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Dermpath surgical pathology


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Dermpath surgical pathology

  1. 1. PATHOLOGY (DERMATOPATH) BERNADETTE R. ESPIRITU, M.D. FPSP Anatomic & Clinical Pathologist
  2. 2. FUNCTIONS:  Protection  Sensation  Thermoregulation  Metabolic functions (Vitamin D is synthesized in the epidermis and subcutaneous fat is a major energy store)
  3. 3. NORMAL SKIN  Epidermis  Dermis ◦ Hair follicle ◦ Sebaceous glands ◦ Multiple bundles of collagen
  4. 4. NORMAL EPIDERMIS ● Outer layer of skin ● Inner layers are dermis and subcutaneous tissue ● Superficial fascia marks deep boundary between skin and underlying soft tissue ● Epidermis forms outer layer of keratin that is protective and waterproof ● Cells present include melanocytes, keratinocytes, Langerhans’ cells and Merkel cells
  5. 5. The epidermis is composed of 5 sublayers and the dermis is composed of 2 sublayers, the papillary layer and the reticular layer.
  6. 6. EPIDERMIS ● Stratified squamous epithelium containing keratinocytes in 4 layers: ◦ inner basal ◦ squamous ◦ granular ◦ outer cornified ● Keratinization takes 30-45 days ◦ Alterations in pattern and speed cause dermatoses, hyperkeratosis or parakeratosis
  7. 7. EPIDERMIS ● Stratum Basalis or Stratum Germinatum) Basal layer: These cells are cuboidal and are separated from the dermis by a basement membrane. Merkel Cells Tactile cells of located in the basal layer of the epidermis. It is from the basal layer that cells emerge and change morphology as they migrate to the upper layers of the epidermis. Basal cell carcinoma originates in this level. Other cells within the epidermis include: Melanocytes to provide pigmentation. They occur within the basal layer. Langerhans cells and macrophages also occur within skin.
  8. 8. EPIDERMIS ● Squamous layer (stratum spinosum) - Prickle Cell or Malpighian layer - Has several layers of cells, larger than basal layer, which become flat and eosinophilic as they approach the surface due to an increase in keratin and reduction in ribosomes - May have clear vacuolated cytoplasm - Cells are attached to each other by fine spiny bridges with central dot-like desmosomes (Bizzozero’s nodule) - Loss of spiny bridges causes acantholysis
  9. 9. EPIDERMIS ● Stratum granulosum: Granular layer - 1 to 3 layers of flattened cells with intensely basophilic keratohyaline granules, which contain precursors of filaggrin protein, which causes aggregation of keratin filaments - These cells have multiple cytoplasmic granules that are keratohyalin. In the outermost layer of the stratum granulosum cell death occurs and keratinization is nearly complete. This is not always present; it is seen only in thick skin.  Stratum lucidum: Translucent layer - Homogenous eosinophilic zone - flattened keratinocytes that are present only in soles and palms and exists between the Granular layer and the overlying keratinized or cornified layer
  10. 10. EPIDERMIS Stratum Corneum (Cornified layer)  - Also called horny layer - Basket weave pattern of multiple layers of polyhedral cells without nuclei - Region is thicker and more compact in acral region [peripheral body- limbs, fingers, ears]  This is comprised of dead and dying cells that lack nuclei and are filled with keratin. Ultimately the strong junctions between these cells weaken and desquamation occurs. ● Rete ridges: - Undulating forms of epidermis and dermal papillae at dermoepidermal junction - Flattens with aging
  11. 11. epidermis
  12. 12. DERMIS :  Collagen and elastic fibers within ground substance composed of mucopolysaccharides and mucoproteins  Adnexa, nerves and blood vessels  Degenerates with age and sunlight and becomes basophilic  Divided into superficial papillary dermis and deeper reticular dermis  Papillary dermis contains rete pegs and periadnexal dermis - Has thin and delicate collagen fibers compared to thicker fibers in reticular dermis
  13. 13. DERMIS: ● Acral skin has Sucquet-Hoyel canals – specialized arteriovenous anastomoses, surrounded by glomus cells ● Glomus cells are modified smooth muscle cells that are round with clear cytoplasm and well defined cytoplasmic borders ● Papillary dermis of palms and soles contains Wagner-Meissner corpuscles with a tactile function ● Deep dermis and subcutis of weight bearing areas contain Pacinian corpuscles, sensitive to pressure ● Normal dermis contains a few fibroblasts, mast cells, macrophages, lymphocytes and dermal dendrocytes (Factor XIIIa+)
  14. 14. SKIN ADNEXAE  Hair Growth is from a bulb. A small bundle of smooth muscle is attached to the follicular sheath and the dermal papilla and contracts to make the hair stand on end. This muscle is called erector pili.  Sebaceous glands. These are associated with the hair follicle and secrete an oily substance (sebum) that waterproofs and moisturizes the skin and hair. Sebaceous glands are abundant and discharge directly onto the skin surface at the nipples, lips, eyelids, labia minora and glans penis.  Merkel Cells Tactile cells of located in the basal layer of the epidermis.   Pacinian Corpuscle A nerve receptor located in the subcutaneous fatty tissue that responds to pressure and vibration.   Sweat glands. These are mostly simple coiled glands that secrete a watery substance. They are important in thermoregulation, as evaporation cools blood in peripheral vascular beds.
