasised
  • Broder’s grade is higher: Worse prognosis
  • Site: Lip and ear—high chances of recurrence
  • Immunosuppression: Poor prognosis
  • Perineural involvement: Worse prognosis

This patient with large epithelioma was examined by the postgraduate student and he offered the correct diagnosis. However, he did not examine the inguinal region. The groin had 3–4 hard nodes. He failed the examination.

Melanocytic Tumours

Simple Melanocytic Tumours

• As the fetus develops, melanocytes migrate to different parts of the body, such as the skin, meninges, mucus membrane, eyes, etc.
• Pigmented naevi are composed of modified melanocytes derived from the neural crest. All naevi have excess melanin pigmentation which makes them tanbrown or black in colour. They are located in the basal layer of the epidermis and are benign. They are of the following types:

1. Junctional naevus: Located within the epidermis at the dermo-epidermal junction. They are common in children. They appear as tan-brown to black macules. They are smooth, flat, and hairless moles.

• As they enlarge, they become slightly raised and may evolve into an intradermal or a compound naevus.
• It has no malignant potential. Junctional naevi commonly occur over the palm, sole, digits, and genitalia.

2. Compound naevus: As the mole enlarges, naeval cells also appear in the dermis along the intraepidermal cells. Such moles are described as compound naevi. These are typically found in adolescents and are usually benign.

3. Intradermal naevus: It is the most common mole in adults. Because of its deep-seated nature, it appears blue (hence, the name blue naevus). It is seen over the scalp and face. It contains hair and does not become malignant.

4. Spitz naevus: Commonly occurs over the face and legs. It grows rapidly initially and then remains static. It appears as a reddish-brown nodule and is occasionally deeply pigmented.

5. Spindle cell naevus: Occurs in women, commonly over the thigh. It has malignant potential.

6. Congenital pigmented naevus: It is present at birth, and has a greater potential for malignant change. It may involve extensive areas of the skin (giant).

• Giant congenital pigmented naevus (GCPN) or giant hairy naevus (>20 cm size)
• It is an example of a hamartoma of naevomelanocytes. It involves extensive areas of the skin.
• Naevus cells are present not only in the epidermis but also in the subdermal fat and muscle.
• The risk of malignant melanoma is about 10%.
• Malignant melanoma tends to be axial.
• Removal is performed for aesthetic and oncological reasons.

7. Dysplastic naevi are different from acquired naevi in the following ways:

• Malignant potential is more.
• Family members may have such lesions.
• Such a syndrome is described as familial dysplastic naevus syndrome.

Malignant Melanoma (Melanocarcinoma)

It is a malignant tumour arising from pigment-forming cells (melanoblasts) which are derived from the neural crest. Melanoblasts and melanocytes convert dihydroxyphenylalanine (DOPA) into melanin. This is known as a positive DOPA reaction.

• It is a potentially curable tumour in its early stages. If it is left untreated or is not treated properly, it disseminates rapidly, showers the body with tumour emboli, and offers a very painful death.
• Some interesting ‘mosts’ about malignant melanoma are listed.

Positive Dopa Reaction

Interesting ‘Most’ for Malignant Melanoma

• The most benign form of melanoma is lentigomaligna melanoma.
• The most common form of melanoma is superficial spreading melanoma.
• The most malignant type of melanoma is nodular melanoma.
• The most reliable independent prognostic indicator in malignant melanoma is tumour thickness based on the Breslow classification.
• Most of them (the majority) arise from pre-existing moles.
• Most of the melanomas are pigmented. However, pigmentation is not mandatory for the diagnosis of melanoma.

Common Sites of Malignant Melanoma

• Head and neck: 20–30%
• Lower extremity: 20–30%
• Trunk: 20–30%
• The remaining cases occur in the upper extremities, genitalia, and choroid of the eye.

Malignant Melanoma Aetiopathogenesis

• Risk Factors for Developing Malignant Melanoma
  • Pigmentosa xeroderma
  • Immunocompromised—HIV, Hodgkin’s disease treated with cyclosporin
  • Genetic—History of dysplastic naevus
  • Melanoma excised earlier
  • Early childhood burns and eyes blue, red hair
  • Naevus: GCPN and total number >20 naevi
  • Tendency to freckle
  • Remember as PIGMENT

1. Ultraviolet rays: It is more common in white-skinned people. There is a linear correlation between the intensity of exposure to sunlight and malignant melanoma in white-skinned people. White-skinned people who live close to the equator have an increased risk of developing malignant melanoma.

• The highest incidence is found in Queensland (Australia). For the same reason, malignant melanoma is common in the United Kingdom, North America and Australia.
• Ultraviolet A (UVA) rays have a long wavelength and deep penetration, causing tanning and wrinkling.

