Malignant Epidermal Tumors

Question 1

Squamous cell carcinoma SCC

Answer 1

1/common tumor that typically arises on sun-exposed sites
2/inolderadults.
3/higher incidence in men.

Question 2

Pathogenesis of SCC

Answer 2

1/UV light exposure, which leads to widespread DNA damage and extremely high mutational loads .

2/patients with the rare disorder xeroderma pigmentosum, which disrupts repair of UV-induced DNA damage, are at an exceptionally high risk.

3/activating mutations in RAS and loss-of-function mutations in Notch receptors.

4/Immunosuppression, particularly in organ transplant recipients, is associated with an increased incidence that are likely to be associated with HPV infection.

5/Other predisposing factors include industrial carcinogens (tars and oils), chronic non-healing ulcers, old burn scars, ingestion of arsenicals, and ionizing radiation.

Question 3

Morphology of SCC

Answer 3

1/SCC in situ appear as sharply defined, red, scaling plaques.

2/some appear to arise in association with prior actinic keratoses.

3/highly atypical cells at all levels of the epidermis, with nuclear crowding and disorganization.

4/More advanced, invasive squamous cell carcinomas are nodular, often scaly lesions that may undergo ulceration/variable degrees of differentiation.

Question 4

Clinical feature of SCC

Answer 4

Invasive SCC of the skin often are discovered while small and resectable. Less than 1% will have metastasized to regional lymph nodes at diagnosis.

1/Tumors arising from actinic keratoses may be locally aggressive but generally metastasize only after long periods of time,
2/while those arising in burn scars, ulcers, and non–sun-exposed skin often behave more aggressively.

3/Squamous cell carcinomas arising at internal sites (oropharynx, lung, esophagus, anus) are generally invasive and aggressive,

Question 5

Basal cell carcinoma BCC

Answer 5

1/common slow-growing cancer.
2/that rarely metastasizes.
3/chronic sun exposure and in lightly pigmented individuals.

Question 6

Pathogenesis of BCC

Answer 6

1/The molecular hallmark of BCC is loss-of function mutations in PTCH1, a tumor suppressor gene (negatively regulates Hedgehog signaling).

2/In sporadic BCC, PTCH1 mutations Is due to UV light–induced DNA damage.

2/Gorlin syndrome, an autosomal dominant disorder caused by inherited defects
in PTCH1 that is associated with familial BCC.

patients with Gorlin syndrome also often manifest subtle developmental anomalies.

Mutations in TP53 caused by UV light–induced damage also are common in both familial and sporadic tumors.

Question 7

Morphology of Basal cell carcinomas

Answer 7

1/manifest as pearly papules, often with prominent, dilated subepidermal blood vessels (telangiectasia)

2/Some tumors contain melanin pigment and can have an appearance similar to melanocytic nevi or melanomas.
3/Tumor cells arise from either the epidermis or the follicular epithelium, they are not encountered on mucosal surfaces.

4/Two common patterns are seen: A/multifocal superficial growths, originating from the epidermis, B/nodular lesions growing downward into the dermis as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a fibrotic or mucinous stromal matrix .
Peripheral tumor cell nuclei align in the outermost layer (a pattern termed palisading), which often separates from the stroma, creating a characteristic cleft.

Question 8

Clinical feature of BCC

Answer 8

1/Individual tumors usually are cured by local excision, but approximately 40% of patients develop another BCC within 5 years.
2/ Advanced lesions may ulcerate, extensive local invasion of bone or facial sinuses may
occur if the lesions are neglected.
3/Metastasis is exceedingly rare.
4/Hedgehog pathway inhibitors are used to treat locally advanced or metastatic tumors.

Question 9

Pathogenesis of

Melanocytic(benign neoplasm of melanocytes)Nevi(any congenital lesion of the skin).

Answer 9

1/are benign neoplasms caused by somatic gain-of-function mutations in BRAF or RAS.

2/very few nevi transform into malignant.

3/Superficial nevus cells are larger and tend to produce melanin and grow in nests;
deeper nevus cells are smaller, produce little or no pigment, and grow in cords or single cells.
The deepest nevus cells have fusiform contours and grow in fascicles. (2F😉)

This sequence of morphologic changes is of diagnostic importance, since they are absent from
melanomas.

Question 10

Morphology of melanocytic nevus

Answer 10

1/Common melanocytic nevi are tan-to-brown.(uniformly pigmented).

2/small papules (5 mm or less across) with well-defined,rounded borders.

3/Early lesions= junctional nevi are composed of cells that grow in “nests” along thedermoepidermal junction.With no mitotic activity.

4/compound nevi= junctional nevi grow that into the underlying dermis as nests or cords of cells .

5/Intradermal nevi older lesions that havelost epidermal nests (may be lost entirely)

Question 11

Clinical features of melanocytic nevi

Answer 11

1/usually are of only cosmetic concern.
2/may cause irritation or mimic melanoma, requiring their surgical removal.
3/Compound and intradermal nevi often are more elevated than junctional nevi.

Question 12

Dysplastic nevi

Answer 12

1/may be sporadic or familial(increased risk of developing melanoma).

2/Activating RAS or BRAF mutations are commonly found.

Question 13

Morphology of Dysplastic nevi

Answer 13

1/Are larger than most acquired nevi (often more than 5 mm across) and may number in the hundreds.
2/They are flat macules to slightly raised plaques, with a “pebbly” surface=مغطاة وة كوچگ).
3/They usually have variable pigmentation (variegation)
4/irregular borders.

5/Are mostly compound nevi

6/Nevus cell nests within the epidermis may be enlarged and exhibit abnormal fusion or coalescence with adjacent nests (bridging).

