Pathology of Skin Tumor PDF

Benign epidermal tumors 1. Viral-associated tumor-like lesions Verrucae (warts) Molluscum contagiosum 2. Seborrheic keratosis 3. Fibroepithelial polyp (skin tag, acrochordon): Benign non-epithelial tumors arising from mesodermal (mesenchymal) tissue 4. Keratoacanthoma: controversy -...

Benign epidermal tumors 1. Viral-associated tumor-like lesions Verrucae (warts) Molluscum contagiosum 2. Seborrheic keratosis 3. Fibroepithelial polyp (skin tag, acrochordon): Benign non-epithelial tumors arising from mesodermal (mesenchymal) tissue 4. Keratoacanthoma: controversy - benign or malignant ? 26 Verrucae (warts) Cause: Human papillomavirus (HPV), low-risk types: (1, 2, 4, 6, 11, 42, 44, etc.) Transmission: Direct contact Clinical: o Common in children and adolescents (except: condyloma acuminata, more common in active reproductive age) o Usually self-limiting and regress within 6 months to 2 years Pathogenesis: o HPV affects cell cycle control causing increased proliferation of epithelial cells and production of viruses. 27 Verrucae (warts) Classification: based on clinical morphology and location 1. Verruca vulgaris (most common) o Occurs anywhere. Usually dorsum & periungual area of hand o Gray-white, dome-shaped, 0.1 to 1-cm papule, with rough surface 2. Verruca plantaris o Occurs on sole o Rough scaly coalesce plaque 3. Verruca palmaris o Occurs on palm o Rough scaly coalesce plaque 4. Condyloma acuminata (venereal / genital wart) o Occurs in anogenital regions (usually associated with HPV type 6 and 11) o Soft tan cauliflower-like masses 28 Verruca vulgaris: papules with rough surface Verruca plantaris: rough scaly coalesce plaque Condyloma acuminata: venereal / genital wart 29 Verrucae (warts) Histopathology: o Marked hyperkeratosis o Acanthosis: epidermal hyperplasia o Prominent papillomatosis: papillary dermis hyperplasia with long delicate dermal papillae o Hypergranulosis: cells with condensed keratohyaline granules o Koilocytosis (koilocytic atypia): viral cytopathic changes with perinuclear halo, hyperchromatic nuclei with irregular nuclear membrane, may be binucleated 30  Hyperkeratosis, papillomatosis, acanthosis Hypergranulosis Koilocytosis In-situ hybridization with HPV 31 Molluscum contagiosum Cause: Poxvirus mollusci (Molluscum contagiosum virus) Transmission: Direct contact Clinical: o Common in children and young adults o Firm, pruritic, umbilicated small papules, 0.2 to 0.4 cm o Curd-like or cooked rice-like whitish material at central umbilication o Usually self-limiting 32 Molluscum contagiosum Histopathology: o Cup-like (verrucous) epidermal hyperplasia containing molluscum bodies within stratum granulosum and corneum o Molluscum bodies: large homogenous eosinophilic cytoplasmic inclusions 33  Seborrheic keratosis Benign keratinocytic tumor with hyperkeratosis Pathogenesis: o Activating mutation in fibroblast growth factor receptor-3 (FGFR-3)* gene in 40-85% of patients Clinical: o Common in middle-aged to older patients o Common in head, neck, trunk, and extremities o Well-demarcated, round, flat, coin-like (stuck-on appearing) plaques, vary in size (mm to cm) o Uniformly tan to dark-brown color with granular surface Prognosis: Usually benign 34 * FGFR3: transmembrane tyrosine kinase receptor (TRK) involving in signal transduction regulating cell growth and differentiation Seborrheic keratosis Histopathology: o Exophytic and well-demarcated sharply from adjacent epidermis o Acanthosis and marked hyperkeratosis at surface o Benign-appearing epidermal keratinocytes (small size) with variable melanin pigments o Small keratin-filled cysts (horn cysts) within the tumor 35 Seborrheic keratosis Leser-Trelat sign o Sudden explosive onset of many seborrheic keratosis o Often produced by other malignant tumors (e.g. GI tract, lung, or breast cancers): – paraneoplastic syndrome o Caused by increased production of growth factor (e.g. TGF-α) or growth factor receptor (e.g. EGFR) by other malignant tumors o May associated with acanthosis nigricans Acanthosis nigricans Brown-to-black velvety hyperpigmentation of skin, usually found at body folds (axilla, groin, posterior neck) May associated with obesity or endocrinopathy (DM): benign acanthosis nigricans May associated with other malignant tumors (e.g. adenocarcinoma of GI tract, lung, uterus): malignant acanthosis nigricans 36 Leser-Trelat sign Acanthosis nigricans 37 Fibroepithelial polyp Synonyms: Skin tag, squamous papilloma, acrochordon Clinical: o Common