[SP] P.02A The Skin.pdf

SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 OUTLINE B. MACROSCOPIC TERMS IN DERMATOPATHOLOGY I. THE SKIN.............................

SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 OUTLINE B. MACROSCOPIC TERMS IN DERMATOPATHOLOGY I. THE SKIN..................................................................... 1 Table 1.1 Descriptive macroscopic terms referring to skin lesions and A. Normal Histology of the Skin................................... 1 disorders B. Macroscopic Terms in Dermatopathology............... 1 MACROscopic Terms C. Microscopic Terms................................................. 3 II. THE DISORDERS OF PIGMENTATION............................ 6 1. Excoriation Ø Traumatic lesion characterized by A. Freckles............................................................... 6 breakage of the epidermis, B. Lentigo................................................................. 7 causing a raw linear area C. Melanocytic Nevus............................................... 7 o I.e., a deep scratch D. Dysplastic Nevi..................................................... 9 E. Melanoma.......................................................... 11 III. CASE....................................................................... 13 IV. REFERENCES........................................................... 13 I. THE SKIN A. NORMAL HISTOLOGY OF THE SKIN Figure 4. Excoriations in the abdominal area Figure 1. Normal Skin Histology Figure 5. Excoriated wound 2. Lichenification Ø Thickened and rough skin characterized by prominent skin markings Ø Usually the result of repeated rubbing/scratching in susceptible persons o Example: people with allergic contact dermatitis Figure 2. Normal epidermal layer Figure 6. Lichenification due to contact dermatitis Figure 3. Layers of the epidermis Figure 7. Lichenification DUMLAO, GAYAO, LOPEZ L., RAPOSAS SURGICAL PATHOLOGY Page 1 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 3. Macule Ø Circumscribed lesion of 5 mm flatness Ø May be caused by coalescence Ø Usually discolored (often red) of papules Figure 8. Macule Figure 11. Plaque of psoriasis vulgaris 7. Pustule Ø Discrete, pus-filled, raised lesion 4. Onycholysis Ø Separation of nail plate from nail Ø Essentially a papule filled with pus bed Figure 9. Onycholysis Figure 12 & 13. Pustule 5. Papule Ø Elevated dome-shaped or flat- topped lesion 5 mm in diameter characterized by flatness Ø Usually discolored (often red) Figure 19. Acanthosis Ø Exaggerated interdigitating papillary dermis (blue arrow) Ø Exaggerated rete ridges (red arrow) Ø Thickened epidermis (green arrow) Figure 17. Patch 3. Dyskeratosis Ø Abnormal keratinization occurring prematurely within individual cells or groups of cells below the stratum granulosum Ø Keratinization: normal above stratum granulosum DUMLAO, GAYAO, LOPEZ L., RAPOSAS SURGICAL PATHOLOGY Page 3 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 Figure 20. Premature keratinization (red box) below the stratum granulosum (blue) Figure 24. Infiltration of lymphocytes and polymorphs (inflammatory cells) in the epidermis 6. Hydropic Ø Intracellular edema of Swelling keratinocytes (Ballooning) Ø Usually seen in viral infections o Part of the cytopathic effect of the virus Figure 21. Acantholytic dyskeratotic keratinocytes Ø A few of the keratinocytes are detached and prematurely keratinized (red box) below the stratum granulosum 4. Erosion Ø Discontinuity of the skin exhibiting incomplete loss of Figure 25. Hydropic swelling the epidermis Figure 26. Some keratinocytes are clearly swollen in the stratum spinosum Figure 22. Erosion of the epidermis 7. Hypergranulosis Ø Hyperplasia of the stratum Ø Epidermis (blue) is eroded (red granulosum box) Ø Often due to intense rubbing Ø Abundance of neutrophils o Seen in patients with (yellow circle) psoriasis Ø Dermis (green) is infiltrated by lymphocytes 5. Exocytosis Ø Infiltration of the epidermis by inflammatory or circulating blood cells Figure 27. Exaggeration of the stratum granulosum 8. Hyperkeratosis Ø Thickening of the stratum corneum Ø Often associated with a Figure 23. Exocytosis exhibited at the qualitative abnormality