  15. 15. NORMAL SKIN ADNEXAE  Hair follicles  Sebaceous glands - waterproofs & moisturizes the skin & hair. - abundant and discharge directly onto the skin surface at the nipples, lips, eyelids, labia minora and glans penis.  Eccrine Sweat glands - impt in thermoregulation: evaporation
  16. 16. FOLLICULAR UNIT ● Functional complex of terminal and vellus hair follicle, sebaceous gland, erector pili muscle and (depending on site) apocrine gland ● Often contains Demodex folliculorum mites, clumps of Staphylococcus epidermidis or Pityrosporum yeasts ● Each follicle has an epithelial and mesenchymal component ● Embryologically, the epithelial buds (hair germs) derive from the fetal epidermis and project downward, interacting with mesenchymal cells which form the dermal sheath and dermal papillae
  17. 17. Contains protected repositories of epithelial stem cells Forms hair via cyclic process of (a) anagen or growing phase (b) catagen or involuting phase (c) telogen or resting phase Matrix (regenerative) cells line the dermal papillae, are mitotically active, give rise to hair shaft and inner root sheath
  18. 18.  HP: demonstrating the deeply pigmented hair shaft towards the center, surrounded by the cells of the hair sheath.
  19. 19. • inner and outer hair sheath. •The two sebaceous glands are attached to the hair follicle above the erector pili muscle.
  20. 20.  Normal Sweat Glands •Multiple sections of the ampullary region of the normal sweat gland. •The eccrine sweat gland is composed of numerous acinar structures with a large central lumen. •These are multiple cuts across a single, convoluted stucture.
  21. 21. Normal Sebaceous Gland •Towards the periphery of this single acinus of a sebaceous gland is a single layer of cuboidal cells that are somewhat deeper staining. •Towards the center are large cells which are pale staining cytoplasm and a central pyknotic nucleus. •At the very center is a dark staining structure that represents the duct of this gland. •The central, light-staining cells are normally shed as such into the hair shaft and form the oily secretion that coats the hair as well as the overlying skin.
  22. 22. NORMAL SKIN ADNEXAE Positive stains ● Eccrine and apocrine glands: EMA, CEA, keratin, S100 ● Myoepithelial cells: actin, calponin, caldesmon, S100
  23. 23. Subcutaneous tissue  Also called subcutis  Contains lobules of mature adipose tissue and thin connective tissue septa  Pacinian Corpuscle : A nerve receptor located in the subcutaneous fatty tissue that responds to pressure and vibration.
  24. 24. SUBCUTIS
  25. 25. ANTHRAX  Etio: endospores of Bacillus anthracis, a common soil organism  Manifestations: Cutaneous, Pulmonary or Gastrointestinal symptoms Culture: nonhemolytic, nonmotile, ground- glass colonies that retain their shape when manipulated; grow readily on sheep red blood cell agar (no special conditions needed) Gram stain: gram positive, spore-forming rods Treatment: antibiotics, reduces mortality from 20% to less than 1%
  26. 26. ANTHRAX: MICRO ESCHAR  Coagulative necrosis of epidermis and dermis  Prominent edema of underlying viable dermis  Frequent focal hemorrhages,  Intense, reactive-appearing mononuclear inflammatory infiltrates around small vessels and some adnexae  PMNs only around necrotizing sebaceous glands  Sharp demarcation between superficial necrotic and deeper edematous viable tissue (at periphery)  Islands of regenerating epidermis under necrotic layer of eschar  Vessels with degenerated endothelial cells and focal thrombi  No abscess, No granulation tissue
  27. 27. ANTHRAX  Bacterial images: bacteria, in CSF (inhalation anthrax)  EM images: anthrax spores
  28. 28. SUBCUTIS : Carbuncle  Painful localized bacterial infection of skin and subcutis, usually with several openings through which pus is discharged CMV (cytomegalovirus)  Gross/clinical images: punched out ulcers in immunocompromised patients
  29. 29. CMV Infection of Skin Numerous cleanly punched out ulcers that occur in the case of an acute CMV infection in an immunocompromised individual.
