#7 35 Pathology Skin Tumor Bayan N. Mohammad 15/10/2015 Mohammad al-orjani Page 0 of 23
بسم هللا الرحمن الرحيم GREETINGS This lecture is about skin tumors, all the slides are included and every slide will be explained separately, if I didn't add any notes that is because the doctor only read the slide. So, lets start. The first slide is just the lecture title so we will start from slide #2 Slide #2 Contents : Tumors of skin: Explanation: Epidermis Dermis Skin appendages Melanocytic tumors Mesenchymal: Vascular tumors etc Skin tumors arise from different types of cells, for example when we talk about mesenchymal cells we take about connective tissue type of cells ( fibroblasts, endothelial cells of blood vessels.. ) If you remember what we took in neoplasia there are tumors of epithelial origin, lymphoid origin, and mesenchymal origin which arise from (fibrous tissue, skeletal muscles, smooth muscles, blood vessels, cartilage of the bone and the bone itself) Vascular tumors which occur in the skin mainly dermis because the epidermis doesn t contain any blood vessels. Page 1 of 23
Slide #3 Cell of Origin Benign Malignant Keratinocyte Seborrheic keratosis!actinic keratosis!bowen disease BCC & SCC Melanocyte Melanocytic nevus Melanoma Merkel cell ---- Merkel cell Ca. Explanation BCC: basal cell carcinoma SCC: squamous cell carcinoma Note the presence of an exclamation mark beside both Actinic keratosis and Bowen disease and that is because they are not truly malignant they are premalignant tumors. Malignant tumors have the ability to metastasize and invade other tissues. Tumor that are in situ are considered to be premalignant. Melanocytic nevus: small, regular, the same shape, the same color, and they are benign while melanoma is the malignant counterpart. There is no benign counterpart of Merkel cell, Merkel cells are found in the epidermis and they are found in the neuroendocrine and they are a source of a bad cancer which is Merkel cell carcinoma. Page 2 of 23
Slide #4 Mesenchymal Hemangioma Dermatofibroma Neurofibroma Angiosarcoma Kaposi sarcoma Dermatofibrosarcoma MPNST. Lymphocyte ---- Mycosis fungoides(t) Lymphoma(B) Mast cell Urticaria pigm. Systemic. Mastocytosis Mast cell degranulation Dermal adnexa:from skin appendages Adenoma Carcinoma Hemangioma involves blood vessels. Dermatofibroma..(BFH) benign fibrous histyocytoma occurring in the skin. Neurofibroma involves nerve sheaths (peripheral nerves) doesn t involve the CNS. Kaposi sarcoma and Angiosarcoma both are malignant but Angiosarcoma is of a low grade while Kaposi sarcoma varies from low to high. Kaposi sarcoma is associated with Kaposi sarcoma herpesvirus (HHV-8) MPSNT : malignant peripheral nerve sheath tumor. Schwannoma: another tumor that occurs in nerve sheaths but it is not listed here because it occurs in deep tissues. Skin appendages: sweat sebaceous glands are examples. Page 3 of 23
Slide #5 EPIDERMAL TUMORS: could be benign malignant and premalignant. A. BENIGN: SEBORRHEIC KERATOSIS: Slide #6 Benign neoplasm most in elderly Raised, flat, soft, well-demarcated (coin-like) brown lesion. Located mostly on the trunk, limbs & head. Micro: proliferation of squamous epithelium + cysts filled with keratin * FGFR3 (fibroblast growth factor receptor 3) activating mutation Here notice the well circumscribed browncolored coin-shape lesion with flat surface, and regular in shape slide #7 here you can notice a thickened epidermal layer, hyperkeratosis, papillomatous proliferation, pseudocysts because they are opened outside and cysts filled with keratin in such lesions. Page 4 of 23
slide #8 B. PREMALIGNANT: Actinic Keratosis: Due to excessive, chronic exposure to sunlight TP53 mutation Considered as premalignant prolif. Micro: Explanation: Stratum corneum w/parakeratosis & atypical keratinocytes, may evolve to CA Typically seen as hyperkeratotic, scaly plaques on the face, neck, limbs & trunk. Affects most commonly old patients. In situ Invasive Squamous Cell CA Premalignant carry the ability to transform into malignant. Actinic keratosis occurs in sun exposed parts of the body while Bowen disease occurs in covered parts of the body, but they are similar in their manner of proliferation. P53 is a tumor suppressor gene, inactivating mutation of this gene causes the proliferation of these cells. Actinic keratosis can be graded as mild, moderate, severe depending in the thickness of skin involved by dysplasia. So, if it involves the lower third then it is mild, two thirds moderate, and if involves the whole thickness then severe. Page 5 of 23