7/single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction, producing so-called lentiginous hyperplasia.

8/Cytologic atypia consisting of irregular, often angulated, nuclear contours and hyperchromasia.

9/alterations in superficial dermis:-(عبارة عن استجابة مناعية)
A-lymphocytic infiltrate.
B-release of melanin pigment (melanin incontinence), that is phagocytosed by dermal macrophages.
C-linear fibrosis surrounding epidermal nests of melanocytes.

Question 14

Clinical features of dysplastic nevi

Answer 14

1/have a tendency to occur on body surfaces not exposed to the sun as well as on sun-exposed sites.
2/Familial dysplastic nevus syndrome is strongly associated with melanoma, 100%.
3/In sporadic cases, only individuals with 10 or more dysplastic nevi appear to be at an increased risk for melanoma.

most melanomas appear to arise de novo and not from a preexisting nevus.

Question 15

Melanoma

Answer 15

1/is less common but much more deadly than
BCC or SCC.
2/most melanomas are cured surgically.

Question 16

Melanoma pathogenesis

Answer 16

1/mainly caused by UV light–induced DNA damage.
2/ much of the population is fair-skinned.

3/Hereditary predisposition also plays a role in an estimated 5% to 10% of cases,(familial dysplastic nevus syndrome).

4/The initiating event is an activating mutation in BRAF or (less commonly)
RAS. In the vast majority of cases, this produces only a benign nevus unless other mutations are superimposed.

5/germ-line mutations in the CDKN2A locus /40% of the rare individuals /who suffer from familial melanoma.
This complex locus encodes two tumor suppressors p14 +p16

6/The earliest phase is proposed to consist of lateral expansion of melanocytes along the **dermoepidermal junction (lentiginous hyperplasia and lentiginous compound nevus

7/Then progresses to the phase of melanoma in situ, which is marked by radial growth within the epidermis, often for a prolonged period.
A-commonly harbor mutations that activate the expression of telomerase.
B-do not have the capacity to invade and metastasize.)

8/In vertical growth phase , in which the tumor grows downward into the deeper dermal layers /mass lacking cellular maturation /development of a nodule in a previously flat lesion /emergence of metastatic potential.
A-With loss of CDNK2A and its encoded tumor suppressor p16/shifts to the invasive vertical phase of growth.

B-exposure to UV light adds to the mutational burden and increases the chances of tumor progression.

C-with additional mutations in genes such as tumor suppressors TP53 and
PTEN, the tumor acquires the capacity for metastasis.

D-This phase is marked by the appearance of aneuploidy (genomic copy number alterations).

9/less common melanomas that arise in non–sun-exposed acral(palms of the hands, soles of the feet, and nails, all of which are non-hair-bearing sites)and mucosal sites :-
-The most common initiating mutation in these tumors is a gain-of-function mutation in the KIT receptor tyrosine kinase.
10/melanomas arising in the uvea of the eye/mutations that activate the GTP-binding proteins GNAQ or GNA11.
11/melanomas express neoantigens that should be subject to recognition by the immune system.

12/tumor cells must acquire the ability to either suppress or evade the host immune response.

13/advanced melanomas response to immune checkpoint inhibitors, agents that unleash muzzled melanoma-specific T cells, allowing them to attack the tumor.

Question 17

Morphology of melanomas

Answer 17

1/often exhibit striking variations in pigmentation, including shades of black, brown, red, dark
blue, and gray.
2/The borders are irregular and often “notched.”
3/malignant cells grow as:-
A-poorly formed nests or as individual cells at all levels of the epidermis (pagetoid spread) /radial growth phase.
B-in expansile dermal nodules;/vertical growth phases.
4/superficial spreading melanomas are often associated with a brisk lymphocytic infiltrate .
5/Increasing thickness strongly correlates with worse biologic behavior of melanomas (termed Breslow thickness).
6/Individual melanoma cells usually are considerably larger than nevus cells.
7/large nuclei with irregular contours/chromatin clumped at the periphery of the nuclear membrane/ prominent “cherry red” eosinophilic nucleoli .
8/Immunohistochemical stains can be helpfulin identifying metastatic deposits

Question 18

Clinical features of melanoma

Answer 18

1/most of these lesions arise in the skin, they also may occur in the oral and anogenital mucosa surfaces, the esophagus, the meninges, and the eye.

2/Melanoma of the skin usually is asymptomatic, although pruritus may be an early manifestation.

3/The most important clinical sign of skin melanoma is a change in the color or size of a pigmented lesion.

4/The main clinical warning signs are as follows:
A-Rapid enlargement of a preexisting nevus
B- Itching or pain in a lesion
C- Development of a new pigmented lesion during adult life
D-Irregularity of the borders of a pigmented lesion
E-Variegation of color within a pigmented lesion
** These principles are expressed in the so-called “ABCs”of melanoma: asymmetry, border, color, diameter, and evolution (change of an existing nevus).**

5-superficial lesions are curable surgically, while metastatic melanoma has a very poor prognosis.

6-The probability of metastasis is predicted by measuring the depth of invasion in millimeters of the vertical growth phase nodule from the top of the granular cell layer of the overlying epidermis (Breslow thickness).

7-Metastasis risk also is increased in tumors with:-
A- a high mitotic rate
B-in those that fail to induce a local immune response.

8-If metastasis occur it can involve regional lymph nodes ,liver, lungs, brain, and virtually any other
site that can be seeded hematogenously.

9-Agents that selectively inhibit mutant BRAF and KIT have produced dramatic responses in patients with metastatic tumors with BRAF and KIT mutations, respectively.