2. Age and sex: Malignant melanoma is more common in females. The higher incidence of the disease is found during the reproductive age period. Even though oestrogen and progesterone receptors are found in malignant melanoma in some patients, their true role is not yet established.

• The leg is the most common site in females. The incidence of melanoma is 1.7 times higher in women than men <39 years of age.
• After 70 years of age, the incidence of melanoma is 2.2-fold higher in men than women.

3. Genetic factors: Tumour suppressor gene mutation 9p21, Deletion or rearrangement of chromosomes 10 and 8p. Familial, atypical, multiple, mole, melanoma syndrome—previously known as familial, dysplastic naevus syndrome.

• Multiple, large (> 5 cm) atypical dysplastic nevus in areas covered by clothing is characteristic.
• The disease is also common in individuals of the Celtic race who have a family history of malignant melanoma (3–5%).

4. Pre-existing mole: Approximately 2/3rd of melanomas arise in a pre-existing mole, and the remaining 1/3rd arise de novo. Malignant change occurs in the junctional or compound naevus.

• Malignancy should be suspected when certain changes occur in a mole.
• Patients with atypical mole, large naevus in those with red hair, blue eyes, and Fitzpatrick skin type are predisposed to malignant melanoma.

Glasgow—Check List

1. Change in size
2. Change in shape
3. Change in colour
4. Inflammation
5. Crusting, ulceration, bleeding
6. Sensory change
7. Diameter >6 mm

5. Immunosuppression: Increased incidence of malignant melanoma has been found in patients with renal transplantation, leukaemia, and AIDS.

6. Xeroderma pigmentosum and albinism patients are susceptible to melanomas.

Malignant Melanoma Pathology

Microscopic picture: Anaplastic, pigment-laden melanocytes confined to the epidermis. The cells which have vacuolated cytoplasm (Paget’s cells resembling those seen in Paget’s disease of the breast) are found.

• Cells also invade the dermis. Along with pigment-laden macrophages, dermal infiltration of lymphocytes1 may be present. Rarely, anaplastic melanocytes do not form pigment (amelanotic melanoma).
• All melanomas (except nodular) show radial growth initially, in the form of intraepidermal growth.
• However, nodular melanoma has a vertical growth phase, which involves the dermis and results in nodule formation. This has a poor prognosis.

Pathological Grading of Malignant Melanoma

Breslow described staging depending on the maximum thickness at the centre of the lesion.

• Stage 1: Thickness <0.75 mm
• Stage 2: 0.76–1.5 mm
• Stage 3: 1.51–3.0 mm
• Stage 4: >3 mm
• <1 mm is regarded as thin melanoma.

Malignant Melanoma Clinical Types

Clinical types of malignant melanoma

Malignant Melanoma Clinical Features

• Malignant melanoma may present as changes in the pre-existing mole.
• ABCDE of Evaluating a Changing Mole
  • An Asymmetry: One half does not match the other
  • B Border irregular: Ragged or blurred
  • C Colour variation: Tan, black, brown
  • D Diameter: >6 mm
  • E Evolving (elevation): Change in a pre-existing lesion
• The patient may present as a nonhealing ulcer of the sole of the foot.
• It is a painless ulcer with irregular borders. Ulcer bleeds easily on touch.
• The lesion is firm in consistency and induration is absent. A halo may be present around the ulcer.
• Ugly duckling sign: A lesion that stands out as different from the patient’s own nevi
• Typically, the ulcer is pigmented. In 10% of patients, pigment is absent. They are called amelanotic melanoma.
• The lesion moves with the skin and is usually not fixed to underlying structures.
• Satellite nodules (within 5 cm of the primary) may be found surrounding the lesion and are due to intradermal lymphatic spread. Such patients will have greatly enlarged, firm, non-tender nodes.
• In-transit lesion—disease found in the dermis or subcutaneous tissue >5 cm away from the primary melanoma, but before the regional lymph node basin.

The acral lentiginous variety

• Acral Lentiginous
• Least common subtype
• Popularly called hand and foot melanoma
• Occurs in the palms and soles
• This subtype occurs in dark-skinned people (21–22%)
• In subungual region—blue-black discolouration of posterior nail fold (most common on great toe or thumb)
• Pigmentation in proximal or lateral nail folds (Hutchinson’s sign) due to radial spread

Amelanotic Melanoma

The lesion appears pink. It has a poorer prognosis than nodular melanoma.

Amelanotic Melanoma Differential Diagnosis

• Pigmented basal cell carcinoma, histiocytoma (sclerosing angioma)
• Naevus, Kaposi’s sarcoma, cavernous haemangioma.

