Skin tumors For MBBS Students Taught by MD Path

Pathology

1. Skin Tumors Dr. Om Jha

2. THE SKIN: MORE THAN A MECHANICAL BARRIER Functions Of Skin !!!

3. Skin Structure Epidermis: Composed of stratified squamous epithelium. Produces keratin. Dermis: Consists of fibrous and fibroadipose tissue and supports the epidermis. Contains blood vessels, nerves and sensory receptors and skin appendages. Subcutis/hypodermis: Lies beneath dermis and consists of adipose tissue Contains larger blood vessels.

4. The skin is composed of: An epidermal layer (e) from which specialized adnexa—hair follicles (h), sweat glands (g), and sebaceous glands (s)—descend into the underlying dermis (d). The projection of the epidermal layer and underlying superficial dermis demonstrates the progressive upward maturation of basal cells (b) into cornified squamous epithelial cells of the stratum corneum (sc). Melanin-containing dendritic melanocytes (m) (and rare Merkel cells containing neurosecretory granules) and mid-epidermal dendritic Langerhans cells (lc) are also present. The underlying dermis contains small vessels (v), fibroblasts (f), perivascular mast cells (mc), and dendrocytes (dc), which participate in dermal immune responses and repair.

5. Layers of Epidermis: Stratum Basale : Single layer of cuboidal to low columnar basal cells. These cells proliferate continuously with repeated mitotic divisions. The cells then displace upwards with associated maturation. Stratum spinosum : Basal cells are attached to and mature into cells of stratum spinosum also known as pricle cell layer. Stratum Granulosum: Keratinocytes mature into stratum granulosum or granular layer where process of keratinization is started.

6. Contd.. Stratum corneum : Progressing upwards the surface, cells loose their nuclei and cytoplasm becoming flattened interconnected as keratin squames that comprises the stratum corneum. Stratum lucidum seen in areas of thick skin, palm and sole

7. Skin adnaxae (appendages) Nails Hair follicles Sebaceous glands Eccrine (sweat glands) Apocrine glands They are predominantly located in dermis. Usually arise as downward growths from epidermis into dermis during embryological development.

8. Summary: The skin has come to be appreciated as a surprisingly complicated organ—the largest in the body. It’s the first lines of defense against potentially harmful infectious and physical agents. The skin is also a highly sophisticated sensory organ and even has important endocrine roles, particularly the synthesis of vitamin D. It is composed of several cell types and structures that function interdependently and cooperatively.

9. SQUAMOUS EPITHELIAL CELLS (KERATINOCYTES) are normally “glued” tightly together by cell junctions known as desmosomes and produce abundant amounts of keratin protein, both of which serve to create a tough, durable physical barrier. In addition, keratinocytes secrete soluble molecules such as cytokines and defensins that augment and regulate cutaneous immune responses. MELANOCYTES within the epidermis are responsible for the production of melanin, a brown pigment that absorbs and protects against potentially injurious ultraviolet (UV) radiation in sunlight.

10. DENDRITIC CELLS: Skin serves as one of the first lines of defense against microorganisms and is constantly exposed to microbial and nonmicrobial antigens, which are processed by intra-epidermal dendritic cells known as Langerhans cells. Langerhans cells secrete factors that augment innate immune responses and migrate from the skin to regional lymph nodes where they present their antigenic cargoes to T lymphocytes, thereby stimulating the adaptive immune system. Specialized dendrocytes, another type of dendritic cell found within the dermis, perform similar functions.

11. LYMPHOCYTES : Following their stimulation by dendritic cells in regional lymph nodes, T cells expressing an adhesion molecule called cutaneous lymphocyte-associated antigen (CLA) and chemokine receptors such as CCR4 and CCR10 leave the lymph node and home back to the dermis, a process that is directed in part by chemokines secreted by activated keratinocytes. In addition, small numbers of B cells are found in the dermis that can participate in humoral responses to antigens encountered in the skin.