of the center of the image (red box) keratin DUMLAO, GAYAO, LOPEZ L., RAPOSAS SURGICAL PATHOLOGY Page 4 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 11. Parakeratosis Ø Mode of keratinization characterized by the retention of the nuclei in the stratum corneum Ø On mucous membranes, parakeratosis is normal o Parakeratosis at the skin surface is abnormal Figure 28. Hyperkeratosis of the stratum corneum 9. Lentiginous Ø Referring to a linear pattern of melanocyte proliferation within the epidermal basal cell layer Ø Lentiginous melanocytic Figure 31. Keratinocytes retain their nuclei hyperplasia can occur as a at the stratum corneum reactive change or as part of a neoplasm of melanocytes 12. Spongiosis Ø Intercellular edema of the epidermis o Vs. hydropic degeneration: intracellular edema Figure 29. Linear proliferation of basal melanocytes 10. Papillomatosis Ø Surface elevation caused by hyperplasia and enlargement of contiguous dermal papillae in between ridges Figure 32. Increase in the intercellular o A conglomerate space between keratinocytes hyperplastic dermal papillae will form a papilla seen clinically as a palpable lesion Ø Commonly seen in warts Figure 33. Spongiosis 13. Ulceration Ø Discontinuity of the skin exhibiting complete loss of the epidermis Figure 30. Papillomatosis Ø Often revealing portions of the dermis and even subcutaneous Ø Marked hyperplasia of the fat dermal papillae (red arrow) DUMLAO, GAYAO, LOPEZ L., RAPOSAS SURGICAL PATHOLOGY Page 5 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 Figure 34. Removal of the entire epidermis exposing the dermis Figure 35. Area of ulceration (black arrow) 14. Vacuolization Ø Formation of vacuoles within or adjacent to cells Ø Often refers to assess at the dermo-epidermal junction Figure 36. Vacuolization DUMLAO, GAYAO, LOPEZ L., RAPOSAS SURGICAL PATHOLOGY Page 6 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 DISORDERS OF PIGMENTATION AND MELANOCYTES MELANOCYTIC NEVUS FRECKLE (EPHELIS) LENTIGO DYSPLASTIC NEVI (PIGMENTED NEVUS, MOLE) Ø Most common pigmented lesions Ø Plural: lentigenes Ø Common benign neoplasms of Ø May be direct precursors of in childhood in lightly pigmented Ø Benign localized hyperplasia of melanocytes melanoma and when individuals melanocytes Ø Diverse, dynamic, and multiple in number are a Ø Occurs at all ages, but most biologically fascinating marker of an increased risk Ø Once present, freckles fade and commonly appears in infants and neoplasms for melanoma darken in a cyclic fashion during children Ø Become more prominent during Ø The vast majority of dysplastic winter and summer, respectively Ø No sex or racial predilection pregnancy, indicating a degree of nevi are clinically stable and o Not because of changes in Ø No waxing and waning (do not hormone sensitivity never progress to melanoma the number of darken when exposed to light) Ø Not all melanomas in DESCRIPTION/CLINICAL melanocytes, but in the individuals with dysplastic FEATURES degree of pigmentation nevus syndrome arise from dysplastic nevi Ø These lesions are best viewed as indicators of increased melanoma risk Ø Dysplastic nevi may also occur as isolated lesions (risk of malignant transformation is very low in these individuals) Ø It is unclear whether freckles Ø Cause and pathogenesis are Ø Mostly caused by acquired Ø Development of dysplastic result from: unknown activating mutations in nevi and their eventual o A focal abnormality in components of the RAS progression to melanoma, pigment production in a signaling pathway presumably through discrete field of o Many have acquired stepwise acquisition of melanocytes mutations that lead to mutations or epigenetic o Enhanced melanin transfer constitutive activation of changes to adjacent basal NRAS or the serine/ Ø Dysplastic nevi also keratinocytes threonine kinase BRAF frequently have acquired o Some combination thereof o Oncogene-induced activating mutations in the PATHOGENESIS senescence may answer NRAS and BRAF genes why nevi only rarely give rise Ø Individuals often have to melanomas inherited loss of function o Permanent growth arrest mutations in CDKN2A is mediated by the (encodes p16) accumulation of p16/INK4a Ø