Epidermal Tumours Flashcards
Xeroderma Pigmentosum
- Autosomal recessive
- Makes individuals highly sensitive to ultraviolet (UV) light
- XP is caused by mutations in one of several genes involved in nucleotide excision repair (NER)
- There are 8 known types of XP (designated XP-A through XP-G and XP variant) based on the specific gene that is mutated.
- Premature skin aging, prone to skin cancers
Warts (verrucae)
- Common viral infection of skin and mucosal epithelial cells
- Caused by human papilloma virus (HPV) (Ann Ig 2018;30:28)
- Most infections clear within 2 years
- P16 IHC
Can be associated with:
WHIM syndrome
* rare primary immunodeficiency
* Warts, hypogammaglobinemia, Infections, Myelokathexis
WILD syndrome
* Warts, Immunodeficiency, Lymphoedema, Dysplasia (Anogenital)
Types:
* Verruca vulgaris: common wart (HPV 1, 2, 4 and 7)
* Condyloma acuminata: genital warts (HPV 6 and 11)
* Verruca palmaris / verruca plantaris: palmar / plantar warts (HPV 1, 2, 4 and 7)
* Myrmecia: special type of palmoplantar wart
* Verrucae planae: Plane warts (HPV 3, 10, 27 and 41)
Micro:
* Hyperkeratosis, papillomatosis, hypergranulosis
* Columns of parakeratosis, especially over projecting dermal papillae
* Vacuolated superficial keratinocytes with pyknotic raisin-like nuclei (koilocytes)
* Koilocytes may not be seen in older lesions
* Inward bending of rete ridges at borders of lesion (toeing in)
* Dilated capillaries in dermal papillae
* Projects above the plane of the epidermis
Palmar / plantar warts (verruca palmaris and verruca plantaris):
* Similar to verruca vulgaris (clinical distinction based on location)
* Endophytic growth - greater proportion of the lesion lies beneath the plane of the epidermis
* HPV 1
Seborrheic keratosis
- Common, benign keratinocyte proliferation of middle aged and elderly
- Most common benign skin tumor
- Head, neck, trunk (most common), Genitals (rare)
- Never on palms, soles or mucosal surfaces
Dermatosis papulosa nigra
* Multiple seborrheic keratosis on the face (usually cheeks)
* Present in adolescents
* More common those of Asian and African descent
Leser-Trélat sign:
Sudden appearance of multiple seborrheic keratoses, rapid increase in size, pruritic
Paraneoplastic phenomenon typically associated with gastrointestinal adenocarcinoma
Micro:
* Intraepidermal, well demarcated edges with a flat base
* String sign: can draw a horizontal line along the base of the lesion
* Basaloid keratinocyte proliferation without dysplasia
* Hyperkeratotic with horn pseudocyst formation (intralesional cysts of loose keratin)
Multiple variants (no clinical or prognostic significance)
* Acanthotic type
* Reticulated (adenoid) type
* Clonal type –> Pale basaloid keratinocytes in nests (Borst-Jadassohn phenomenon)
* Irritated type
* Pigmented
* Macular
Clear cell acanthoma
- Benign epidermal tumor, typically of the leg, with acanthosis and accumulation of glycogen in keratinocytes leading to pale staining cytoplasm
- Pink to tan papule or plaque on the distal lower extremity of older adults
Micro:
* Bland, intraepithelial tumor of clear, glycogen rich keratinocytes
Abrupt transition to normal epidermis
* Often in a pattern of psoriasiform hyperplasia
* Parakeratosis
* Typically lacks the thinning of the suprapapillary plate seen in psoriasis
* Often the vessels within the dermal papillae are dilated, tortuous and run vertically up the papillae
* Often spares hair follicles / adnexal structures
* Some cases have hyperplasia of underlying sweat ducts
Keratoacanthoma
- Keratoacanthoma (KA) is a well differentiated, cutaneous squamous cell carcinoma, which often spontaneously regresses
- Regression is thought to be due to immune mediated destruction of squamous cells
- Good prognosis; vast majority of cases spontaneously regress
- Head and neck most common sites, followed by extremities
- Typically large, scaly, dome shaped tumor with central keratinous plug
Micro:
