Premalignant Skin Lesion (Skin Tumors) PDF

Skin tumours Farooqa Rodaina 1 BENIGN, PREMALIGNANT & MALIGNANT EPITHELIAL TUMORS OF SKIN DR MUHAMMAD ABRAR BARAKZAI MBBS, MPhil (Histopath), FCPS (Histopath),  LEARNING OBJECTIVES 1. Discuss the classification of tumors of the skin. 2. Desc...

Skin tumours Farooqa Rodaina 1 BENIGN, PREMALIGNANT & MALIGNANT EPITHELIAL TUMORS OF SKIN DR MUHAMMAD ABRAR BARAKZAI MBBS, MPhil (Histopath), FCPS (Histopath),  LEARNING OBJECTIVES 1. Discuss the classification of tumors of the skin. 2. Describe the pathogenesis, diagnostic features and natural history of relevant tumors of the skin. - Read the slide.  BENIGN EPITHELIAL LESIONS Benign epithelial neoplasms are common and probably arise from stem cells residing in the epidermis and hair follicles Biologically insignificant, although they may cause significant psychological discomfort for the affected individual These tumors grow to a limited size and generally do not undergo malignant transformation - ِ‫ﷲ اﻟرﱠ ﺣْ ﻣٰ ِن اﻟرﱠ ِﺣﯾْم‬ ِ ِ‫ﺑِﺳْ م‬ - Read the slide. - In the pictures: stem cells are important. Whenever there's a proliferation you have, stem cell is responsible. - Second point: In older ages, there are skin lesions on the skin growing. If it's abnormal growth that's benign and it's not the face: then it may cause psychological discomfort. If it arrives on the face that's a cosmetic problem.  BENIGN EPITHELIAL TUMORS Seborrheic Keratosis Fibroepithelial polyp Acanthosis Nigricans Actinic keratosis - Read the slide. - Actinic keratosis: Although it's within benign lesions, it is the first step towards malignancy. - Seborrheic dermatitis: We did that in the first few dermpath lectures and that is totally different.. It's an inflammatory disease.  SEBORRHEIC KERATOSIS Occur most frequently in middle-aged or older individuals They arise spontaneously and are particularly numerous on the trunk, extremities, head, and neck In people of color, multiple small lesions on the face are termed dermatosis papulosa nigra Characteristically appear as round, flat, coin-like, waxy plaques that vary in diameter from millimeters to several centimeters, dark brown and have a velvety to granular surface - Read the slide. - It is acquired. You might have seen this on your grandparents. - It has a well demarcated surface. These are not moles.  MORPHOLOGY Histologically, these neoplasms are exophytic and sharply demarcated from the adjacent epidermis composed of sheets of small cells resemble basal cells of the normal epidermis Variable melanin pigmentation is present within these basaloid cells (brown coloration) Exuberant keratin production (hyperkeratosis) occurs at surface, and small keratin-filled cysts (horn cysts) and invaginations of keratin into the main mass (invagination cysts) When seborrheic keratoses become irritated and inflamed, they develop whirling foci of squamous differentiation - Read the slide. - You can see a typically small demarcated, round and velvety area. - The clinch of diagnosis is: 1) The cells are small like basal cells or basaloid cells. 2) Pigment, they are brown. 3) hyperkeratosis - Look at the microscopic picture: You can see small cells, brown color and you can see hyperkeratosis on the top. - These are the differentiating points for SK and are not seen in any other lesions. - The blue arrow: Invagination cysts. - The purple arrow: Horn cysts. The whole weird “U” shape is the cyst.  PATHOGENESIS. Activating mutations in the fibroblast growth factor receptor-3 (FGFR3) gene which possesses a tyrosine kinase activity that stimulates Ras and the PI3K/AKT pathways. May occur explosively in large numbers, as part of a paraneoplastic syndrome (Leser-Trélat sign), produced by tumor cells, of the GI tract - Read the slide. - There's a mutation of FGFR3. - A tumor of GIT and a patient will have a large number of lesions.  ACANTHOSIS NIGRICANS It is marked by thickened, hyperpigmented skin with a “velvet-like” texture Seen in flexural areas (axillae, skin folds of the neck, groin, and anogenital regions). Divided into two types, the benign type, which constitutes about 80% of all cases, develops gradually and usually occurs in childhood or during puberty. The most common association are with obesity and diabetes The malignant type refers to lesions arising in middle-aged and older individuals in association with underlying cancers, (GI adenocarcinomas) Acanthosis nigricans sometimes occurs as a paraneoplastic process resulting from the production of growth factors by a variety of tumors. - Read the slide. - This also resembles but there's no encircling lesions like in SK. - All the flexors area are involved. - Those who have diabetes insulin resistant– that is basically AN (the title).. Nigrican means black. It doesn't mean a male or female isn't washing the body part properly… it's because of obesity or diabetes. - Look at the picture: You can see an axilla that is dark brown in color. This is what you see in obesity and diabetes.  