Amelanotic Melanoma Spread

1. Local spread occurs mainly by continuity and contiguity. Satellite nodules are due to local and lymphatic spread, situated within 5 cm of the primary lesion.

• Malignant melanoma rarely infiltrates the deep fascia unless and until a ‘blunder biopsy’ is done.
• Inadequate local excision may result in local recurrence later. Hence, initial surgery should attempt to achieve a cure.

2. Lymphatic spread is the principal mode of spread. Regional nodes get involved very early, altering the prognosis. Thus, nodes may get very enlarged even when the lesion looks innocent.

• Spread occurs by both permeation and embolisation. Permeation produces satellite nodules and in-transit nodules which develop between primary and secondary. Embolisation occurs rapidly, producing massive regional nodes early.
• In-transit metastases appear in the skin as intracutaneous metastases. They are thought to be due to melanoma cells trapped within lymphatic vessels.

Malignant Melanoma Sole

Lymph Node Metastasis in Malignant Melanoma

• It is the single most important prognostic index and it presents stage 3 disease.
• Number of nodes is more important than size of nodes.
• Poor survival in ulcerated malignant melanoma, even if node-negative.
• The extranodal extension has a poor prognosis.
• Lymph node metastasis proceeds as an orderly process. Thus, the concept of the first node to get involved—sentinel node (SN).
• Elective lymphadenectomy is not indicated in thin melanoma (1 mm).
• In thick melanoma, do a sentinel node biopsy. If positive, proceed to
  complete lymphadenectomy (block dissection).

3. Blood spread occurs relatively early and causes secondaries in the liver, lungs, brain, and bones, producing miserable, pathetic situations.

Spread of malignant melanoma

A 55-year-old lady presented to the hospital with enlarged inguinal lymph nodes. Clinical examination revealed nodules in the leg with firm to hard enlarged nodes in the inguinal region. On careful observation, the little toe was missing. On questioning, the patient admitted that the toe had been amputated elsewhere five years back for a painless, blackish lesion.

Amelanotic Melanoma Staging

Definition of regional lymph node (N)

Definition of primary tumour (T)

Clinical Staging

Definition of distant metastasis (M)

Important Changes In The New AJCC Staging Of Malignant Melanoma

1. Thickness and ulceration in T-category rather than level of invasion.
2. Number of metastatic nodes is more important.
3. LDH (details are given later) is included in the ‘M’ category (metastatic spread).
4. If there is ulceration, 3 stages are upgraded.
5. Satellite nodules and in-transit deposits are grouped into stage 3 disease.

Cutaneous Melanoma American Joint Committee On Cancer (Ajcc 8th Edition) 4 Stages

• Stage 0: In situ carcinoma.
• Stages 1 and 2: Primary tumours confined to the skin without regional lymph node involvement— depending on the thickness (depth) of the tumour, and the presence or absence of ulceration of the overlying epithelium.
  • Stage 1A: <0.8 mm thick, NO ulceration
  • Stage 1B (T1B): <0.8 mm thick with ulceration or 0.8–10 mm thickness ± ulceration
  • Stage 1B: T2a or Stage 2: >10 mm thick with any features
• Stage 3: With clinical or pathological evidence of regional lymph node + OR the presence of in-transit or satellite metastases.
• Stage 4: Disease is defined by the presence of distant metastasis—biopsy proven.

Cutaneous Melanoma Investigations

1. Blood tests such as haemoglobin, total RBC, and WBC counts are done. Lactic dehydrogenase (LDH) has been included under the M (Metastasis) category.

• LDH represents a strong prognostic factor in unresectable, metastatic (stage IV) melanoma.
• Levels >500–1000 U/L suggest a high tumour burden. LDH which is present in the normal cells gets released when the cells are destroyed by the tumour.

2. A chest X-ray is taken—if it shows metastasis, it is a stage 4 disease. However, a negative chest X-ray does not rule out metastasis.

3. Biopsy: A full-thickness biopsy of the lesion with a narrow (1 to 2 mm) margin of grossly normal skin is made. The depth of excision should include the full thickness of the dermis and, thus, should extend into the subcutaneous tissue.

• Accurate measurement of tumour thickness is important because it is critical for the prognosis and affects surgical recommendations. Incision biopsy is indicated only in advanced lesions.
• Once the specimen is removed, the following details have to be studied—Breslow thickness, ulceration, dermal mitotic rate, microsatellitosis, pure desmoplasia, and deep and peripheral margin status.
• In subungual melanomas, a biopsy may be taken after removal of all or a large part of the nail and one or more punch biopsies of the base of the nailbed.