12. THE SKIN IS A LARGE AND COMPLEX ECOSYSTEM THAT PROVIDES NICHES FOR A BROAD SPECTRUM OF ORGANISMS, INCLUDING BACTERIA, FUNGI, VIRUSES, AND MITES. These organisms have evolved symbiotic relationships with their human hosts and appear to contribute to health in a number of ways. By occupying skin niches, the normal “zoo” of organisms (the skin microbiome) prevents colonization of the skin by other potentially harmful organisms, just as the gut microbiome.

13. AFFERENT NERVE FIBERS AND A DIVERSE SET OF ASSOCIATED SPECIALIZED STRUCTURES REFERRED TO AS NEURAL END ORGANS are responsible for physical sensations including touch, vibration, itchiness, cold, and heat. In addition, autonomic efferent nerve fibers regulate adnexal components such as sweat glands and effector pili muscles and can also influence the function of innate and adaptive immune cells in the dermis. Another cell type found in skin that remains cloaked in mystery is the Merkel cell; these cells are located in the epithelial basal cell layer and may have neuroendocrine or mechanoreceptor functions.

14. ADNEXAL COMPONENTS. Sweat glands guard against deleterious variations in body temperature, and hair follicles, in addition to manufacturing hair shafts, have protected niches harboring epithelial stem cells capable of regenerating superficial epithelial skin structures following their disruption by trauma, burns, and other types of injuries. Perturbations that disrupt the delicate homeostasis that exists among skin cells may produce conditions as varied as wrinkles and hair loss, blisters and rashes, life-threatening cancers, and disorders of immune regulation.

15. COMMON MACROSCOPIC SKIN LESIONS

16. EXCORIATION : Traumatic lesion breaking the epidermis and causing a raw linear defect (i.e., deep scratch); often self-induced.

17. LICHENIFICATION: Thickened, rough skin (similar to lichen on a rock); usually the result of repeated rubbing.

18. MACULE, PATCH: Circumscribed, flat lesion distinguished from surrounding skin by color. Macules are 5 mm in diameter or less; patches are greater than 5 mm.

19. ONYCHOLYSIS: Separation of nail plate from nail bed.

20. PAPULE, NODULE: Elevated dome-shaped or flat-topped lesion. Papules are 5 mm or less across; nodules are greater than 5 mm in size.

21. PLAQUE: Elevated flat-topped lesion, usually greater than 5 mm across (may be caused by coalescent papules).

22. PUSTULE: Discrete, pus-filled, raised lesion.

23. SCALE: Dry, horny, plate-like excrescence; usually the result of imperfect cornification.

24. VESICLE, BULLA, BLISTER: Fluid-filled raised lesion 5 mm or less across (vesicle) or greater than 5mm across (bulla). Blister is the common term for either lesion.

25. Wheal: Itchy , transient, elevated lesion with variable blanching and erythema formed as the result of dermal edema.

26. COMMON MICROSCOPIC SKIN LESIONS

27. ACANTHOSIS: Diffuse epidermal hyperplasia

28. DYSKERATOSIS: Abnormal , premature keratinization within cells below the stratum granulosum.

29. HYPERKERATOSIS: Thickening of the stratum corneum, often associated with a qualitative abnormality of the keratin

30. PARAKERATOSIS: Keratinization with retained nuclei in the stratum corneum. On mucous membranes, parakeratosis is normal.

31. ULCERATION: Discontinuity of the skin marked by complete loss of the epidermis revealing dermis or subcutis.

32. Summary:

33. Classification of Skin Tumors

34. MELANOCYTIC LESIONS (A) Benign Pigmented Lesions:- MELANOCYTIC NEVUS Junctional nevus Compound nevus Intradermal nevus DYSPLASTIC NEVUS (B) Malignant Pigmented Lesion:- Malignant Melanoma

35. MELANOCYTES Melanocytes are pigment-producing cells with dendritic projections that are normally interspersed among basal keratinocytes.