* Low power magnification shows large, well differentiated squamous tumor with central keratin filled crater
* Surrounding epidermis forms a lip around the invaginating crateriform tumor
* Tumor is composed of bland squamous cells with abundant eosinophilic or glassy cytoplasm and enlarged hyperchromatic to vesicular appearing nuclei
* Mitotic activity and cellular atypia are usually seen at the periphery of tumor
* Intraepidermal neutrophilic microabscesses and keratin horn pearls are seen within the tumor
* Regressing tumors show epidermal atrophy, bland cytologic features, dermal inflammation and fibrosis at the periphery of tumor
Molecular:
* Transforming growth factor beta receptor 1 can cause multiple self healing squamous epithelioma (MMSE); most common cause of multiple KA
* Germline mutations of hMSH2 and hMLH1 mismatch repair genes causing Muir-Torre syndrome have been implicated in solitary and multiple KA formation
* BRAF kinase inhibitors utilized to treat KA has been reported to induce reactive KA by paradoxical activation of the ERK MAPkinase pathway
Actinic keratosis
- Intraepidermal keratinocytic lesion secondary to solar damage
- Most common precursor of cutaneous squamous cell carcinoma
- Sun exposed sites: face, scalp, upper chest and distal arm
- Single or multiple erythematous and hyperkeratotic macules or papules
- Usually < 1 cm in diameter
- Sometimes pigmented or ulcerated
- Chronic sun damage of background skin
Micro:
* Atypia of basal keratinocytes with loss of polarization, crowding and overlapping
* Can progress to involve the mid to upper epidermal layers
* Can extend along adnexal structures; typically limited to infundibular extension
* Never full thickness
* Lost / attenuated granular layer
* Dermal changes: solar elastosis, mild inflammatory infiltrate (usually lymphocytes; plasma cells present in longstanding lesions)
Prognosis:
* Can remain stable for long periods or regress
* Rate of transformation to SCC: closer to 1/100
* Proliferative variant has higher risk of invasion
2 main pathways for progression to SCC
* Classical: atypical basal keratinocytes in an actinic keratosis invade the mid to upper epidermis and transform to invasive SCC
* Differentiated: invasive SCC develops directly from actinic keratosis with dysplasia limited to the basal layer
Bowen disease
- Squamous cell carcinoma in situ
- 3-5% progress to SCC
- 10% if Erythroplasia of Queyrat (eg at glans, vulva, oral cavity
Aetiology:
* UV exposure –> Sunlight/tanning beds
* Radiotherapy
* Alpha genus HPV
* UV radiation-induced mutation of TP53
Micro:
* By definition requires full thickness keratinocyte atypia, although may be surrounded by normal keratinocytes
* Architectural and cellular atypia, apoptotic cells, individual cell dyskeratosis
* Markedly altered maturation but usually still some surface keratinization and intercellular bridges present
* Marked nuclear atypia, including nuclear hyperchromasia and multinucleation
* Numerous mitotic figures, atypical mitotic figures
AK vs Bowen’s
AK
* Crowding, overlappig ad atypia involving the epidermal base
* Highlighted with p53 IHC
Bowen’s
* Crowding, overlapping and atypia sparing the epidermal base
* Highlighted with p16 IHC
SCC of Skin
- Cutaneous squamous cell carcinoma is a malignancy of epidermal keratinocytes
- Displays variable degrees of differentiation and cytological features
- Most often in sun exposed areas
- Thin squamous cell carcinoma: erythematous scaly thin papule or plaque
- Thicker tumors typically present as erythematous plaque, nodule, ulce
Aetiology:
* Ultraviolet light radiation and other forms of radiation
* Chronic immunosuppressions
* Actinic keratosis (precursor lesion)
* Albinism (lack of pigmentation in skin)
* Arsenic
* Burn scars
* Chronic ulcers
* Chronic inflammation
* Sinus tract
* Human papillomavirus infection
* Tars / oils
* Xeroderma pigmentosa
Prognostic factors:
* Diameter: > 2 cm doubles the risk of recurrence, triples the rate of metastasis
