"INTERNAL MEDICINE"

MALIGNANT SKIN TUMORS

Cutaneous malignancies are broadly divisible into

1. Non-melanoma skin cancer (NMSC).
2. Malignant melanoma.
3. Appendageal Skin malignancies
4. Soft tissue malignancies and
5. CTCL.

1.NON MELANOMA SKIN CANCER (NMSC)

a) Basal Cell Carcinoma (BCC)

b) Squamous Cell Carcinoma (SCC)

RISK FACTORS FOR NON MELANOMA SKIN CANCER

Environmental Factors

Host susceptibility Factors

RISK FACTORS FOR NMSC
(contd.)

Environmental factors include the following four risks:

a) Ultraviolet Radiations (including PUVA and UVB-NB therapies): Cause damage by

o Direct damage to cellular DNA.

o Production of reactive oxygen species.

o Immunosuppression

b) X-rays and thermal radiations:

o X-rays---risk for health professionals and patients.

o Thermal radiations---Kangri cancer and Erythema ab igne.

C) Chemical carcinogens:

o Tar

o Mineral oils and Cutting oils

o Aromatic Hydrocarbons

o Arsenicals

d) Human Papillom

a Virus

o Known cause of cervical and anogenital neoplasms.

o BCC in immunocompromised.

o Strains of HPV causing Epidermodysplasia verruciformis (5,8,9,12,115 17, 21-26, 36-38, 49, 50) are implicated in causation of NMSC.

HOST SUSCEPTIBILITY FACTORS

These include:

1. Familial Cancer Syndromes:

GORLIN’S SYNDROME:

o Defective gene on chromosome 9.

o Multiple BCCs. Acrocordon (s

kin tags), Keratin cysts, Epidermoid cysts, Palmoplantar pits

o Characteristic facies (macrocephaly, hypertelorism, broad nasal root).

o Mishappen or bifid ribs, Spina bifida, jaw cysts.

o Cleft lip and palate, hypogonadism, cataracts, blindness.

o Associated tumors like medulloblastoma, Ovarian and cardiac fibromas and Rhabdomyosarcomas

BAZEX DUPRE CHRISTO

L SYNDROME

X-linked recessive.

Multiple BCCs.

Follicular atrophoderma---ice pick scars on hands, elbows, feet and face.

Hypotrichosis and hypohidrosis.

ROMBO SYNDROME

Autosomal dominant

Vermiculate atrophoderma

Hypotrichosis

Milia

Trichoepitheliomas

Cyanotic discoloration of hands and lips.

In addition other familial cancer syndromes include:

Self healing Epitheliomas: Autosomal dominant, Heal itself leaving unsightly scars.

Muir –Torre Syndrome: Autosomal dominant, Combination of sebaceous neoplasms, non polyposis colonic neoplasm and NMSC.

Xeroderma Pigmentosum: Autosomal recessive, excessive susceptibility to sun burns because of impaired repair of DNA damage.

Other host susceptibility factors are:

CHRONIC INJURY AND SCARRING:

NMSC may develop in

Burns.

Discoid lupus erythematosus.

Necrobiosis lipodica.

Dystrophic Epidermolysis Bullosa

Skin fistulae.

IMMUNOSUPPRESSION:

As in renal transplant patients and those receiving prolonged phototherapy.

BASAL CELL CARCINOMA

Basal cell carcinoma (BCC) is the most common skin cancer.

It arises from the pluripotent stem cells of the basal layer of the epidermis

About two thirds of the carcinomas occur in sun-exposed areas and one third occur in non-sun-exposed areas, emphasizing the genetic susceptibility of the basal cell cancer patients.

ETIOLOGY AND INCIDENCE:

v Ancestry: Common in Australians, Irish and Scots. Uncommon in dark races.

v Light hair and eye color, fair skin, freckling and inability to tan predispose to BCC.

v Outdoor professions like farming are high risk factors.

v History of childhood sunburns and sudden severe sun damage are also predisposing factors.

v Naevi and solar elastosis add to BCC risk whereas acne appears as a protective factor.

v More common in males

MORPHOLOGICAL VARIANTS

Nodular:. Nodular BCC is the most common type of BCC and usually presents as a round, pearly, flesh-colored papule with telangiectases. As it enlarges, it frequently ulcerates centrally, leaving a raised, pearly border with telangiectases, which aids in making the diagnosis.

Most tumors are observed on the face, although the trunk and extremities also are affected.

Cystic:

An uncommon variant of nodular BCC, cystic BCC is often indistinguishable from nodular BCC clinically, although it might have a polypoid appearance.

Typically, a bluish-gray cyst-like lesion is observed. The cystic center of these tumors is filled with clear mucin that has a gelatin-like consistency.

Superficial spreading: Less common, with an irregular raised thread like border and central atrophy and scaling.

MORPHEIC /SCLERODERMIFORM

Uncommon, found usually on the face as a thickened yellowish plaque because of a lot of fibrous stroma.

Pigmented: a variant of the nodular form that may be confused with melanoma.

