Pathology Week 5 p1-14

DERMATOPATHOLOGY: LECTURE 1 – Cutaneous Tumors

Mon. 09/13/10

Normal Histology:

3 main layers. Hair follicles, sebaceous glands, etc. within.

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Many tumors originate from epidermis – probably because it is the most superficial. Stratum corneum is outermost layer. Site of keratinocytes being continuously sloughed off – keratinocytes have lost nuclei. S. granulosum – cells are identifiable by bluish granules in the cytoplasm. S. spinosum – can see web-like connections. Lamina densa = basement membrane. Attaches epidermis to dermis. Merkel cell – involved in mediating reception of light touch. Melanocytes – have dendritic processes. Melanin is involved in protecting keratinocyte DNA from damage.

Definitions: Hyperkeratosis

Increase in stratum corneum (scale)

Parakeratosis

Acanthosis

Abnormal keratinization characterized by retained nuclei in stratum corneum (scale)

Papillomatosis

Dysplasia  Acanthosis w/upward projections (wart; seborrheic keratosis)

Cytologic atypia:  1) Variation in size and shape of nucleus (nuclear pleomorphism) 2) Variation in staining (hyperchromatism) 3) Increased and abnormal mitotic figures (cancer; precancer)

Thickened epidermis

Solar Elastosis

Bluish discoloration of collagen in the dermis. Cutaneous Tumors • Epithelial • Epidermal tumors • Adnexal tumors • Melanocytic • Nevi • Melanoma • Mesenchymal – from fibroblasts in the dermis. • Dermatofibroma – benign. • Dermatofibrosarcoma protuberans (DFSP) – malignant. • Hematopoietic • Mycosis fungoides • Langerhans cell histiocytosis • Mastocytosis – tumor of mast cells Seborrheic Keratosis • Common • Occur >30 years • Trunk/face • Rarely as paraneoplastic syndrome w/an internal malignancy. – Sign of Leser-Trelat • Papules – raised. • Smooth, rough, or “greasy” surface • Light to dark brown • “Stuck on” appearance • People often scratch them off.

Epidermal Tumors • Benign Epithelial Tumors – Seborrheic keratosis • Premalignant/Malignant Epithelial Tumors – Actinic keratosis – Squamous cell carcinoma – Basal cell carcinoma – Keratoacanthoma (controversial) – malignancy or not?

Irritation Inflammation

^ Solitary

^ Multiple

• Hyperkeratosis – increased s. corneum  • Acanthosis (bland keratinocytes) • Epidermal invaginations; keratin-filled “pseudo-cysts” Test q: A 45y/o male develops multiple seborrheic keratosis over a period of a few months. He is diagnosed w/Leser-Trelat syndrome which is associated with: internal malignancy. Test q: A 56y/o farmer presents w/numerous macules and papules on his face. Biopsy shows hyperkeratosis, parakeratosis, and dysplasia in the lower dermis. Diagnosis: Seborrheic keratosis

Above: Dermatosis Papulosis Nigra – Multiple seborrheic keratoses.

Actinic Keratosis • Fair-complexioned individuals (Irish/Anglo-Saxon heritage) • Chronically sun-exposed areas • Induced by ultraviolet radiation • Course – stable – regress – progress to squamous cell carcinoma • Macules - flat • Papules - raised • Scale • Hyperkeratosis (increased stratum corneum); parakeratosis • Dysplasia of lower epidermis • Solar elastosis

Test q: A 58y/o farmer has had a lesion on his face that has been enlarging for the past 3yr. This lesion is excised, and microscopic exam shows basal cell hyperplasia. Some of the basal cells show nuclear atypicality associated w/marked hyperkeratosis and parakeratosis. Solar elastosis is present. Which of the following lesions best accounts for these findings? Actinic keratosis. Test q: A 50y/o male presents w/a maculopapular scaly lesion on the back of his neck. A biopsy shows dysplasia of the keratinocytes in the lower epidermis and marked solar elastosis in the dermis. Diagnosis: actinic keratosis.