* Depth: > 2 mm, tenfold higher risk of local recurrence
* Beyond subcutaneous fat, elevenfold higher risk of metastasis
* Perineural invasion: involved nerves ≥ 0.1 mm associated with increased nodal metastases
* Differentiation: poor differentiation indicates poor prognosis
* Lymphovascular invasion: risk factor for lymph node metastasis
* Site: high risk anatomic sites (scalp, ear, lip, nose, eyelid)
* Immunosuppression: increased recurrence (13%) and metastasis (5 - 8%)
* Previously treated / recurrent: worse prognosis compared to primary tumors
* Arising in scar: arising from ulcer, burn scar, radiation dermatitis and other chronic wounds have increased rate of metastasis
Micro:
* Carcinoma of keratinocytes that infiltrates the dermis
* An associated precursor lesion (actinic keratosis / keratinocytic dysplasia / squamous cell carcinoma in situ) is often present
* Spectrum of histologic features; all share downward growth below level of adjacent or overlying epidermis
- Grading based on degree of differentiation and keratinization
Well differentiated
Moderately differentiated
Poorly differentiated
Undifferentiated - Histologic patterns:
Low risk histologic variants:
* Keratoacanthoma
* Verrucous carcinoma
* Clear cell
High risk histologic variants:
* Acantholytic:
* Acantholytic cutaneous squamous cell carcinomas
* Invasive Bowen disease
* Spindle cell squamous cell carcinoma
* Desmoplastic squamous cell carcinoma
* Adenosquamous carcinoma
IHC:
* Keratins: AE1 / AE3, MNF 116, 34 beta E12, CK5/6, CK5
* EMA
* p63, p40
Basal cell carcinoma
- Basal cell carcinoma (BCC) arises from the interfollicular or follicular epithelium
- Most common malignant tumor type in humans
- Local aggressive course
- Low disease associated death rate; metastases to lung and bone exceptionally rare
When multiple, associated with a number of genetic conditions:
* basal cell nevus (Gorlin)
* Bazex-Dupré-Christol
* Rombo syndromes
* xeroderma pigmentosum
* Oculocutaneous albinism
* Muir-Torre syndrome
- Sun exposed skin
- 64% on the head region (most often nodular variant)
- 24% on the trunk (most often superficial variant)
Histological type associated with risk of local recurrence
Lower risk:
* nodular
* superficial
* pigmented
* infundibulocystic
* fibroepithelial –> Fibroepithelioma of Pinkus
Higher risk:
* basosquamous
* sclerosing / morpheaform
* keloidal
* infiltrating
* BCC with sarcomatoid differentiation
* micronodular variants
Micro:
* Relatively circumscribed mass
* Epidermal or follicular attachment variably present
* Large basaloid lobules with peripheral nuclear palisade
* Lobules may be solid or show central cyst formation due to excessive mucin production
* Fibromyxoid stroma
* Cleft formation between tumor lobules and stroma
* Pleomorphism is generally mild
* Variable mitotic activity and apoptosis
* Sometimes necrosis en masse
Molecular:
* Mutations in TP53 gene
* PTCH1 gene mutations
* Activating mutations in SMO gene
* Other genes including mutations in the CDKN2A gene and RAS genes
IHC:
* CK AE1 / AE3 (100%), BerEP4 (80 - 100%)
* p63 (100%)
* CAM 5.2 (20 - 95%)
* androgen receptor (33 - 66%)
* p53 (74.5 - 83%)
* 34 beta E12 (high molecular weight CK)
* BCL2 (diffuse pattern)
* CD10 (positive in tumor cells, negative in stroma)
Gorlin Syndrome
- also known as nevoid basal cell carcinoma syndrome (NBCCS)
- mutations in the PTCH1 gene (located on chromosome 9)
- autosomal dominant
- Basal Cell Carcinomas (BCCs): People with Gorlin syndrome often develop multiple BCCs, typically starting in childhood or adolescence. These are usually skin lesions, and while they are slow-growing and rarely spread to other parts of the body, they can be locally destructive.
- **Jaw Cysts (Keratocystic Odontogenic Tumors, or KCOTs): **Individuals with Gorlin syndrome often develop non-cancerous cysts in the jaw, which can cause swelling, pain, and sometimes tooth displacement. These cysts may recur even after surgical removal.