DIFFERENTIAL DIAGNOSIS

Melanocytic naevus.

Molluscum contagiosum

Seborrheic Hyperplasia

Viral Warts.

Keratoacanthoma.

SCC.

Malignant melanoma.

Eczema.

Psoriasis.

Bowen’s disease

Morphea.

TREATMENT

A. MEDICAL CARE

Some superficial cancers respond to local therapy with 5-flourouracil.

Topical treatment with 5% IMIQUIMOD cream, with 5 applications per week for six weeks has a reported 70 - 90% success rate at reducing, even removing the BCC. Imiquimod may be used prior to surgery to reduce the size of the carcinoma.

B. SURGICAL CARE

Common methods are "electrodessication and curettage“ and “cryosurgery”.

Surgical excision is another option with the margins of excised tissue examined under the microscope.

Moh’s microsurgery has the highest cure rate and is especially indicated for recurrent tumors or tumors in areas (e.g.. eyelid or nose) where minimal amounts of tissue removal are important.

SQUAMOUS CELL CARCINOMA

Cutaneous squamous cell carcinoma (SCC) is the second most common form of skin cancer and frequently arises on the sun-exposed skin of middle-aged and elderly individuals.

General risk factors associated with the development of SCC are as follows:

Age older than 50 years

Male sex

Fair skin

Geography (closer to the equator)

History of prior nonmelanoma skin cancer

Exposure to UV light (high cumulative dose)

Exposure to chemical carcinogens (e.g., arsenic, tar)

Exposure to ionizing radiation

Chronic immunosuppression

Chronic scarring condition

Genodermatoses

Human papilloma virus (HPV) infection (specific subtypes)

Incidence: Incidence rates of SCC vary in different countries. The highest incidence occurs in Australia.

Race: SCC is the second leading cause of skin cancer in whites. Persons of Irish or Scottish ancestry have the highest prevalence. SCC is relatively rare in people of African and Asian descent, although it is the most common form of skin cancer in these groups.

Sex: SCC occurs in men 2-3 times more frequently than it does in women, most likely as a result of greater cumulative lifetime UV exposure.

Age: The typical age at presentation is approximately 70 years; however, this varies widely, and, in certain high-risk groups ( organ transplant recipients [OTRs], patients with epidermolysis bullosa), SCC often manifests at a much younger age.

MORPHOLOGIC VARIANTS

SCC in situ (SCCis): SCCis is defined histologically by atypia involving the full thickness of the epidermis but without invasion into the dermis. Clinically, lesions of SCCis range from a scaly pink patch to a thin keratotic papule or plaque similar to an AK. Bowen’s disease is a subtype of SCCis characterized by a sharply demarcated, pink plaque arising on non–sun-exposed skin. Erythroplasia of Queyrat refers to Bowen disease of the glans penis, which manifests as one or more velvety red plaques.

Periungual SCC and Nail involvement: Periungual SCC typically mimics a verruca and is frequently misdiagnosed for years as a wart prior to biopsy.

Marjolin ulcer: This subtype of SCC appears as a new area of induration, elevation, or ulceration at the site of a preexisting scar or ulcer

Verrucous carcinoma (VC): VC is a subtype of SCC that can be locally destructive but rarely metastasizes. Lesions appear as exophytic, fungating, verrucous nodules or plaques, which may be described as “cauliflower-like”. VC is further subdivided based on its location in the anogenital region (Buschke-Lowenstein tumor), the oral cavity (oral florid papillomatosis), and the plantar foot (epithelioma cuniculatum).

STAGING

SCC is staged according to American Joint Committee on Cancer guidelines, which use the TNM classification system. Most cutaneous SCCs are not metastatic at the time of presentation; therefore, the tumor stage in such cases is based solely on the characteristics of the primary lesion.

TX - Primary tumor cannot be assessed

T0 - No evidence of primary tumor

Tis - Carcinoma in situ

T1 - Tumor less than 2 cm in greatest diameter

T2 - Tumor 2-5 cm in greatest diameter

T3 - Tumor greater than 5 cm in greatest diameter

T4 - Tumor with deep invasion into cartilage, muscle

TREATMENT

A. MEDICAL CARE:

Topical chemotherapy: Topical formulations of 5-fluorouracil (5-FU) Topical immune response modifier: Imiquimod.

Photodynamic therapy: Treatment with PDT involves the application of a photosensitizer (given topically or systemically) followed by exposure to a light source.

Radiation therapy:

Systemic chemotherapy: Capecitabine (Xeloda), an oral form of 5-FU, either alone or in combination with interferon alfa, has shown some efficacy.

B. SURGICAL CARE:

Cryotherapy.

Electrodesiccation and curettage

Excision with conventional margins

Mohs micrographic surgery

MALIGNANT MELANOMA

Malignant melanoma is a neoplasm of melanocytes. Melanocytes arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis.

Incidence:Queensland, Australia, has the highest incidence of melanoma in the world. Israel also has one of the highest incidences.

Race: Melanoma is more common in whites than in blacks and Asians. The rate of melanoma in blacks is estimated to be one twentieth that of whites.