4. Imaging: Ultrasound abdomen is economical and easily available. The presence of iliac or para-aortic lymph nodes and secondaries in the liver can easily be made out. However, in all cases of stage 3 melanomas (lymph nodes positive), a contrast-enhanced CT scan of the chest and abdomen should be done.

5. PET with fluorodeoxyglucose (FDG): It is used for staging patients with advanced melanoma, but its role in earlier stages is unclear because it is expensive and associated with substantial radiation exposure.

6. FNAC of the lymph nodes: Clinically palpable lymph nodes may be subjected to ultrasound-guided aspiration. In melanoma, even a palpable lymph node is enough to decide about block dissection.

7. Genetic: Melanocyte protein, also known as melanosome protein (PMEL), is a protein that is encoded by the PMEL gene. This may be used as a specific immunohistochemical marker for melanoma.

Cutaneous Melanoma Treatment

Surgery is the main treatment modality for malignant melanoma. All other modalities are only palliative and supportive. In early stages without lymph node enlargement and the tumour with good histology, it is still a curable cancer. Surgery can be divided into treatment of the primary lesion and metastatic lymph nodes.

Treatment of the Primary

1. Excision biopsy-wide excision: A small lesion of 1 mm may be excised even under local anaesthesia with 1 cm of healthy margin around (narrow excision). The defect may be closed by primary suturing.

• While excising the tumour, it is better not to handle the tumour. It is possible to remove the tumour by strictly adhering to the principle of the ‘No touch’ technique. Wide excision is based on the principle of ‘centrifugal spread of melanoma.’ One of the causes of recurrence is inadequate excision.
• Desmoplastic melanoma: Has a high rate of recurrence; hence, a wide margin of excision is required.

2. Subungual malignant melanoma is treated by amputation of the digit.

3. Amputation (advanced and large lesions).

4. Malignant melanoma of the choroid has a good prognosis. The choroid does not have lymphatic drainage.

However, metastasis may occur through the haematogenous route even after many years. It is treated by enucleation of the eye.

Treatment of Lymph Nodes

1. If lymph nodes are situated adjacent to the primary lesion, block dissection is done along with the primary lesion in continuity to include ‘in-transit’ deposits.

2. If lymph nodes are away, radical block dissection is done. Example: For a lower limb malignant melanoma, inguinal nodes along with the iliac nodes are removed (ilioinguinal block dissection).

• If these groups of nodes are positive on the frozen section, lymph node clearance should include lymph nodes of obturator vessels (ilio-obturator block dissection), or if the pelvic CT scan is positive or the Cloquet node is positive, the obturator group of lymph nodes is removed.
• To get the best results if facilities are available sentinel lymph node mapping is done. Depending upon the results of the findings, lymph node dissection is done. Details are given below.

Sentinel lymph node mapping: Isosulfan blue is injected intradermally and the node that gets stained is identified and sent for frozen section (haematoxylin and eosin stains and immunohistochemical technique).

• If the node is positive, regional lymphadenectomy is done even if the nodes are clinically not palpable. At least 20–30% of patients who are in stage 1 will be identified as stage 3 after sentinel node biopsy (SNBx).
• There is a definite survival advantage in patients who undergo SNBx and regional lymphadenectomy when the nodes are not palpable.

Types of lymph node dissections:

• If sentinel node biopsy is negative, prophylactic block dissection is indicated only if the melanoma has poor prognostic histological factors.
• If lymph nodes are positive after FNAC: TLND— therapeutic lymph node dissection is done.
• In patients with no clinical lymph nodal metastasis but ELND—elective or prophylactic lymph node dissection is beneficial. In cases of 1–4 mm thick melanoma, melanoma without ulceration, extremity melanoma, patients <6 years of age. In these patients, only 25% of patients show occult metastasis.

Summary of skin tumours

Stagewise Treatment (More Details) And Recent Advances

Surgery in the form of wide excision is the most important curative treatment in stage I and stage 2B. Other various forms of treatment are available.

Stagewise Treatment Clinical Tisnomo, Stage 0 Clinically Localized Melanoma Or Melanoma In Situ

Melanoma in situ by definition is not invasive or metastatic. However, metastatic melanoma to regional nodes has been observed occasionally from melanoma in situ with histologic evidence of regression.

• Examine the nodes clinically.
• Radiological studies are not necessary.
• Wide excision alone in the majority of cases.

Principles Of Wide Excision

Full-thickness excision of skin and subcutaneous tissue to the underlying deep fascia.

• A 5 mm margin is the standard recommendation, but melanoma in situ may extend beyond its visible extent.
• Thus, if cosmetically acceptable, it is reasonable to obtain a margin of as much as 1 cm, especially if the original biopsy was incomplete.