MORPHOLOGY The epidermis and underlying enlarged dermal papillae undulate sharply to form numerous repeating peaks and valleys Variable hyperplasia may be seen, along with hyperkeratosis and slight basal cell layer - Read the slide. - He's drawing on the white board (13:40): Making peaks and points that as dermal papillae and epidermis, they both go up and down together. - He drew the bottom pic you see on the slide basically… in between the peaks you have a lot of keratocytes. There are valleys and peaks. Valley is in between the peaks. - Circle: Peak - Blue arrow: Valley and you see epithelium proliferation and in between them you see a lot of keratosis. - You don't see any circular areas just like in SK. The cells are also bigger and squamoid. You won't see any invagination cyst. - Look at the pic on the top: The dark color looks like a dark brown color seen in obesity and diabetes and some malignant condition. 10  FIBROEPITHELIAL POLYP It has many names (squamous papilloma, skin tag) It is generally detected as an incidental finding in middle-aged and older individuals On the neck, trunk, face, as a soft, flesh-colored, bag-like tumor often attached to the surrounding skin by a slender stalk - Read the slide. - After certain age people develop these on the abdomen, axilla or the neck or wherever. - It has a stalk which is covered with skin. - PLEASE PAY ATTENTION TO THE PICTURES!!! HE HAS A LOT OF PICTURES IN THE EXAM FOR THE MCQs.  Which of the following statements about benign epithelial neoplasms is correct? A. They frequently undergo malignant transformation and are highly aggressive. B. They are biologically insignificant but may cause psychological discomfort for the affected individual. C. Leser-Trélat sign is a benign condition unrelated to underlying malignancies. D. Acanthosis nigricans lesions are most commonly found on the trunk and extremities without involvement of flexural areas. Correct Answer: B. 12  MORPHOLOGY. Histologically these tumors consist of fibrovascular cores covered by benign squamous epithelium Fibroepithelial polyps are usually insignificant, but can occasionally be associated with diabetes, obesity, and intestinal polyposis - Read the slide. - Picture at the bottom: You can see the fibrovascular stalk covered by squamous epithelium. - 3 lesions so far, a summary: 1) SK: invaginating and horn cysts, basaloid cells 2) AN: peaks & valleys and valleys are filled with hyperkeratosis 3) FP: fibroblast polyps, slender stalk covered by squamous epithelium  PREMALIGNANT EPIDERMAL TUMORS ACTINIC KERATOSIS Epidermal malignancy is typically preceded by progressively worsening dysplastic changes, which are analogous to the precursor lesions that give rise to squamous cell carcinoma In the skin, these precursor lesions are called actinic keratoses; these usually occur in sun-damaged skin and exhibit hyperkeratosis They occur with particularly high incidence in lightly pigmented individuals. Exposure to ionizing radiation, industrial hydrocarbons and arsenicals may induce similar lesions - 4th one is IMPORTANT. - Read the slide. - It never happens that the lesion is benign today and tomorrow it will be malignant. It takes years to change from benign to malignant. The in between area of progressing to squamous cell carcinoma (SCC) is AK. The cells slowly and gradually become dysplastic. - In dysplastic nevi… it can stay as it is throughout life. It won't change into malignant melanoma. In AK also without changing it will remain AK. It can give rise to SCC but we have to be cautious. It's not 100% possible that it may change. - 3rd point: Again people with brown color are blessed. It's not only the UV light but also industrial hydrocarbons and arsenicals. - Picture: You can see the brown lesions on the face. The skin isn't smooth and it's giving sandpaper like skin which is rough.  ACTINIC KERATOSIS Actinic keratoses are usually less than 1 cm in diameter; are tan-brown, red, or skin-colored; and have a rough, sandpaper-like consistency Some lesions may produce so much keratin that a “cutaneous horn” develops. Such horns may become so prominent that they actually resemble the horns of animals Sun-exposed sites (face, arms, dorsum of hands) are most frequently affected. The lips may also develop similar lesions (termed actinic cheilitis) - Read the slide. - Sandpaper like skin. You feel irregularities when you touch the skin. - 3rd point: If in Lips: actinic cheilitis  MORPHOLOGY. Cytologic atypia is seen in the lowermost layers of the epidermis and may be associated with hyperplasia of basal cells or, alternatively, with atrophy that results in thinning of the epidermis The atypical basal cells usually have pink or reddish cytoplasm due to dyskeratosis. Intercellular bridges are present, in contrast to basal cell carcinoma, in which they are