36. Melanocytic nevus Benign, exophytic, usually pigmented, congenital lesion of the skin or mucosa composed of focal collections of rounded melanocytes (nevus cells). • The term nevus commonly used for mole. • Nevi mostly occur on skin, occasionally occur on mucous membrane. • Its also called birthmark.

37. Pathogenesis Most cases have acquired gain-of –function mutations in RAS or BRAF These mutations lead to unbridled BRAF/RAS signaling that induces melanocytic proliferation

38. Clinical features Usually are of only cosmetic concern but may cause irritation or mimic melanoma very common in white people Most naevi appear in adolescence, early adulthood & during pregnancy some nevi can possibly transform to melanoma May become more prominent during pregnancy, indicating a degree of hormone sensitivity.

39. Morphology- Gross Most nevi are tan to brown , uniformly pigmented and small (usually < 6 mm diameter) , Relatively flat macules or elevated papules with well-defined, rounded borders Small, uniform, symmetric relatively flat lesion ( junctional type nevus) Compound type nevus is raised and dome-shaped.

40. Morphology- Microscopic Nevi progress through a series of morphologic changes over time. Earliest stage lesions called Junctional nevi consist of aggregates or nests of round to oval nevus cells that grow along the dermoepidermal junction . (k/a junctional activity ) This rounded nests of nevus cells originating at the tips of rete ridges along the dermoepidermal junction.

41. Nuclei of nevus cells are uniform and round, contain inconspicuous nucleoli, and show little or no mitotic activity

42. Most junctional nevi grow into underlying dermis as nests or cords of cells to form compound nevi. Thus, compound nevi consists of nevus cells both at dermo -epidermal junction and dermis.

43. In older lesions, epidermal nests may be lost entirely to form pure intradermal nevi . These nevus cells grow in small nests, cords or as single cells.

44. Morphology contd - Maturation of nevus cells Growth of nevus cells from the dermoepidermal junction into the underlying dermis is accompanied by morphologic changes: Superficial nevus cells are larger, tend to produce melanin and grow in nests Deeper nevus cells are smaller , produce little or no pigment , and appear as cords and single cells. Deepest nevus cells are often spindled schwannian -like cells having oval nuclei and grow in fascicles resembling neural tissue (neurotization ). These changes are helpful in distinguishing benign nevi from melanomas, which lack such features

45. Maturation (metamorphosis) of nevus cells

46. 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. Nevi may exist at any stage in this sequence for variable periods of time, although many are believed to progress through this sequence.

47. DYSPLASTIC NEVUS Direct precursors of melanoma, when multiple they imply increased risk for melanoma. Evidences supporting that some dysplastic nevi are precursors of melanoma: Study of families affected by dysplastic nevus syndrome (AD, Familial case) in which tendency to develop multiple dysplastic nevi and melanoma are co-inherited. Dysplastic nevus syndrome pt - >50% chance of developing melanoma by age 60 Histological transformation of dysplastic nevi to melanoma has been documented

48. Pathogenesis Acquired activating mutations in NRAS or BRAF genes Increased CDK4 activity due to Activating mutations in the CDK4 gene Inherited loss-of-function mutations in CDKN2A

49. Clinical features Dysplastic nevi may be sporadic or familial . Familial cases have an increased risk of developing melanoma . However, vast majority never progress to melanoma May also occur as isolated lesions in normal individuals  risk of melanoma transformation is very low. Acquired cases are common than congenital Can occur on both sun-exposed and protected body surfaces

50. Morphology of dysplastic nevi- GROSS Larger than most acquired nevi ( often >5 mm diameter ) and may number in the hundreds in familial cases May appear as flat macules to slightly raised plaques with a “pebbly” surface, or target-like lesions with a darker raised center and irregular flat periphery. [variability in pigmentation ( variegation), and irregular borders]

51. Morphology of dysplastic nevi-microscopic Involve both epidermis and dermis Exhibit both architectural & cytologic atypia Architectural atypia :- Nevus cell nests within the epidermis may be enlarged and often fuse or coalesce with adjacent nests ( Bridging of nests of melanocytes at the dermo-epidermal junction ) Single nevus cells begin to replace normal basal cell layer along dermoepidermal junction, producing lentiginous hyperplasia.