- **Skeletal Abnormalities: **This can include features like spina bifida, bifid ribs, and flattening of the skull. There may also be other bone-related issues like limb abnormalities.
- Other Tumors: People with Gorlin syndrome have an increased risk of developing other types of tumors, including medulloblastomas (a type of brain cancer), ovarian fibromas, and fibromas of the skin.
- Neurodevelopmental Features: Some individuals may experience developmental delays, learning disabilities, or other neurological concerns, though these are not always present.
- Increased Risk for Other Cancers: There is a higher risk for some other cancers, particularly medulloblastomas (a type of brain tumor), especially in children.
- Distinctive Facial Features: Certain facial characteristics, such as a broad forehead, prominent eyes, and a rounded jaw, may be present in individuals with Gorlin syndrome, though these features are not always prominent.
Merkel cell carcinoma
- Merkel cell carcinoma (MCC) is an uncommon and highly aggressive primary cutaneous neuroendocrine carcinoma
- Primarily affecting elderly and immunosuppressed individuals
- There is emerging evidence of distinct Merkel cell polyomavirus associated and UV mediated oncogenetic pathways
- Mutations in TP53 and RB1
- High mortality
- Rarely, complete spontaneous regression of the tumor can occur
AEIOU acronym for clinical characteristics:
* Asymptomatic / lack of tenderness
* Expanding rapidly
* Immune suppression
* Older than age 50
* UV exposed site
Prognostic factors:
* Tumor size
* depth of invasion
* locoregional nodal involvement
* disseminated metastasis
Negative clinical prognostic indicators:
* advanced disease stage at diagnosis (most important)
* age > 60
* male gender
* head and neck site
* immunosuppression
* Merkel cell polyomavirus negative subtype
Micro:
* Expansile, nodular or diffusely infiltrative tumor within the dermis, variably in subcutis
* Variable mixture of nodules, sheets, nests and trabeculae of neoplastic cells
* Generally, small round blue cell tumor with high N:C ratio, round / oval nuclei, finely dispersed chromatin (salt and pepper), indistinct nucleoli and scant cytoplasm
* Conspicuous mitoses and apoptotic bodies
* Variable nuclear molding and crush artifact
* Majority of cases display pure neuroendocrine morphology (pure Merkel cell carcinoma)
* Minority of cases feature neuroendocrine and other elements (combined Merkel cell carcinoma) such as divergent differentiation (e.g. squamous, sarcomatoid) or intimate association with other cutaneous neoplasms (most commonly in situ or invasive squamous cell carcinoma)
IHC:
* Broad spectrum keratins: CAM 5.2, AE1 / AE3 (paranuclear, cytoplasmic or mixed pattern)
* CK20 (classic dot-like paranuclear pattern)
* Chromogranin, synaptophysin
* CD56
* neuron specific enolase
* Neurofilament (dot-like pattern)
* Variable MCPyV (nuclear pattern) –> large T antigen
* Can express PAX5, TdT, BCL2, CD99, FLI1
IHC BCC vs SCC
mmunohistochemistry is a crucial tool in distinguishing between Basal Cell Carcinoma (BCC) and Basaloid Squamous Cell Carcinoma (basaloid SCC).
BerEP4 is a marker commonly expressed in BCCs. Its positivity indicates the presence of epithelial cells with basal cell characteristics. It is not commonly expressed in basaloid SCCs.
Cam 5.2 is a broad-spectrum cytokeratin antibody that stains many types of epithelial cells. Its positivity in BCCs reflects the epithelial nature of the tumour. Cells with squamous differentiation and less uniform epithelial character composed to BCC are less likely to stain positive for Cam 5.2.
Epithelial Membrane Antigen (EMA) is often negative in BCCs. This lack of EMA staining helps differentiate BCC from some other epithelial tumours. EMA is commonly positive in SCCs.
BerEP4 and Cam 5.2 negativity, combined with EMA positivity, indicates basaloid SCC. This profile is characteristic of basaloid SCC’s squamous differentiation and more aggressive nature.