Stage 1: Clinical T1a

1. Thin Primary Melanoma

Thin melanomas, such as T1a melanomas, are those <1 mm thick, with <1 mitosis per mm2, and without ulceration. In the absence of any clinical evidence of metastasis, these are clinical-stage IA melanomas. 5-year survival rate of 94%.

Treatment of T1A

• Wide excision with a 1 cm margin (including skin and all underlying subcutaneous tissue to the deep muscle fascia).
• The margin should be measured from the visible edge of the pigmented lesion or from the biopsy scar, whichever is larger.
• After excision, primary closure is performed. However, if on the face, palms, or feet, skin grafts or rotation flaps are used.

2. Melanomas of the Trunk and Proximal Extremities

• Wide local excisions should involve measuring the appropriate margin (usually 1–2 cm) around the entire scar from the biopsy, or
• From the visible edge of residual melanoma, and extending the incision to make an ellipse that is approximately three times as long as it is wide.

Incision or Excision Principles

• Extremities—ideally, the direction of the scar should be longitudinal.
• Over the joints, on the trunk and neck—along skin lines.
• On the upper back—it is usually best for the scar to run transversely.
• The excision should include all skin and subcutaneous tissue up to the deep fascia (but not including the fascia).
• When a major cutaneous nerve runs along the deep fascia to innervate distal cutaneous structures—preserve the nerve.
• Wide excisions can almost always be performed under local anaesthesia.

3. Clinical T2A, T2B Melanomas

• Melanomas 1–2 mm thick, with or without ulceration.
• History and physical examination—may suggest metastatic disease.
• In the absence of such findings, a very low yield of additional staging studies—hence, not recommended.
• No evidence of metastasis—wide excision with a 1–2 cm margin and SNBx.

4. Primary Melanomas of the Fingers and Toes

• Subungual melanomas of any finger or toe—amputation at the interphalangeal joint of the toe or just proximal to the distal interphalangeal joint of the finger.
• SNBx should usually be performed for melanomas of the fingers or toes if they are at least T1b lesions.

5. Sentinel Node Biopsy

• If the SNBx is negative, then the patient is pathologically staged as T2aN0M0 (stage IB) or T2bN0M0 (stage 2A).
• No additional surgical management is required, and no adjuvant systemic therapy is indicated.

Stage 2 Melanoma (T2b–T4b)

Clinical T3A Melanomas (Clinical Stage 2A)

• Melanomas 2–4 mm thick without ulceration represent T3a lesions, and in the absence of metastases, these are clinical stage 2A lesions.
• Serum LDH level: LDH is a key enzyme in the process of energy production in cancer cells. It catalyzes the conversion of pyruvate to lactate in hypoxic conditions. LDH levels are increased in response to tissue injury or during disease states. LDH may be a marker of tumour burden for advanced cancer patients.
• Wide excision with a 2 cm margin plus SNBx.

Clinical T3B Melanomas (Clinical Stage 2B)

• Wide excision with a 2 cm margin plus SNBx.
• If the nodes are negative, treat them like stage 2B (T3bN0M0).
• No additional surgical therapy is required.
• HDI (high-dose IFN α-2-b) and pegylated-interferon—postsurgical adjuvant therapy in resected stage 2B–3 melanoma.

Clinical T3B Melanomas (Clinical Stage 2B)

• Melanomas 2–4 mm thick with ulceration represent T3b lesions—clinical stage 2B.
• If symptoms suggest metastatic disease, perform imaging.
• Staging with CT scans of the chest, abdomen, and pelvis (or PET/CT scan) plus MRI scan of the brain—symptomatic cases.

Thick Melanomas (T4A, T4B, >4 mm Thick)

• Thick melanomas: A 50% risk of metastasis and mortality over 5–10 years.
• Ulceration increases this risk: T4a melanomas are clinical stage IIB, whereas T4b melanomas are clinical stage 2C.
• CT scans of the chest, abdomen, and pelvis plus an MRI of the head.
• Wide excision with ≥2 cm margin plus SNBx.
• In patients with negative sentinel nodes, adjuvant low-dose interferon (LDI) should be considered.
• If the sentinel node biopsy is positive: These are melanomas > 10 mm thick with or without ulceration.
• Subsequent management should follow recommendations given later for stage 3A melanoma (T2a with positive SNBx involving 1–3 nodes) or stage 3B melanoma (T2b with positive SNBx involving 1–3 nodes).
• Low-dose interferon alfa (LDI-α): Interferon-α-2a is approved for clinically lymph node-negative melanoma patients with a tumour thickness of ≥1.5 mm.