52. Cytologic atypia includes : nuclear enlargement; irregular, often angulated, nuclear contours; and nuclear hyperchromasia

53. Associated alterations in the superficial dermis include:- sparse lymphocytic infiltrates ; release of melanin from dead nevus cells into the dermis ( melanin incontinence ), where it is phagocytosed by dermal macrophages ( melanophages ) (H) Peculiar linear fibrosis (F) surrounding the epidermal rete ridges that are involved by the nevus

54. Malignant Melanoma Most deadly of all skin cancers; strongly linked to acquired mutations caused by exposure to UV radiation in sunlight. But can be cured if detected and treated at its earliest stages. Sites: Majority : sun exposed skin surfaces  upper back in men and the back and legs in women Lightly pigmented individuals (White race) are at higher risk. Other sites include: oral and anogenital mucosal surfaces, esophagus, meninges, uvea.

55. Risk factors UV exposure Number of normal or atypical moles Family history of melanoma Immunosuppression Increasing age Gender: males> females

56. Clinical features Usually asymptomatic; pruritus or pain may be early manifestations Majority of lesions >10 mm in diameter at diagnosis Most important clinical signs are changes in the color, size, or shape of a pigmented lesion.

57. Clinical features Warning signs: ABCDEs of melanoma: Asymmetry Irregular Borders Varied Color Increasing Diameter Evolution/ change over time, especially if rapid

58. Phases of melanoma development Key phases of melanoma development are marked by radial and vertical growth phases. Earliest phase: lateral expansion of melanocytes along dermoepidermal junction ( lentiginous hyperplasia and lentiginous compound nevus ) This then progresses to the phase of melanoma in situ marked by radial growth which describes the horizontal spread of melanoma within epidermis and superficial dermis. (Grossly flat macular lesion )

59. Radial growth phase

60. With time, a vertical growth phase (VGP) supervenes, in which tumor grows downward into deeper dermis as an expansile mass lacking cellular maturation. (Grossly, nodular lesion ) Tumors with VGP has metastatic potential.

61. Morphology of melanoma- GROSS striking variations in color, appearing in shades of black, brown, red, dark blue & gray . Zones of white or flesh-colored hypopigmentation also noted due to focal regression of tumor. The borders of melanomas are irregular and often notched. Typical lesions are irregular in contour and pigmentation . Macular areas correlate with the radial growth phase, while raised areas correspond to nodular aggregates of malignant cells in vertical growth phase.

62. Morphology of melanoma- microscopic Melonama cells grow as poorly formed irregular nests or as individual single cells at all levels of epidermis ( pagetoid spread )  constitues the Radial growth phase (RGP) RGP is seen in Superficial spreading melanoma

63. Microscopy ( contd ) Later Vertical growth phase (VGP): tumor cells invade downward into the deep dermis as expansile mass of nodular aggregates . VGP is characteristically seen in Nodular melanoma . Maturation or “ neurotization ” is absent from the deep invasive portion of melanoma.

64. Individual melanoma cells are:- larger than nevus cells have enlarged nuclei with irregular contours, clumped peripheral nuclear chromatin, and prominent “cherry red” ( eosinophilic ) nucleoli Immunohistochemical (IHC) stains for melanocytic markers (e.g. HMB-45 ) is helpful in identifying metastatic deposits. Microscopy ( contd )

65. Prognosis The prognosis for patients with malignant melanoma depends upon the stage at presentation. Metastatic spread of malignant melanoma is very common and takes place via lymphatics to the regional lymph nodes and through blood to distant sites like lungs, liver, brain, spinal cord, and adrenals.

66. Prognostic factors:malignant melanoma

67. Determinants of a more favorable prognosis: Thinner tumor depth, No or very few mitoses (< 1 per mm2), A brisk tumor infiltrating lymphocyte response, Absence of regression, Lack of ulceration.

68. Thank you