not visible The superficial dermis contains thickened, blue-gray elastic fibers (elastosis), a probable result of abnormal elastic fiber synthesis by sun-damaged fibroblasts. The stratum corneum is thickened, and show (parakeratosis) - Read the slide. - He draws how the cytologic atypia is in the lowermost layer and then it goes up and goes to the top. If it fills the whole area it's known as carcinoma in situ until the basement membrane is intact. If the basement membrane gets broken down, it's called a malignancy. - Here you see atrophy, thinning of the epidermis. - 2nd point: All squamous epithelium show intercellular bridges formed by desmosomes. - 3rd point: Not only the epidermis is showing dysplastic changes but also the dermis.  ACTINIC KERATOSIS - The horn becomes so big that it goes up. - Second pic: Blue arrow- You see the thickness is so less. They have a larger nuclei. There is hyperkeratosis. - Third pic: You can see full thickness here so it's called carcinoma in situ. The last layer is called elastosis. If the dermis change to blue it's called elastosis. It's only seen in sudden exposed areas.  MORPHOLOGY Whether all actinic keratoses would inevitably lead to skin cancer (usually squamous cell carcinoma), if given enough time, is hypothetical Studies indicate that lesions may regress or remain stable during a normal life. Local eradication is done by gentle curretage, freezing, or topical application of chemotherapeutic agents More recently, a reagent called imiquimod, which activates the innate immune system through stimulation of Toll-like receptors (TLRs), has been used to eradicate the abnormal cells that compose this tumor - Read the slide. - 2nd point: They are regressed by gentle curettage, freezing, or topical application of chemotherapeutic agents. - 3rd point: Innate immune: lymphocytes  SQUAMOUS CELL CARCINOMA Second most common tumor arising on sun-exposed sites in older people, exceeded only by basal cell carcinoma These tumors have a higher incidence in men than in women. Invasive SCC usually discovered while they are small and resectable Less than 5% of these tumors metastasize to regional nodes; these lesions are generally deeply invasive and involve the subcutis - Read the slide. - First most common: basal cell carcinoma - 2nd point: Why men? Because men go out and females are inside.. So they are kept away from the sun exposed area. SCC is in skin so whatever changes are going on you can see it. - 3rd point: One case: A female with 10cm big lesion ulcerated on her breast… the bigger lesion, the worse prognosis. Before it metastasizes you already go to the doc (OR AT LEAST YOU SHOULD!)  MORPHOLOGY. Squamous cell carcinomas that have not invaded through the basement membrane of the dermo-epidermal junction (termed in situ carcinoma) appear as sharply defined, red, scaling plaques More advanced, invasive lesions are nodular, show variable keratin production (appreciated grossly as hyperkeratotic scale), and may ulcerate Invasive SCC shows variable degrees of differentiation, ranging from tumors composed of polygonal cells arranged in orderly lobules and having numerous large areas of keratinization (Keratin pearl) to neoplasms associated with geographic necrosis consisting of highly anaplastic cells The latter tumors may be so poorly differentiated that immunohistochemical stains for keratins are needed to confirm the diagnosis - Read the slide. - For poorly differentiated: The immunohistochemical staining: AE1 or AE3 or chem5.2 → stains for scc. Given in combination.. If it's squamous it will take up this stain. - There are some tumors which are in between called moderately differentiated, you won't be able to see the keratin pearls but you see that they are highly dysplastic and then you do the immunohistochemical stain or if they are well differentiated you see the keratin pearl.  SQUAMOUS CELL CARCINOMA - The pic on the right: Someones head was a little ulcerated and elevated. - After taking biopsy: 2nd image: The blue arrow shoes how the basement membrane gets ruptured. - The pic on the left: The white thingy: intercellular bridges. This is only is SCC.  Which of the following is true regarding actinic keratosis and squamous cell carcinoma (SCC)? A. Actinic keratosis is most commonly seen in individuals with dark skin and occurs independently of sun exposure. B. Actinic keratosis lesions are rough, sandpaper-like plaques that may develop into SCC over time. C. Invasive squamous cell carcinoma frequently metastasizes to distant organs in over 50% of cases. D. Actinic keratosis lesions always progress to squamous cell carcinoma if left untreated. B 22  PATHOGENESIS DNA damage induced by exposure to UV light. It is proportional to the degree of lifetime sun exposure Association is with immunosuppression, most notably chronic immunosuppression as a result of chemotherapy or organ transplantation Immunosuppression