Sex: Melanoma is slightly more common in men than women (1.2:1).

Age: Melanoma may occur at any age, although children younger than 10 years rarely develop a de novo melanoma. The average age at diagnosis is 57 years, and up to 75% of patients are younger than 70 years

RISK FACTORS/ETIOLOGY

Exposure to ultraviolet radiation (UVR) is a critical factor in the development of most melanomas.

Both ultraviolet A and ultraviolet B potentially are carcinogenic and actually may work in concert to induce a melanoma.

UVR appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA.

Interestingly, melanoma does not have a direct relationship with the amount of sun exposure because it is more common in white-collar workers than in those who work outdoors.

The greatest risk for melanoma is associated with acute, intermittent, blistering sunburns, especially on areas that occasionally receive sun exposure. LMM is an exception to this rule, because it frequently appears on the head and neck of older individuals who have a history of long-term sun exposure.

Importantly, other factors exist that may predispose an individual to melanoma; chemicals and viruses and genetic predisposition are other etiologic agents that also have been implicated in the development of melanoma.

Greatly elevated risk factors for cutaneous melanoma

Changing mole

Dysplastic nevi in familial melanoma

Greater than 50 nevi, 2 mm or greater in diameter

Moderately elevated risk factors for cutaneous melanoma

One family member with melanoma

Previous history of melanoma

Sporadic dysplastic nevi

Congenital nevus

Slightly elevated risk factors for cutaneous melanoma

Immunosuppression

Sun sensitivity

History of acute, severe, blistering sunburns

Freckling

MORPHOLOGIC VARIANTS

Superficial spreading melanomas

Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type and often arise from a pigmented dysplastic nevus.SSM may be found on any body surface, especially the head, neck, and trunk of males and the lower extremities of females.

Nodular melanomas

Nodular melanomas (NMs) represent approximately 10-15% of melanomas and also are found commonly on all body surfaces, especially the trunk of males. These lesions are the most symmetrical and uniform of the melanomas and are dark brown or black in color. The tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion. Amelanotic melanomas represent approximately 5% of all NMs.

Lentigo maligna melanomas

Lentigo maligna melanomas (LMMs) also account for 10-15% of melanomas. They typically are found on sun-exposed areas (eg, hand, neck). LMMs may have areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna precursor lesion (Hutchinson’s melanotic freckle).

Mucosal lentiginous melanomas

Mucosal lentiginous melanomas (MLMs) develop from the mucosal epithelium that lines the respiratory, gastrointestinal, and genitourinary systems. These lesions account for approximately 3% of the melanomas diagnosed annually and may occur on any mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus

DIAGNOSIS

A) The ABCD for differentiating early melanomas from benign nevi include the following:

A - Asymmetry (melanoma lesion more likely to be asymmetric)

B - Border irregularity (melanoma more likely to have irregular borders)

C - Color (melanoma more likely to be very dark black or blue and have variation in color than a benign mole, which more often is uniform in color and light tan or brown)

D - Diameter more than 1 cm.

The Glasgow seven point check list

MAJOR CHECKS

Change in size

Change in shape.

Change in color.

MINOR CHECKS

Size more than 5 mm

Inflammation

Oozing and bleeding

Mild itch or altered sensation

DIFFERENTIAL DIAGNOSIS

Benign melanocytic lesions
Dysplastic nevus
Squamous cell carcinoma
Metastatic tumors to the skin
Blue nevus
Epithelioid (Spitz) tumor
Pigmented spindle cell tumor
Halo nevus
Atypical fibroxanthoma
Pigmented actinic keratosis
Sebaceous carcinoma
Histiocytoid hemangioma

Staging: The staging system for cutaneous melanoma was revised by the American Joint Committee on Cancer (AJCC) in early 2002.

Clark staging

Level I - All tumor cells above basement membrane (in situ)

Level II - Tumor extends into papillary dermis

Level III - Tumor extends to interface between papillary and reticular dermis

Level IV - Tumor extends between bundles of collagen of reticular dermis (extends into reticular dermis)

Level V - Tumor invasion of subcutaneous tissue

Breslow classification (thickness)

Less than or equal to 0.75 mm

0.76-1.5 mm

1.51-4 mm

Greater than or equal to 4 mm

TREATMENT

Medical Care: Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy and treatment of patients with advanced melanoma.

Because fewer than one half of patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival, these patients are considered high risk and should be considered for adjuvant therapy.

A recent study showed improvement in both long-term survival and disease-free survival using high-dose interferon-alpha-2b (IFN).

Advanced-stage melanoma (stage IV) Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen

Immunotherapy with high-dose interleukin-2 (IL-2) shows promise because it may cure a small percentage (<5%)>

Melanoma vaccines and gene therapy are 2 additional treatment options that may become available. Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies.

Surgical Care: Surgery is the definitive treatment for early stage melanoma. A wide local excision with sentinel lymph node biopsy and/or elective LND is considered the mainstay of treatment for patients with primary melanoma.