Stage 3 Melanoma

Regionally Metastatic Melanoma (Stage 3)

• They should be managed with a curative intent.
• Primary lesion with lymph node metastasis, satellite lesions, and in-transit metastases
• Wide excision—maximum of 2 cm margin
• Complete lymph node dissection (CLND)
• Observation or adjuvant immunotherapy with Nivolumab or BRAF mutation gene positive—Tremenitib or IFN-α

Indications for Adjuvant Systemic Therapy (Stages 2b, 2c, and 3)

• HDI—for 1 month followed by 1 year of intermediate dosing IFN for 1–2 years. Interferon—at a low dose administered for 1–3 years. Pegylated IFN was administered for a target period of 5 years.
• Interferon is administered by IV infusion, 20 million U/m2, for 5 consecutive days every 7 days for 4 weeks during the “induction” phase.
• For the subsequent 48 weeks, 10 million U/m2 are administered by subcutaneous injection on alternate days for a total of 3 doses every 7 days in the “maintenance” phase.
• The HDI is used for the treatment of stage 3 melanoma patients (6 µg/kg/week for 8 weeks then 3 µg/kg/week for up to 5 years).
• Toxicity: Fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression.

Management of Palpable Metastatic Melanoma in Regional Nodes: Therapeutic or Completion Lymphadenectomy

• Inguinal block dissection has two components: Block dissection of
• Superficial inguinal lymph nodes along the long saphenous vein (vertical) and horizontal group of lymph nodes below the inguinal ligament
• Deep inguinal node dissection: They are located medial to the femoral vein and under the cribriform fascia. There are approximately 3–5 deep nodes. The superiormost node is located under the inguinal ligament and is called Cloquet’s node.
• This node is deep to deep fascia on the medial side of the femoral vein. They are 1–3 in number. One of them may lie in the femoral canal (lymph node of Cloquet). Afferent: From the deep lymphatics of the lower limb and the superficial inguinal LNs.
• Efferent: To the external iliac LNs. Metastasis to a regional node represents stage 3 (A, B, or C) disease. It may be curable. Hence complete lymphadenectomy should be done.
• Complete lymph node dissection refers to clearing the anatomically complete dissection of the nodal basin, elective ilio-obturator dissection when inguinofemoral nodes are positive or >3 nodes are positive or when pelvic CT is positive or when Cloquet node is positive. The Cloquet node is the transitional node between the inguinal region and the iliac region.
• The lymphatic anatomy of the inguinal canal, the importance of various lymph nodes, and the types of dissection are given below.
• An iliac node dissection involves skeletonizing the external iliac vessels. It is generally combined with the removal of the iliac node-bearing tissue and the obturator fat pad (obturator dissection).

Regional Metastases: Definitions

• Local recurrence: Recurrence of melanoma in the scar from the original excision or at the edge of the skin graft (if used for closure).
• Satellite metastases: Either occur simultaneously with the original diagnosis or arise subsequent to the original excision. Typically, recurrences that are separate from the scar but within 2–5 cm of it are considered satellite metastases.
• In-transit metastases: Regional recurrences beyond 5 cm of the scar but proximal to regional nodes.
• Regional node metastases are typically in a draining nodal basin near the lesion.

1. Intratumoral Therapies

• Intralesional BCG: Regression of uninjected and injected lesions.
• Intralesional injection of melanoma metastases with an oncolytic herpes virus encoding granulocyte-macrophage–colony-stimulating factor (GM-CSF).

2. Solitary In-transit Metastasis or a Localized Cluster of In-transit Metastases

• Excision plus SNBx
• The margin of excision: 5–10 mm

3. Hyperthermic Isolated Limb Perfusion with Melphalan Infusion

• Complete responses in 60–90% of patients
• Risk of limb loss

4. Palliative Treatment of Regional Metastasis

• Radiation therapy: After surgical resection.
• Intralesional therapy with IFN, IL-2, BCG, or oncolytic replication-competent virus injections.
• Highest response rates to intralesional therapy—intratumoral IL-2, intratumoral electrochemotherapy with bleomycin or cisplatin.
• Dyes like Rose Bengal or application of diphencyprone.
• Topical treatment of superficial metastases with imiquimod.

Stage 4 Melanoma

Metastatic disease: M1a: Skin, soft tissue, remote nodes;

M1b: Visceral pulmonary and M1c: Visceral nonpulmonary. Stage 4 disease with metastasis and increased LDH is the highest risk category—Stage 4C.