reduces host surveillance and increasing the susceptibility of keratinocytes to infection and transformation by oncogenic viruses, HPV subtypes 5 and 8 Other risk factors for SCC include: industrial carcinogens (tars and oils), chronic ulcers and draining osteomyelitis, old burn scars, ingestion of arsenicals, ionizing radiation, and (in the oral cavity) tobacco and betel nut chewing - Read the slide. - 1st point: How long have you been exposed to the sun light depends. Majority of the western males wear hats commonly to cover themselves because they need to have that or else they'll form SCC. - 2nd point: Notably people who take immunosuppressants, they can develop HPV subtypes 5 & 8. - In cervical: HPV 16 and HPV 18. If it's condyloma: HPV 6 to 8 - Read the examples: Ionizing: Like x rays. Tobacco and betel nut: Very common in Pak, india or bangladesh. He talks about this thing called “pan” and how it causes ulcer because now it's mixed with tobacco. The ulcer will slowly and gradually develop a carcinoma. Even young people develop this. A fibrosis can occur inside the mouth and they can hardly open their mouth to eat something. This item is now banned but it's still very common. - Look at the pic: You can see keratin pearls. Read the labellings. This is well differentiated SCC.  PATHOGENESIS Normally, DNA damaged by UV light is sensed by checkpoint kinases such as ATM and ATR, which send out signals that upregulate the expression and stability of p53 p53 in turn (1) arrests cells in G1 phase of cell cycle and promotes either “high-fidelity” (2) DNA repair or the elimination of cells that are damaged beyond repair by (3) apoptosis When these protective functions of p53 are lost, DNA damage induced by UV light is more likely to be “repaired” by error-prone mechanisms, creating mutations that are passed down to daughter cells and cause neoplastic process - Read the slide. - 1st point: 2 kinases: ATM & ATR. If p53 is sleeping, the ATM and ATR wake up. - 2nd point: p53 is stopping to cross G1. They only allow movement after the DNA is repaired. If it's not repaired that results in apoptosis. This is normal. - 3rd point: if P53 is damaged, even the DNA that aren't repaired will cross G1 phase. - Look at the diagram: Normally the p53 stops the cell at G1 until the DNA is repaired then the DNA goes for the S phase. If not repaired, there's cell apoptosis and this is NORMAL.  KERATOACANTHOMA Some regard it as a variant of well-differentiated SCC, while others consider it to be a distinct entity It differs from conventional SCC in that after a period of rapid growth, it usually regresses spontaneously Grossly, it is a symmetric cup-shaped tumor with a central depression filled with keratin debris Histologically, the tumor is composed of lobules of squamous cells with glassy cytoplasm that undergo kertinization without an intervening granular layer, elicit a brisk lymphocytic and eosinophilic host response - Read the slide. - This is NOT BENIGN. It starts proliferating and then it stops. It stays there for a while and for example you diagnose it don't leave it because you can give chance to AK (acanthotic keratosis) because it is still pre malignant. - It looks like a volcano. There's a “lava” in between and that is keratin.  KERATOACANTHOMA - These are abnormal squamous cell epithelial cells. The basement membrane is not intact. You can see the cup shape and you can see keratin pearls. - Epithelium is hypochromic, pleomorphic. - He talks about if you see this in the gallbladder then it's normal because it only has 3 layers. Sometimes the gland goes down and up because no submucosal layer. He is drawing on the white board (45:07). This isn't important. You have to be careful at which organ you're looking at. - Nowadays the surgeons are so good that they take biopsies and then they take that area and they paint the outer area by an ink. Under microscope, if we see the malignant lesion is touching the ink that means the tumor has crossed. That means some of the tumor cells are left behind and we need to detach more area. Then you check for further malignancy. This is an early malignancy so if you take out the whole cup, your good.  BASAL CELL CARCINOMA BCC is the most common invasive cancer in humans, with nearly 1 million estimated cases per year in the US. These are slow-growing tumors that rarely metastasize They occur at sun-exposed sites and in lightly pigmented people. As with SCC the incidence of BCC rises sharply with immunosuppression and in people with inherited defects in DNA repair such as xeroderma pigmentosum Some tumors contain melanin appear similar to melanocytic nevi or melanomas. Advanced lesions may ulcerate, and extensive local invasion of bone or facial sinuses may occur after many years, designation rodent ulcers - Read the slide. - 1st point: Locally malignant. The survival rate is good. - 3rd point: Mostly these tumors are present near the eye. Some people only have ulcers there so the only treatment is you take out the tumor and then do skin grafting.  