Squamous Cell Carcinoma • Common: >200,000 cases/year • May metastasize • M>F; >70 years • Head and neck • Predisposing factors: – Ultraviolet light exposure – Industrial carcinogens (tars and oils) – Chronic ulcers – Immunosuppression; HIV infection – Mutations in p53 common • Flesh-colored to erythematous (red) • Smooth or warty surface • Ulceration • Firm • Hyperkeratosis; parakeratosis • Acanthosis • Dysplasia of entire epidermis – large nuclei within the entire epidermis • Extension of tumor into dermis • Squamous “pearls” • Solar elastosis Cells still make keratin – result is keratin pearls. Have s. corneum but it’s trapped beneath rather than being at the surface of the skin.

Basal Cell Carcinoma • Most Common malignant skin tumor: >700,000/year • Locally invasive; rarely metastasize • M>F; 60 years • Head and neck • Predisposing factors: – Fair complexion – Chronic sunlight exposure – Immunosuppression – Nevoid basal cell carcinoma syndrome

Test q: The most common cutaneous malignancy is: basal cell carcinoma

Nevoid Basal Cell Carcinoma Syndrome • Autosomal dominant • PTCH gene • Receptor for SHH (sonic hedgehog) gene product • PTCH mutation present in 30% of sporadic BCC Test q: A 22y/o male develops more than a dozen basal cell carcinomas on his upper face. This syndrome is autosomal dominant and is associated w/mutation of which gene? PTCH. Test q: A 5y/o male presents w/a basal cell carcinoma on his forehead. The genetic basis for this disease is: PTCH.

Basal Cell Carcinoma • Papules or nodules (nodules = big papules) • Smooth surface (translucent; pearly) • Telangiectasia – dilated blood vessels within the lesion • Central ulcer See peripheral palisading (below) – cells lined up parallel to the periphery of the lobule.

Test q: A 66y/o female farmer has a pearly nodule on her forehead. The nodule is focally ulcerated and shows prominent dilated blood vessels. Histologically you would expect to see: peripheral palisading. Test q: All of the following regarding basal cell carcinoma are true except: Tumor exhibits full thickness atypia of the epidermis (Other choices – Retraction spaces are seen around tumor lobules; Peripheral palisading is a feature; The nose is a frequent site; Sun exposure is a risk factor)

Keratoacanthoma • Benign vs. malignant • Rapidly growing tumor • M>F • Sun-exposed skin • May spontaneously involute (regress) • Rarely aggressive • Cup-shape • Keratin plug • Glassy keratinocytes Test q: A 70y/o man develops a keratoacanthoma on his nose. The lesion is cupshapes and filled w/glossy keratinocytes. The lesion can be expected to: Spontaneously regress. Test q: A 60y/o man has noted the appearance of a nodule on his ear during the past month. On phys exam, there is a 1.2cm flesh-colored, dome-shaped nodule on his right ear lobe. The nodule has a central keratin-filled crated surrounded by proliferating epithelium. The lesion regresses and disappears within 1mo. Which of the following is the most appropriate diagnosis of this lesion? Keratoacanthoma.

Adnexal Tumors • Most benign • Derived from adnexal structures including follicle, sebaceous gland, eccrine gland, apocrine gland Cylindroma  • Benign adnexal tumor, derived from eccrine glands • Occurs on forehead and scalp • Multiple lesions may coalesce into hat-like growth (“turban tumor”) Similar to basal cell carcinoma, but cells are a little more responsible – try to make basement membrane (pink web) and ducts (eccrine glands). 

Melanocytic Tumors: Melanocytic Nevi (Moles) • Common – Congenital (1% of population) – Acquired (1-35 years) • Trunk, extremities, face Acquired Melanocytic Nevi: - Macules and papules - Tan to black - Regular in shape and border - 5mm diameter Occur on sun-exposed and nonsun-exposed skin Clinical significance unclear: – Isolated lesions: not very significant – Multiple lesions: probably increased risk of melanoma (only very slightly) – Dysplastic nevus syndrome (atypical mole syndrome) Autosomal dominant

Melanoma Sites

Chest in men. Lower legs in females. Faces in both. Melanoma Risk Factors • Light complexion, hair, eyes – don’t make as much melanin. • History of blistering sunburn(s) • Proximity to the equator • Indoor occupation; outdoor hobbies – more likely to get burnt. • Family history of melanoma or dysplastic nevi • Precursor lesions (congenital or dysplastic nevi) • Xeroderma pigmentosa – inhibits ability to repair DNA. Test q: In the US, the highest incidence of melanoma can be found in: Texas (other choices: CA, ME, NC, IN. Proximity to equator) Test q: Malignant neoplasms develop in patients w/xeroderma pigmentosum because these patients: Lack an enzyme necessary for DNA repair.