Mutations in CDK4 that (disrupted in melanoma) make the CDK4 protein resistant to inhibition by p16/INK4a DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 7 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 MELANOCYTIC NEVUS FRECKLE (EPHELIS) LENTIGO DYSPLASTIC NEVI (PIGMENTED NEVUS, MOLE) Maturation Sequence of Nondysplastic Melanocytic Nevi Ø Progressive growth of nevus cells from the dermoepidermal junction into the underlying dermis reflects oncogene- induced senescence (Figure 6) Ø Correlates with the maturation of nevus cells: o Superficial nevus cells: larger, tend to produce melanin, and grow in nests o Deeper nevus cells: smaller, produce little or no pigment, and appear as cords and single cells o Most mature cells: deepest portion of the nevus § Cells often acquire fusiform contours and grow in fascicles resembling neural tissue (neurotization) Ø This metamorphosis correlates with enzymatic changes (progressive loss of tyrosinase activity and acquisition of cholinesterase activity) in deeper, nonpigmented, “nerve- like” nevus cells Figure 5. Maturation sequence of nondysplastic melanocytic nevi. A, Normal skin shows only scattered dendritic melanocytes within the epidermal basal cell layer. B, Junctional nevus. C, Compound nevus. D, Dermal nevus. E, Dermal nevus with neurotization, a change that is also referred to as maturation. DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 8 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 MELANOCYTIC NEVUS FRECKLE (EPHELIS) LENTIGO DYSPLASTIC NEVI (PIGMENTED NEVUS, MOLE) Ø Increased ratio of melanocytes to Ø May involve mucous membranes Ø Common acquired melanocytic Ø Larger than most acquired keratinocytes (normal 1:4-10) as well as skin nevi are tan to brown nevi (often > 5 mm across) Ø Clinically, these are small (1 mm to Ø Consist of small (5-10 mm across), Ø Uniformly pigmented Ø May appear as: several mm in diameter), tan-red oval, tan-brown macules or Ø Small (6 mm) FEATURES o Course (fast, continually growing) o Elevation o Firm o Growing Ø Mostly arises in the skin; other sites of origin include the oral and anogenital surfaces (i.e., oropharynx, GI, and GU tracts), the esophagus, the meninges, and the uvea of the eye Ø In about 10-15% of affected patients, the risk of melanoma is inherited as an AD trait with variable penetrance Ø Predisposing factors: o Inheritance of genes (“driver” mutations): § Mutations that disrupt cell cycle control genes: CDKN2A gene mutation seen in 40% of autosomal dominant familial melanoma § Mutations that activate pro-growth signaling pathways: o Activating mutations in BRAF: 40% to 50% of melanomas o Activating mutations in NRAS: additional 15% to 20% of tumors § Mutations that activated telomerase: TERT mutations in roughly 70% of PATHOGENESIS tumors § WNT/beta-catenin mutations § Melanomas arising in non-sun exposed cutaneous sites: likely due to activating mutations in the receptor tyrosine kinase KIT o The overwhelming majority of melanoma is sporadic due to a single predisposing environmental factor: ultraviolet radiation (UVR) damage from sun exposure Ø Melanomas most commonly arise on sun-exposed surfaces, particularly the upper back in men and the back and legs in women Ø Lightly pigmented individuals are at higher risk than darkly pigmented individuals Ø Various colors Ø On occasion, zones of white or flesh-colored hypopigmentation also appear, sometimes due to focal regression of the tumor GROSS Ø Borders: irregular and notched Figure 21. Melanoma; >6mm, variegated appearance, irregular borders and asymmetrical Figure 22. Melanocytic Nevus (left) vs. Melanoma (right) DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 14 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 MELANOMA Table 1: Progression of melanoma A. Radial growth Ø Horizontal spread of melanoma within the epidermis and superficial dermis Ø Tumor cells seem to lack the capacity to metastasize Ø Several clinicopathologic classes: Lentigo maligna Superficial spreading Acral/mucosal lentiginous melanoma: Indolent lesion on the face of older men that Most common type of melanoma, usually Unrelated to sun exposure may remain in the radial growth phase for