MORPHOLOGY Histologically, the tumor cells resemble those in the normal basal cell layer of the epidermis. They arise from the epidermis or follicular epithelium and do not occur on mucosal surfaces. Two patterns are seen: 1. Multifocal growths originating from epidermis and sometimes extending over several square centimeters or more of skin surface (multifocal superficial type) 2. Nodular lesions growing downward deeply into the dermis as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix, and often surrounded by many fibroblasts and lymphocytes - Read the slide. It is known as basal cell carcinoma as it arises from BASAL CELL LAYER. Two patterns: - Multifocal: multiple growth. RADIAL - Nodular: VERTICAL. The cells are small and hyperchromatic.  BASAL CELL CARCINOMA The cells at the periphery of the tumor cell islands tend to be arranged radially with their long axes in parallel alignment (palisading). In sections, the stroma retracts away from the carcinoma creating clefts or separation artifacts that assist in differentiating basal cell carcinomas from certain appendage tumors - Pic on the left: nodular, it may ulcerate later on. It is going down, vertical growth. - Pic on the right: 1) Mitotic figure 2) pleomorphic hyperplasia 3) Palisading appearance in the periphery 4) Retraction from the stroma. - Summary: palisading appearance, basaloid cells, hyperchromasia, retraction from the stroma.  PATHOGENESIS Nevoid basal cell carcinoma syndrome (NBCCS; also known as basal cell nevus or Gorlin syndrome) is an autosomal dominant disorder characterized by multiple basal cell carcinomas Most of these tumors develop before age 20. The gene associated with NBCCS, located on chromosome 9q22.3, is PTCH The pathogenesis of basal cell carcinomas in NBCCS fits the classical Knudson “two-hit” hypothesis for familial retinoblastoma. Individuals with NBCCS are born with a germline mutation in one of the PTCH alleles; the second normal allele is inactivated in tumors by a mutation acquired by chance or due to exposure to mutagens (such as UV light) - Read the slide. - 2nd point: PTCH is the gene. - 3rd point: The Knudson theory states that the first "hit" occurs when a person is born, with one allele already affected. Later, exposure to factors like UV light can damage the second allele, leading to tumor development. One mutation is present at birth, and the second occurs later in life. They develop tumors around 20-25 age. In normal people: You need have two hits which takes more time and they develop tumor later at around 40-50 age.. - In classical knudson two hit: One allele is already damaged, only one hit is left.  PATHOGENESIS The PTCH gene encodes a receptor for the protein product of the sonic hedgehog gene (SHH), a member of the hedgehog (HH) family of genes The PTCH protein forms a receptor complex with another transmembrane protein, known as SMO (for “smoothened”). In the absence of its ligand, SHH, PTCH inactivates SMO and sequesters it from transducing a down-stream signal Binding of SHH to PTCH releases the suppression of SMO, causing the up-regulation of hedgehog target genes through a signal cascade that involves the GLI1 transcription factor. In NBCCS the mutation of PTCH gene causes constitutive activation of SMO, leading to the development of basal cell carcinoma - Read the slide. - The PTCH gene has a receptor for SHH gene. When SHH gene attaches to the receptor, two things are there now. One is the PCTH gene and one is SMO. They are joined together. If SHH is not there, SMO and PTCH join and don't allow for proliferation.  Which of the following best describes a keratoacanthoma? A. A slowly growing tumor that rarely regresses and resembles invasive squamous cell carcinoma. B. A rapidly growing, symmetric, cup-shaped tumor with a central keratin-filled depression that often regresses spontaneously. C. A malignant tumor caused by mutations in the PTCH gene, leading to the activation of the hedgehog pathway. D. A tumor with irregular lobules of squamous cells that fail to keratinize and lack any host immune response. B 32 Left Side: Normal Pathway: SHH (Sonic Hedgehog) binds to the PTCH receptor. This binding causes the dissociation of PTCH and SMO. The now-active SMO initiates signal transduction. Transcription factor activates and leads to the activation of gene expression, regulating normal growth and development. Right Side: Mutated Pathway: A mutation in PTCH prevents it from regulating SMO. SMO remains active even without SHH binding. Active SMO triggers transduction. This abnormally activates the transcription factor in the nucleus. The result is unregulated gene expression, causing: ○ Uncontrolled cell division (e.g., basal cell carcinoma). GOOD LUCK, May Allah make it easy for all of us. Ameen QUESTIONS…..