Melanoma • Not just a disease of older patients – Most common cause of cancer-related mortality in young women – Well documented pediatric cases • Warning signs – Change in pre-existing mole – Itching/pain in pre-existing mole – New pigmented lesion as adult – ABCDs Malignant Melanoma: ABCD’s  A: Asymmetry B: Border C: Color D: Diameter – anything over 10mm should be looked at more closely. Melanoma: Pathologic Concepts • Radial and vertical growth phase – RGP: intraepidermal growth +/- minimal involvement of dermis – VGP: significant invasion into dermis Radial Growth Phase: Spread of melanoma cells within the epidermis and papillary dermis, often for a prolonged time. No capacity for metastasis. Vertical Growth Phase: Pattern of growth assumes a vertical component, the melanoma grows downward into the deeper dermis as an expansile mass. This correlates with the emergence of a clone of cells with true metastatic potential.

Malignant Melanoma In Blacks and Asians • Soles • Mucous membranes • Palms • Nail beds

• Depth of dermal involvement correlates with prognosis. – Clark’s level (anatomic location of tumor) – Breslow level (quantitative measurement) Test q: In melanoma, the single most important prognostic factor is: depth of invasion Test q: The Breslow measurement is used to: assess melanoma tumor stage and prognosis (as opposed to tumor grade and prognosis)

 Vertical – growing down into the dermis and subcutaneous fat.

Clark’s Levels  I – tumor cells are confined to the epidermis (melanoma in situ) II – superficial papillary dermis III – filling papillary dermis IV – in reticular dermis, where collagen fibers are thicker (distinguishes from papillary dermis) V – has the greatest risk of metastasis. Test q: A 37y/o red-haired female has a pigmented papule on her back that measures 0.8cm in diameter. On excisional biopsy, melanoma is diagnosed. The melanoma is confined entirely to the epidermis. The Breslow measurement is .75mm. This melanoma is most accurately described as: Melanoma in situ REPEATED x2 (once – it was 1.0cm in diameter) Test q: A 39y/o woman has a nodule on her back that has become larger over the past 2mo. On phys exam, there is a 2.1cm pigmented lesion w/irregular borders and an irregular brown-black color. An excisional biopsy w/wide margins is performed and microscopic exam of the biopsy specimen shows a malignant melanoma composed of epithelioid cells that extends 3.5mm (one year, was “2mm”) down to the reticular dermis. There is a band of lymphocytes beneath the melanoma. Which of the following statements is most appropriate to make to this patient regarding these findings? Metastases are probable. REPEATED x2 (One year, answer was “The prognosis is poor.” Other choices were the same both times: Her immune system will prevent metastases; Other family members are at risk for this condition; The primary site for this lesion is probably the eye; Nevi elsewhere on her body will become malignant.)

Breslow Level: • Perpendicular distance from granular layer • Measured in mm • More reproducible

Melanoma can metastasize to various locations in the body, including axillary nodes, lung, and liver. 

Melanoma: Histologic features • Asymmetric • Irregular nests • Single cell pattern • Pagetoid spread – upward spreading of melanocytes into the epidermis. • Nuclear atypia • Absence of maturation • Dermal mitotic figures

Above: Pagetoid spread. Can see nests of melanocytes. Also single cells growing into the epidermis.

Pagetoid spread.  Nuclei do not get smaller as they grow down. In the middle picture, see atypical cells. In the picture on the right, see mitotic figures. Melanoma – Molecular mechanisms: • Deletions of CDKN2A (INK4A) – Deletion of p16 protein product leads to: • Unrestricted phosphorylation of Rb (inactive Rb) • Unrestricted cell growth – Deletion of p14 (alternative protein product) leads to • Decreased p53 function (via decreased function of MDM2) • Enhanced growth of altered cells • BRAF mutations – Found in melanomas and nevi – Part of RAS/RAF/MAP kinase pathway