1. Cytotoxic Chemotherapy and Biochemotherapy

• Biochemotherapy consisting of dacarbazine 800 mg/m2 on day 1, cisplatin 20 mg/m2 on days 1–4; vinblastine 1.2 mg/m2 on days 1 –4; IL-29 MU/m2 per day continuous4 administration on days 1–4.
• Interferon 5 MU/m2 subcutaneously on days 1–4, 8, 10, and 12; and granulocyte colony-stimulating factor 5 µg/kg per day subcutaneously on days 7–16. Biochemotherapy cycles are given every 21 days for 3 cycles (9 weeks total).

Interferon – α

• It has a stimulatory effect on natural killer cells (NK)
• It has anti-angiogenic activity
• It is toxic—weight loss and myelosuppression can occur
• IL-2—can cause capillary leak syndrome—hypotension and renal failure

2. Cytotoxic T-lymphocyte Antigen 4 and PD-1 Blockade in Adjuvant Therapy

Ipilimumab is a fully human immunoglobulin G1 monoclonal antibody that blocks CTLA4, which has demonstrated improvement in OS in the treatment of metastatic melanoma in two randomized clinical trials.

3. Interleukin-2

• 4 bolus infusion of 600,000 to 720,000 IU/ kg every 8 hours to tolerance using 2 cycles separated by approximately 10 days (maximum of 15 doses/cycle).
• Significant toxicity (but reversible).

4. Chemotherapy

• Inherent resilience of melanocytes, which have to be naturally resistant to apoptotic death when exposed to UV radiation from the sun.
• Dacarbazine, an imidazole carboxamide, is a classic alkylating agent. It is given intravenously at daily doses of 200 mg/m2 for 5 days every 3–4 weeks.
• Temozolomide is an orally available prodrug—not superior.
• Combination chemotherapy.
• 20% response for carboplatin-paclitaxel-sorafeniband, and 18% for carboplatin-paclitaxel.

5. Anti-cytotoxic T-Lymphocyte Antigen 4 Blocking Antibodies

• Inactivated tumour vaccines, dendritic cell vaccines or immune-stimulating cytokines like IFN and IL-2 are aimed at turning T cells against cancer.
• Tumour responses tend to be durable (counted in years) in most cases.
• Thus, there is interest in this mode of therapy for advanced melanoma.

6. Adoptive Cell Transfer Therapy

• Adoptive cell transfer (ACT) therapy refers to an immunotherapy approach for the treatment of cancer that involves the infusion to the tumour-bearing host of cells with antitumour activity that may recognize cancer antigens and result in the destruction of cancer cells.
• Although it is still experimental, ACT has emerged among the most effective treatments for patients with metastatic melanoma.
• 50–70% of patients with metastatic melanoma experience objective cancer regressions as per RECIST criteria when treated with ACT
• RECIST criteria: Response Evaluation Criteria In Solid Tumours. Response to the tumour or lymph nodes by chemotherapy radiotherapy or any other therapies is measured by means of a CT scan or X-rays or with callipers. A few other lesions are non-measurable such as pleural effusions, pericardial effusions, etc.

Indications to Radiotherapy

Radiation Therapy for Regional Metastasis

• Melanoma is a radioresponsive tumour and conventional and high dose per fraction schedules are equally effective clinically.
• 8.0 Gy × 4 fractions (32 Gy total) in 21 days delivered once weekly or 2.5 Gy × 20 fractions (50 Gy total) in 26–28 days delivered 5 days a week.

Adjuvant Radiation Therapy in the Management of Primary Melanoma Lesions

• Lentigo maligna: Medically inoperable, or if the proposed resection would result in a poor cosmetic outcome.
• Desmoplastic melanoma: High chances of recurrence.
• Neurotropic melanoma: Propensity to recur at the skull base by tracking along cranial nerves.
• Palliation of unresectable primary disease.

Genetic Testing And Immunotherapy

BRAF mutation test may be performed using the mutation-specific PCR tests for the use of vemurafenib, dabrafenib, or trametinib.

Melanoma Antigen Gene as in Cancer Immunotherapy

• Immunization against antigenic tumour epitopes is achieved by injecting recombinant tumour antigen protein along with an immunostimulant to induce both humoral and cellular immune responses.
• Patients receiving recombinant MAGE-A3-based vaccine will develop MAGE-A3-specific antibodies and have more clinical benefits.

Melanoma Antigen Gene (MAGE)

Modern immunotherapies mainly aim to activate immune responses by either stimulating the activities of specific components of the immune system or by counteracting signals produced by cancer cells, such as immune checkpoint modulators and immune cell therapy.