Bowen disease also is a carcinoma in situ means associated with higher risk. Note the plaques with a red discoloration and a hyperkeratotic scale present in the dorsum of the hand. Red, tough to touch (sandpaper like appearance). Slide #10 Hyperkeratosis Parakeratosis Dysplas tic CA in Situ There is a para and a hyperkeratosis can be seen especially on the top of the surface, and there is a dysplastic CA in which there is an abnormal growth and maturation also the arrangement is disordered. There are normal cells at the basal side. There are big atypical cells and a carcinoma in situ with a higher risk to become an invasive CA. Slide #11: Malignant Epithelial Skin Tumors Slide# 12 : These include: Basal Cell Carcinoma** Squamous Cell Carcinoma** Skin Appendage Tumors Page 6 of 23
** Very common & majority present on sun-exposed skin. Explanation: Skin appendage tumors are classified into skin tumors because some of the skin appendages are related to epidermis. BCC and SCC are very common and majorly present in sun-exposed skin. Slide #13 BASAL CELL CARCINOMA Most common malignant tumor due to sun exposure in patients over 40 s with pale skin Mainly on face. Sun exposed skin, never mucosal Infiltrative but NO METASTASES! Pathogenesis: Defects in DNA repair & TP53 mutations PTCH gene mutation Hedgohog Pathway Gorlin Syndrome Rx: Surgical Excision; 40% of treated develop a new BCC in 5 years. Explanation: Pale skin?? less melanin then less protection against sun light damaging effect. Never mucosal unlike SCC which may happen in mucosal cells. Hedgehog pathway a signaling pathway responsible for the maturation of the cell. Page 7 of 23
Occurs in sporadic and familial forms, familial like Gorlin syndrome and those with this syndrome will develop the cancer earlier. Proper surgical excision is usually enough, sometimes you will notice that there is a perineural infiltration, so this tumor may respread along the nerve to another site of the skin. But if the tumor is superficial or nodular and doesn t show a perineural or vascular infiltration then they will be completely excised and this has a very low risk to reoccur. Slide #14 Picture: Superficial multifocal or Nodular growth Other variants: Ulcer (Rodent Ulcer) Pigmented Basosquamous.etc Gross: Papule, rodent ulcer, pigmented lesion etc Micro: nests of epithelial cells that resemble basal cells forming palisades separated from surrounding fibroblasts by a cleft-like space. Explanation: At the edge of the nest tumor cells are arranged in a certain linear arrangement and parallel to each other (palisades). Page 8 of 23
Slide#15 Notice the production of an ulcerated lesion A papule, it is a raised lesion with an irregularity at the edge and an elevation. Under the microscope there is a nodular form of the disease infiltrating the epidermis, tumor cells are similar to the basal cells of the epidermis The depth of the invasion is very important in these tumors ( BCC and SCC) from the skin surface down through the dermis and as long the invasion is deeper then the possibility of curing the disease is less. Slide #16 The basal cells are palisading at the edge of the nodules(black arrow) and you can see the cleft separating it from the surrounding dermis( white arrow). Page 9 of 23
Slide #17 Squamous Cell Carcinoma Commmon tumor but less common than BCC Develops in sun-exposed skin of fair patients with light hair & freckles, nonexposed skin or mucosa Etiology: Explanation: Exposure to sunlight, UVB light & radiation Arsenicals & industrial carcinogens (tar, oil ) Actinic keratosis Any chronic scarring processes, e.g. burn scars, chronic ulcers Immunosuppression (HPV 16 & 18) Xeroderma pigmentosum Xeroderma pigmentosum: a predisposing condition and it is a genetic problem in DNA repair. Slide #18 Genes involved: TP53, Notch receptors, HRAS (oncogene) Sites: dorsal surface of hands, face,ears, mucosal surfaces Gross features: Small lesion initially ulceration later Microscopic: Full thickness epidermal dysplasia (CA in situ) Invasive carcinoma Page 10 of 23
Variable degree of keratinization (differentiation) It has an increased tendency to infiltrate and metastasize to regional lymph nodes, for example metastatic tumors in the head will metastasize into cervical lymph nodes. Metastasis usually occurs through lymphatics to the lymph nodes in tumors like BCC and SCC while sarcomas prefer to go to distant sites through the blood. Slide #19 Metastatic tumor at the edge of the nose, there are epitheliomatous boundaries and ulcerated center with subkeratin. Slide #20 SCC microscopically you can see The epidermis and an abnormal proliferation of sequamous cells, some are attached to the epidermis others forms a nest that invade the dermis. I'm not sure that these which I pointed to are the abnormal sequamous cells.. but most likely they are Page 11 of 23