involving sun-exposed skin several decades B. Vertical growth phase Ø Tumor cells invade downward into the deeper dermal layers as an expansile mass Ø Appearance of a nodule Ø Correlates with the emergence of a tumor subclone with metastatic potential Ø Potential for metastasis correlates with Breslow thickness Ø Individual melanoma cells are usually larger than normal melanocytes o Enlarged nuclei with irregular contours o Clumped chromatin at the periphery of the nuclear membrane o Prominent red (eosinophilic) nucleoli MICROSCOPIC Ø Appearance is similar in the radial and vertical growth phases Ø A small fraction of “atypical” lesions fall in a histologic gray zone and have termed melanocytic tumors of uncertain malignant potential o Require complete excision and close clinical follow-up Figure 23. Melanoma in Radial Phase Red circle: Tumor infiltrating lymphocytes at the base of the tumor; Blue line: area of deep dermis; Yellow line: Superficial dermis; Black arrow: Figure 24. Higher magnification of Figure 23. epidermis; Yellow arrow: Dermo-epidermal Red arrow: Individual melanoma cell; Black circle: junction Figure 25. Melanoma in Vertical growth Melanin within melanoma cells; Black rectangle: A. Melanin incontinence in melanoma; Amelanotic melanoma cells (melanoma cells with no pigment) B. Lentiginous proliferation – always look at the stratum basale; Black arrows: coarse collagen fibers indicate that melanoma has already reached the deep dermis or reticular layer DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 15 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 MELANOMA Ø ABCDEs of melanoma o Asymmetry o Irregular borders o Variegated color o Increasing diameter o Evolution/change over time Ø Skin melanoma is usually asymptomatic, although itching or pain may be early manifestations Ø Majority of lesions are >10 mm in diameter at diagnosis Ø Most consistent clinical signs are changes in the color, size, or shape of a pigmented lesion Ø Treatment: drugs that target the RAS and PI3K/AKT pathways o Urgently needed as metaplastic melanoma is resistant to both chemotherapy and radiation treatment o There have also been successful developments of therapeutic regimens using antibodies that inhibit immune checkpoint proteins (e.g., CTLA4 and PD1) Clark Levels Ø Staging system, which describes the level of anatomical invasion of the melanoma in the skin Table 2. Clark Levels Clark Level Melanoma involvement Level 1 Intraepidermal DIAGNOSIS Level 2 Junctional Up to interface of superficial Level 3 dermis and deep dermis Level 4 Up to reticular dermis Level 5 Subcutaneous fat/hypodermis Figure 26. Clark Levels Breslow Thickness Ø Measurement of the depth of the melanoma from the surface of your skin down through to the deepest point of the tumor Ø Distance from the superficial epidermal granular cell layer to the deepest intradermal tumor cells DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 16 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 MELANOMA Melanoma Staging Ø Uses Clark and Breslow together Ø More clinical correlation when Breslow depth is a helpful measure of how far melanoma has invaded the body and the Clark level is a staging system that describes the depth of melanoma Figure 29. Staging of melanoma AJC TNM Staging Ø Took over Clark and Breslow in staging cancers DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 17 of 18  SURGICAL PATHOLOGY P.02A The Skin Dr. Ayochok | August 19, 2024 MELANOMA Figure 30. Nodular form of melanoma Black arrow: Nodule containing proliferating melanoma cells; Figure 31. Melanoma; Red line: Where we measure Breslow Red line: start to do Breslow/measure involvement Favorable Prognostic Factors Ø < 1.7 mm tumor depth Ø Few/absent mitotic figures Ø Many tumor infiltrating lymphocytes (higher the lymphocytes, better prognosis) Ø Absence of regression Ø Female gender Ø Found on an extremity Case: 30-year-old female face excision. Diagnosis? Ø Well-defined elevated papular lesion with clean border Ø Red box: nevus cells within the dermis Ø Histology shows intradermal nevus II. REFERENCES Ø Doc Ayochock’s Lecture DUMLAO, GAYAO, LOPEZ L, RAPOSAS SURGICAL PATHOLOGY Page 18 of 18