in middle-aged and older patients, usually at skin crease areas (neck, groin, perigenital areas) o Soft, flesh-colored, bag-like tumor with small pedunculated stalk (sometimes can be very large in size, called “giant skin tag”) o Usually not harmful o May associated with DM and intestinal polyposis Histopathology: o Pedunculated exophytic lesion with fibrovascular core covered by benign squamous epidermis 38 Keratoacanthoma Controversy whether benign tumor, pseudomalignancy or variant, of well-differentiated squamous cell carcinoma? At present, it is recommended to be called “keratoacanthoma-like squamous proliferation” or “squamoproliferative tumor of uncertain malignant potential, keratoacanthoma-like”. Clinical: o Rapid-growing skin tumor, usually at sun-exposed areas o Flesh-colored, dome-shaped nodule with central keratin-filled plug (crater-like appearance), size 1-2 cm in diameter o Giant keratoacanthoma: a large tumor usually > 3 cm in size) o Clinically mimicking well-differentiated squamous cell carcinoma; therefore, biopsy for pathologic diagnosis may be needed. o Prognosis: Self-limiting and heal spontaneously without treatment (usually within 4-6 months) 39 40 Premalignant & malignant epidermal tumors 1. Actinic (solar) keratosis 2. Squamous cell carcinoma in-situ / Bowen disease 3. Squamous cell carcinoma (invasive) * 4. Basal cell carcinoma * 41 Ultraviolet (UV) carcinogenesis Clonal expansion 42 Actinic (solar) keratosis Definition: o A skin lesion caused by excessive exposure to UV (especially UV-B) o A potential pre-malignant lesion of squamous cell carcinoma (although some regress or remain stable) o Risk of malignant change to invasive squamous cell carcinoma is 6-10% (13-20% in some studies) Clinical: o Middle-aged and elderly patient (usually in lightly-pigmented skin, especially Caucasoid) o Location: usually at sun-exposed areas (face, arm, dorsum of hands) 43 Actinic (solar) keratosis Clinical: o Lesion usually less than 1 cm, red (from angiogenesis) or tan-brown patch or plaque with rough sandpaper-like consistency o May have telangiectasia (dilated superficial capillaries) o May have yellow-white scale (due to increased keratin at surface o May form a “cutaneous horn” (reaction pattern with marked hyperkeratosis) 44 Cutaneous horn (cornu cutaneum) A descriptive clinical findings of hyperkeratotic epithelial lesion resembling an animal horn, characterized by height more than half of diameter of its base A reaction pattern caused by other lesions: o Actinic keratosis (38-40%) o Squamous cell carcinoma o Keratoacanthoma o Seborrheic keratosis o Verruca vulgaris o Others 45 Actinic (solar) keratosis Histopathology: o Mild acanthosis with occasional downward buds with dysplastic keratinocytes displaying cytologic atypia* with hyperkeratosis (particularly parakeratosis) o Early lesion: Dysplastic (atypical) keratinocytes with loss of polarization, crowding, and overlapping begin at basal layer (lower portion of epidermis). o Later lesion: Dysplastic keratinocytes can progress to involve mid to upper epidermal layers, can extend along adnexal structures (typically limited to infundibular extension), but never involve full epidermal thickness. * Cytologic atypia: Increased nuclear size Increased nuclear-to-cytoplasmic ratio Hyperchromatic nuclei (nuclear hyperchromasia) Nuclear pleomorphism Increased mitosis, may have atypical/abnormal mitotic figure 46 Actinic (solar) keratosis Histopathology: o Dermis usually contains thickened fibrillary faint basophilic elastic fibers (called solar elastosis), caused by dermal collagen degradation and replacement with de novo synthesis of elastotic materials (elastin, fibrillin, and glycosaminoglycans) by sun- damaged fibroblasts Solar elastosis Histologic evidence of skin damaged severely by UV (representing photoaging) Inflammatory cells (lymphocytes, histiocytes) reactions at dermis Angiogenesis (due to VEGF produced by UV-damaged keratinocytes) Telangiectasia (dilated small capillaries) 47 48 Acanthotic epidermis, papillomatosis and thick hyperkeratosis. Epidermis with basal atypia, hyperkeratosis and marked solar elastosis A Freudenthal funnel is present in the central portion. with slight lymphocytic infiltrate in the dermis (early lesion) Keratinocytic atypia spares the acrosyringial epithelium. Keratinocytic atypia (loss of polarity in lower half of epidermis with nuclear pleomorphism and hyperchormasia), solar elastosis, and abundant lymphocytic infiltrate 49 50 Squamous cell carcinoma in-situ / Bowen disease An early stage of squamous cell carcinoma that limits in the epidermis, but not yet invades beyond the basement membrane Etiology and risk factors: o UV light (particularly UV-B) o Chemicals (arsenic) o Immunosuppression o High-risk HPV (type 16 and 18) at anogenital lesions Pathogenesis: o Sun-exposed areas: DNA damage induced by UV light exposure o Anogenital area: HPV viral proteins E6 and E7 interfere with the activity of tumor suppressor proteins that regulate cell growth and cell survival. 