Slide #21 In some tumors according to the degree of differentiation you can suggest that this is a sequamous cell carcinoma like here. but in other tumors which are poorly or undifferentiated it is difficult to say that it is sequamous especially when talking about tumors of unknown primary origin so you need special techniques like immunohistochemistry. Here we don t need an immunohistochemistry because the cells itself has the shape of keratinocytes and the presence of cellular bridges, variation in cells shape and size. Here if it is in the skin then it is definitely dysplasia.. if it within the dermis then we are dealing with an invasive tumor. Slide# 22 : Melanocytic Tumors of the Skin Slide #23 Melanocytic NEVUS (mole/ common nevus). Commonest benign tumor in the body Derived from dendritic melanocytes present in basal layer of the epidermis (nevus cells) Contain melanin pigment Immature at junction, but mature as cells migrate down into dermis. BRAF or NRAS mutation identified There are several types: junctional, compound and intradermal Page 12 of 23
Explanation: Not all of them contain melanin, some are pigmented (dark in color) and some of them show a little pigmentation, under the microscope you will see many of these cells non pigmented. Their name depends on the location: If they are in the dermoepidermal junction then called... junctional If purely in the dermis then intradermal And if in both (junction and dermis ) then called compound Acually they megrate from the basal layer towards deeper areas, junctional are more immture than the dermal ones so as long they move through the dermis they will acquire maturation, become smaller in size, more regular in shape and more uniform. Also, you find mitosis in surface components that is not found in the deeper part of the lesion and if happened there should something more serious. Slide #24 Gross: Uniform small regular tan/brown color(uniform in color) with sharp delineation & tendency to be stable in size & shape. Microscopic picture: Nests or cords of uniform nevus cells ± pigment. Malignant transformation is uncommon Page 13 of 23
Slide#25 Melanocytic nevus, the Dr just repeated what he explained before Slide #26 This image is not a well illustrative for what the doctor explained "as he said".. Normally if you look at the cells at the top they are larger than those in the bottom?? why?? Because as long they go deeper they maturate and shrink in size and the cells acquire new features. Something happen to those cells called neutralization they acquire the shape of neural cell shape peripheral nerve sheath (for ur own knowledge ) Slide #27 The most important thing to know about this image is that there is no atypical cells in the deep aspect and no mitosis there. Notice that the nests of melanocytes are close but don't involve the epiderm, they are nonpigmented. Page 14 of 23
Slide #28 Nests inside the epidermis they are pigmented. Also, they are found In the junctional and dermal components so considered as compound. Slide #29 Dysplastic nevus Sporadic: low risk of transformation Familial: Autosomal dominant with melanoma risk up to 100% Considered as a marker for development of melanoma Usually multiple, on exposed or unexposed skin Activating BRAF or RAS mutations Features: Compound nevus with increased melanocytes, junctional cytological & architectural atypia & dermal fibrosis around proliferating cells Explanation: Dysplastic nevus has a different appearance microscopically, grossly, and histologically from previous melanocytic nevi. The familial case here is like neoplasia when we talked about the APC gene and adenomatous polyposis coli those people have a high risk of developing colon cancer. However the sporadic one, if you are sure that this is a dysplastic nevus the patient should be examined carefully and followed well Page 15 of 23
so if there is 10 or more dysplastic nevi in sporadic form then they carry a risk for malignant transformation while if they are less then the risk is small. *usually multiple (especially in familial) Melanoma loves to occur in sun-exposed parts not unexposed, why do we care? Because melanoma mostly arises de novo and minority of these cases are of dysplastic transformation. The most important feature is atypia in the cells and atypia in the architecture of the junction. Slide #30 Multiple nevi, they vary in their size, shape, and if you examine these nevi and compare them to melanocytic nevi you will notice that they have a pale periphery, darker center and irregular border, this could be malignant melanoma or dysplastic nevus, this case has to be examined Slide #31 Compound nevus. Large atypical cells in this compound and the rete pegs are fused. Page 16 of 23