Other Malignant Skin Tumours

Dermatofibrosarcoma Protuberans

• This is a locally malignant tumour arising from the dermis.
• Common sites are the trunk and flexor region of limbs. It presents as a nodular (bosselated) ulcerative lesion of many years duration.
• Regional lymph node involvement is uncommon.
• It is less aggressive and, therefore, curable.
• Treatment is by local-wide excision, followed by primary closure or skin grafting.

Kaposi’s Angiosarcoma 

• Common among the Black population
• It arises from proliferating capillary vessels and perivascular connective tissue cells.
• Multiple, purplish nodules appear in the limb, which ulcerate and bleed. This is its characteristic feature.
• Regional lymph node involvement may occur.
• Increasing incidence due to AIDS.

Other Malignant Skin Tumours Differential Diagnoses

1. Malignant melanoma
2. Soft tissue sarcoma
3. Multiple cutaneous metastases
4. T cell lymphoma

Diseases Associated with Kaposi’s Sarcoma

• Diabetes mellitus
• Lymphoma
• Following renal transplantation
• Acute and chronic immunosuppression (HIV)

Types of Kaposi’s Sarcoma

• European: Elderly males
• African: Young and children
• Transplant: Due to immunosuppression
• AIDS: Homosexuals

Other Skin Lesions

They arise from sebaceous glands, sweat glands, hair follicles, etc. Describe types of exocrine glands.

• A few examples are syringoma, hidradenoma, trichoepithelioma, and sebaceous carcinoma.
• They present as a localised swelling and are treated by excision.
• They have to be kept in mind as a differential diagnosis for malignant skin tumours. Details of a few skin lesions are given in this chapter.

Types of Exocrine Glands

• Holocrine: Entire cell dies or disintegrates to liberate secretion, for example. sebaceous gland.
• Apocrine: Only the luminal part of the cell disintegrates, cell regeneration takes place from the nucleus and basal portion, for example. mammary gland.
• Merocrine: Secretion is discharged without the destruction of the cells. Most of the glands belong to this type.

Keratoacanthoma: Molluscum Sebaceum, Molluscum Pseudocarcinomatosum

• Self-limiting benign neoplasm of viral origin (probably).
• Arises due to overgrowth of the hair follicle.
• Subsequent spontaneous regression is characteristic.
• It is a painless swelling in the skin with a central dark brown core. After an initial rapid growth of 2–4 weeks, spontaneous regression occurs within 24 hours. After the separation of the central core, the lump diminishes in size, leaving a deep indrawn scar.
• Usually single—face is the most common site.
• Like a sebaceous cyst, it presents as a hemispherical swelling.
• It is treated by excision
• If associated with sebaceous carcinoma and visceral malignancy (colon cancer), it constitutes Muir-Torre syndrome.

Turban Tumour

• It is the blanket term used to describe a tumour occupying the whole scalp, resembling a turban.
• It is most often used to describe multiple cylindromata.
• They produce pink nodular masses.
• Diagnosis is confirmed by biopsy.
• For differential diagnoses.
• Treatment includes excision and reconstruction by skin grafting or rotational flaps.

Turban Tumour

• Very, very rare
• Types
  • Multiple cylindromata
  • Multiple nodular basal cell carcinoma
  • Hidradenomata
  • Plexiform neurofibromatosa of scalp

Corn

• It is a popular painful lesion in the plantar surface (sole) of the foot.
• It affects the plantar surface of the toes and the sole of the feet.
• It develops due to intermittent pressure over a limited area.
• Basically, it is a localised area of hyperkeratinisation with a hard central core.
• It is a cone-shaped lesion with a broad surface and is narrow at the deeper plane.
• They are painful and very tender.
• Most are hard corns.
• Soft corn may occur between the toes.

Other Skin Lesions Treatment

• Diabetic patients need to be carefully explained about the consequences of ‘mistreated’ corn. Sensations and pulsation have to be checked.
• Symptomatic corns have to be excised. Excision of a good cone-shaped tissue is necessary for permanent cure. Otherwise, recurrence may occur.

Wart

• A wart is a rough excrescence on the skin
• Papillomaviruses are responsible
• They are pigmented, keratinised, irregular lesions
• Common in young adults
• Common sites: Fingers, feet, genitalia, beard area, etc.
• Venereal warts: They are also called papilloma acuminata. They may occur in the anal region, perineum, and the coronal sulcus of the penis. Some warts may regress spontaneously. Fulguration with diathermy is the treatment.

Merkel Cell Carcinoma

• It is derived from neuroendocrine cells that function as touch receptors.
• It is a highly malignant tumour.
• Elderly white males are affected.
• Sun-affected areas (such as head and neck regions) are involved, probably due to ultraviolet rays.
• Surgery, radiation, and chemotherapy have been tried.
• Histopathological report resembles metastatic oat cell carcinoma.