51 Squamous cell carcinoma in-situ / Bowen disease Clinical: o Mostly middle-aged and elderly patients o Usually in lightly-pigmented skin with history of chronic sunlight exposure o Single or multiple slow-growing, well-circumscribed, irregular, erythematous, scaly or crusted plaques, size ranging from few mm to many cm o Approximately 50% develop invasive component, and 30% have metastatic potential 52  Squamous cell carcinoma in-situ (Bowen disease): well-circumscribed, irregular, erythematous, scaly plaques 53 Squamous cell carcinoma in-situ / Bowen disease Histopathology: o Epidermal full-thickness involvement by dysplastic (atypical) keratinocytes (although may be surrounded by normal keratinocytes), but not extend beyond basement membrane o Architectural and cellular atypia, apoptotic cells, individual cell dyskeratosis o Markedly altered maturation (Some surface keratinization (parakeratosis) and intercellular bridges may be seen.) o Marked nuclear atypia, including nuclear hyperchromasia and multinucleation, numerous mitotic figures, atypical mitotic figures o May extend into eccrine sweat glands (not considered invasive disease) 54  Normal skin histology Squamous cell carcinoma in-situ / Bowen disease: Epidermis shows acanthosis and hyperkeratosis (commonly parakeratosis) and is completely disorganized with full-thickness atypical keratinocytes displaying overt cytologic atypia. 55 56 Squamous cell carcinoma The second most common malignant skin tumors (mostly arising on sun- exposed sites in older people) Usually discovered while they are small and resectable (less than 5%; deeply invasive and involve the subcutis, and metastasize to regional lymph node) 57 Squamous cell carcinoma Etiology and risk factors (resembling those of Bowen disease): o Premalignant lesions: actinic keratosis, arsenic Keratosis, Bowen disease o Ultraviolet radiation o Ionizing radiation o HPV high-risk types: type 16, 18 (anogenital); type 5, 8 o Immunosuppression: chemotherapy, transplantation o Chemical carcinogens: arsenic. hydrocarbon (oils, tars) o Persistent chronic inflammation: chronic ulcer, chronic osteomyelitis, old burn scar, varicose ulcers § Squamous cell carcinoma arising in such conditions is called Marjolin’s ulcer. o Hereditary skin disorders (genodermatoses): § Albinism: tyrosinase defect (no melanin pigment to protect UV) § Xeroderma pigmentosa: inherited defect in DNA repair gene by nucleotide excision repair pathway 58 Squamous cell carcinoma Pathogenesis: o UV light exposure: subsequent unrepaired DNA damage o Deactivating mutation of TP53 (tumor suppressor gene) associated with UV exposure § p53 aids in cell cycle control (G1 arrest) and DNA repair (apoptosis) o Activating mutation of RAS (proto-oncogene) associated with UV exposure o Immunosuppression (chemotherapy or organ transplantation): become easily infected with oncogene viruses HPV types 5 and 8 59 Squamous cell carcinoma Location: o Sun-exposed areas: head and neck, arm, hand, foot (UV-related) o Anogenital area (high-risk HPV-related) Clinical: o Usually erythematous papule, plaque, or nodule, and may be ulcerated Prognosis: o Depends primarily on staging o Rate of recurrence and metastasis depends on tumor size and depth of invasion o 40% of recurrence rate within 2 year o Better prognosis than melanoma, but worse than basal cell carcinoma 60 Bowen disease with invasive squamous cell carcinoma: Bowen disease with invasive squamous cell carcinoma: extensive erythematous scaly plaque with multiple nodules large variegated orange, brown-to-gray plaque, sharply defined, with irregular outline (representing Bowen disease), and a red nodule (representing invasive squamous cell carcinoma) 61 Squamous cell carcinoma: large nodular tumors on lip and jaw Squamous cell carcinoma arising in long-standing ulcer of an elderly patient (Marjolin’s ulcer) 62 Squamous cell carcinoma Histopathology: o Infiltrative sheets and nests of dysplastic/malignant squamous (keratinocytic) cells beyond basement membrane into underlying dermis or other nearby tissue o The neoplastic cells display nuclear hyperchromasia and pleomorphism, increased mitoses (presence of atypical forms) o Evidence of keratinization: keratin pearls, intercellular bridges (usually in well- and moderately-differentiated tumors) o Histologic grading: well-, moderately-, and poorly-differentiated 63 Squamous cell carcinoma 64 65  Squamous cell carcinoma (well- Squamous cell carcinoma (well- Squamous cell carcinoma (well- differentiated): nulear pleomorphism differentiated): minimal pleomophism, differentiated): typical keratin pearl and mitoses, including abnormal form, conpicuous intercellular bridges formation identified keratinization 66 67 Basal cell carcinoma The most common skin malignant tumor Slow-growing and locally aggressive malignant tumor with histologically resembling basal cell 68 Basal cell carcinoma Etiology and risk factors (similar to those of SCC): o Chronic sun (UV) exposure o Lightly-pigmented people o Immunosuppression: post-transplantation with immunosuppressive therapy, AIDS o Hereditary (genodermatosis): § Basal cell nevus syndrome (Nevoid basal cell carcinoma syndrome / Gorlin syndrome): ü Rare, autosomal dominant inheritance, variable clinical expressivity ü PATCH (tumor suppressor gene) mutation ü Associated with many basal cell carcinoma in early life with abnormalities of bone (vertebrae and ribs), nervous system, eyes, and reproductive organs (thecoma-fibroma) § Xeroderma pigmentosa: autosomal recessive 69 Basal cell carcinoma Etiology and risk factors (continued): o Hereditary (genodermatosis): § Basal cell nevus syndrome (Nevoid basal cell carcinoma syndrome / Gorlin syndrome): ü Rare, autosomal dominant inheritance, variable clinical expressivity ü PATCH (tumor suppressor gene) mutation ü Associated with many basal cell carcinoma in early life with abnormalities of bone (vertebrae and ribs), nervous system, eyes, and reproductive organs (thecoma-fibroma) § Xeroderma pigmentosa: autosomal recessive 70 Hereditary cancer syndromes with cutaneous manifestations 71 Basal cell carcinoma Etiology and risk factors (continued): o Chemical carcinogens: arsenic o Smoking o Ionizing radiation o Radiotherapy o Family history of skin cancer 72 Basal cell carcinoma Pathogenesis: o UV light exposure: subsequent unrepaired DNA damage o TP53 (tumor suppressor gene) mutations: associated with UV exposure o PTCH (tumor suppressor gene) mutations: associated with UV exposure Clinical: o Mostly arise at sun-exposed skin (especially face) o Slow growing tumor, rarely metastasis, but can be extensive local invasion of bone, orbit, or sinuses (if left untreated) o Early lesion: § Pearly papule/nodule, often contains telangiectasia (dilated subepidermal blood vessels) on surface, some contains melanin pigment (pigmented type) o Advanced lesion: § Increased size with central ulceration and raised rolled edge (“rodent ulcer”) 73  Majority of the basal cell carcinoma occur in head and neck region. The most common location would be above the line which is drawn from the angle of mouth to the pinna of the ear. 74  Basal cell carcinoma (early lesion): Basal cell carcinoma (advanced lesion): Basal cell carcinoma (pigmented type): characteristic telangiectatic vessels coursing central ulceration and characteristic increased functional melanocyts and over the surface of nodulcystic-type tumor raised rolled border melanin transfer to the neoplastic cells and increased dermal melanophages, clinically resembling malignant melanoma 75 Basal cell carcinoma (advanced and locally aggressive lesion): can be extensive local invasion of bone, orbit, or sinuses (if left untreated) 76 Basal cell carcinoma Histopathology: o Infiltrative sheets and nests of neoplastic cells resembling basal cell layer of the epidermis (basaloid appearance) o Characteristic peripheral nuclear palisading at the tumor border and peritumoral myxoid stroma (clefting) o Evidence of solar damage in the dermis (solar elastosis) Prognosis: o Recurrence rate varies from 1 to 8.7%, depending on location, size, histologic subtypes, and form of primary treatment o Rarely metastasize (less than 1%) 77  Basal cell carcinoma Clinically, the appearance of the tumor vary and they can be nodular, cystic, ulcerated, sclerotic (morphoeic), superficial, pigmented, basasquamous (metatypical), or infiltrating types. While the ulcerated type is the one which is commonly referred to as rodent ulcer. 78