Slide #32 Slide #33 Possible steps in development of melanoma A: normal skin appearance, there is a basal layer and a scattering melanocytes, each melanocyte is found between five to six keratinocyres. Page 17 of 23
B: an increase in melanocytes but it is not that abnormal in shape ( there is an increase in the nuclear size but there is no atypia), this is called lentiginous proliferation or hyperplasia of melanocytes (still benign). C: increased proliferation o melanocytes at the junction and there are melanocytes in the dermis and they acquired atypia this is what we call dysplastic nevus. D: it is the first phase of melanoma, some of the dysplastic nevus spread to the surface to the epidermis, here there is one cell spreading into the dermis but the main component to spread to is the epidermis. This is the horizontal (radial) growth phase of melanoma, lesions here are usually flat. E: nodular phase, excessive proliferation toward the dermis, vertical growth phase because if goes vertically into the dermis, the risk of metastasis here is higher than it in the radial (horizontal) growth. *as we said melanoma arises mostly de novo without this kind of sequence. Slide #34 MALIGNANT MELANOMA Sunlight has an important role in the development of this tumor in the skin Appears most frequently on the upper back (men/women) or legs (women). White individuals have higher risk More in New Zealand & Australia Intense intermittent exposure at early age Sporadic OR Familial (5%-10%) Sites: Skin, mucosa, eye, meninges etc Page 18 of 23
Slide #35 Predisposing factors: Sunlight Pre-existing lesions: Dysplastic nevus Exposure to carcinogens Hereditary conditions: Xeroderma Pigmentosum Retinoblastoma Familial melanoma (40% with p16 ( CDKN2A) mutation) Many gene mutations (CDKN2A (p16), BRAF, NRAS, PTEN, c-kit) Slide #36 Type of Growth First Radial (Superficial) Later downward growth (Vertical/Nodular) Staging & prognosis depends on depth of invasion Breslow Thickness: Depth of invasion in mm.s Clark Level Staging: Depth of invasion by location Spread is by lymphatics & blood to any site (liver, lung, brain...etc) Explanation: There are many things that you can depend on to give the staging like ulceration pigmentation but the main one is the depth of invasion. Page 19 of 23
Slide #37 Clark Levels Leveled from 1-5 " I don t want you to know much of details about this, just that it has to deal with the layers of the skin" :3 then the Dr read all the slide, actually I couldn t determine if it's required or not :3 Level I: confined to the epidermis (top-most layer of skin); called "in situ" melanoma; 100% cure rate at this stage Level II: invasion of the papillary (upper) dermis Level III: filling of the papillary dermis, but no extension in to the reticular (lower) dermis Level IV: invasion of the reticular dermis Level V: invasion of the subcutaneous tissue Slide #38 Clinical Diagnosis Change in color or size of an existing lesion, itching, pain, border irregularity, ulceration New pigmented lesion in an adult Main signs summarized by: ABCDE A. Asymmetry of shape B. Border is irregular C. Color is uneven D. Diameter is enlarged E. Evolution (change of an existing nevus) Page 20 of 23
Slide #39 There is a benign nevus in the left side and the other is malignant, notice how irregular in shape is, how variable the pigmentation is. The site where the malignant nevus is flat with a little pigmentation is the site of radial growth (horizontal phase) while the pigmented and elevated region is the site for vertical growth. Slide #40 Microscopic features: Neoplastic melanocytes are much larger Large nuclei with prominent nucleoli Tumor cells grow horizontally & vertically Loss of nesting pattern (sheets) Loss of maturation Prognosis is good in radial growth where the excision could cure the case but bad in deeper vertical growth Page 21 of 23
slide #41 Radial growth phase of melanoma, abnormal cells spreading through the epidermis. Slide #42 This image illustrates a vertical growth phase Slide #43 Compound, abnormal melanocytes are found everywhere, big nodules inside dermis, we can see how atypical the melanocytes are, and how variable is morphology, how pleomorphic, and you can see mitosis Page 22 of 23