Test q: A 20y/o man has a raised, irregular, pigmented lesion on his forearm that has increased in size and become more irregular in color over the past 4 months. An excisional biopsy specimen shows a malignant melanoma that extends into the reticular dermis. Family history indicates that the patient’s paternal uncle died of metastatic melanoma that spread to the liver after excision of a primary lesion on the foot. His grandfather required enucleation of the left eye because of a “dark brown” mass in the eyeball. Which of the following genes is most likely to have undergone mutation to produce these findings? p16 (cell cycle inhibition) REPEATED x2

Mesenchymal Tumors: Benign Fibrous Histiocytoma(BFH)/Dermatofibroma (DF) Clinical Features: • Solitary, slow-growing nodule, often red-brown in color • Usually on extremities in dermis or superficial subcutis • Presents in early or mid-adult life • Spindled tumor cells • Collagen trapping – at the periphery of the tumor, the tumor cells interdigitate around preexisting collagen fibers of the reticular dermis Test q: A pigmented skin lesion measures 1cm in diameter. Biopsy shows a proliferation of spindled cells in the dermis that appear to “trap collagen”. The epidermis is not involved. Mitoses are not identified. The subcutaneous fat is not involved. Diagnosis: Dermatofibroma Test q: A 50y/o male develops a slightly pigmented nodule on his forearm. On biopsy, one sees a proliferation of spindleshaped cells in the dermis. Collagen trapping is present, but fat-trapping is absent. There are no mitoses. Diagnosis? Dermatofibroma

Dermatofibroma. Large dark pink area = lesion. Proliferation induces acanthosis (thickening) of the overlying epidermis.

Dermatofibrosarcoma Protuberans (DFSP) Clinical Features: • Slow-growing plaque, later nodular • Usually occurs in mid-adult life • Men > women • Trunk, proximal extremities most common site • Locally recurrent (very) • Metastasis 60 subtypes – Certain subsets associated w/squamous cell carcinoma • Common – Common wart (verruca vulgaris) – Plantar/palmar wart - caused by diff HPV subtypes – Genital wart (condyloma acuminatum) – Flat wart • Occur at any age • Self-limited Verruca Vulgaris: Histologic Features • Histology similar across all the different subtypes. • Papillomatosis – projections of epidermis • Acanthosis – thickening of epidermis • Tortuous vessels within papillae KEY FEATURE = Koilocytes. Have clear area within cytoplasm – due to viral particles present.

Molluscum Contagiosum: • Common especially in children • Dome-shaped papules with a central keratinfilled crater • Easily spread through contact • DNA poxvirus • Histologic Features: large, bright pink viral inclusions. • Molluscum body: eosinophilic cytoplasmic inclusion in upper layers of epidermis.

Test q: A 35y/o man has noted a bump on his upper trunk for the past 6wk. On phys exam, there is a solitary 0.4cm flesh-colored nodule on the upper trunk. The dome-shaped lesion is umbilicated, and a curd-like material can be expressed from the center. This material is smeared on a slide, and Giemsa stain shows many pink, homogenous, cytoplasmic inclusions. The lesion regresses over the next 2mo. Which of the following infectious agents most likely produced this lesion? Molluscum contagiosum

Impetigo: • Common superficial infection • Staphylococcus or streptococcus • Exposed surfaces • Characteristic honey-colored crust • Histologic Feature: Subcorneal pustule • A lot of neutrophils in the stratum corneum – can see gram positive cocci here.

Infestations: Scabies (Sarcoptes scabiei)

Above: The scabies mite.

Scabies feces.

Linear burrows.

Scabies like to burrow underneath the stratum corneum. Find them on the penis and web spaces of the fingers. Figure: Scabies organism underneath the stratum corneum. Scabies feces underneath? 

Herpesvirus infections: • HSV-1 – Cold sores, fever blisters – Oral infection most common – Cutaneous blistering eruption, usually linear • HSV-2 – Genital herpes • VZV – varicella zoster – Chicken pox  Figure: Germline mutation: born w/one mutated allele and one wildtype allele. During life, you’ll have hits – from viruses, chemicals, other environmental factors – and you will lose the wildtype allele. Called LOH (loss of heterozygosity)  uncontrolled proliferation.

 Figure: Herpes infects keratinocytes – see multinucleated cells (circled one has 10-15 nuclei)