  30. 30. ERYSIPELAS Streptococcal infection causing upper dermal edema and “orange peel” or peau d’orange appearance
  31. 31.  “orange peel” or peau d’orange appearance
  32. 32. FOLLICULITIS  Inflammation around hair follicles, involving follicular opening or adjacent skin  Infectious cases are either superficial (fungi, bacteria, syphilis, viral) or deep (granulomatous, due to fungi or bacteria)  Fungal forms may be endothrix (spores within hair shaft) or ectothrix (spores on outer surface of hair shaft)
  33. 33. Infectious cases: FOLLICULITIS Superficial ◦ Fungi ◦ Bacteria ◦ Syphilis ◦ Viral Deep ◦ granulomatous, due to fungi or bacteria Fungal forms: ◦ endothrix (spores within hair shaft) ◦ ectothrix (spores on outer surface of hair shaft)
  34. 34. Noninfectious cases: FOLLICULITIS Superficial / Suppurative  Acne vulgaris  Rosacea  Follicular mucinosis  Steroid-induced Deep/Granulomatous  Acne vulgaris-conglobate and keloidal forms or perforating  Spongiotic (Fox-Fordyce disease, atopic dermatitis, pruritic folliculitis of pregnancy)
  35. 35. FOLLICULITIS Perifolliculitis forms:  lymphocytic (lichen planopilaris, pityriasis rubra pilaris)  granulomatous (perioral dermatitis, rosacea) Pseudolymphomatous folliculitis: facial lesion with dense, polymorphic, mixed lymphocytes around hair follicles and infiltrating follicular epithelium
  36. 36. SUBCUTIS:Fungi  Fungi-Candida
  37. 37. FUNGAL: CHROMOBLASTOMYCOSIS  Clinically resembles carcinoma  Color of lesion is due to brown spores  Indolent cutaneous disease due to Phialophora, Fonsecaea or Cladosporium fungi, that multiply by cross wall formation and splitting Cultures (Phialophora): slow growing, dark gray-black and hairlike Gross: verrucous or nodular, resembling CA Micro: marked pseudoepitheliomatous hyperplasia and mixed granulomatous- neutrophilic infiltrate; contains brown spores; fungi have cross walls but no budding
  38. 38. CHROMOBLASTOMYCOSIS  Chronic verrucous chromoblastomycosis of the hand due to Cladophialophora carrionii  tissue hyperplasia forming a white verrucoid cutaneous lesion.  In Australia, chromoblastomycosis due to C. carrionii occurs mostly on the hands and arms of timber and cattle workers in humid tropical forests
  39. 39. CHROMOBLASTOMYCOSIS Laboratory diagnosis: 1. Clinical Material: Skin scrapings and/or biopsy. 2. Direct Microscopy: (a) Skin scrapings should be examined using 10% KOH and Parker ink or calcofluor white mounts; (b) Tissue sections should be stained using H&E, PAS digest, and Grocott's methenamine silver (GMS).
  40. 40. CHROMOBLASTOMYCOSIS  Direct microscopy of tissue is necessary to differentiate between chromoblastomycosis and phaeohyphomycosis where the tissue morphology of the causative organism is mycelial
  41. 41. CHROMOBLASTOMYCOSIS  Skin scrapings from a patient with chromoblastomycosis mounted in 10% KOH and Parker ink solution showing characteristic brown pigmented, planate-dividing, rounded sclerotic bodies.
  42. 42. CHROMOBLASTOMYCOSIS  H&E stained section showing characteristic dark brown sclerotic cells which divide by binary fission and not by budding.  Note all agents of chromoblastomycosis form these sclerotic bodies in tissue.
  43. 43. CHROMOBLASTOMYCOSIS  3. Culture: Clinical specimens should be inoculated onto primary isolation media, like Sabouraud's dextrose agar.  Cultures of the etiologic agents of chromoblastomycosis are typically olivaceous-black with a suede-like surface.
  44. 44. CHROMOBLASTOMYCOSIS  Culture identification is the only reliable means of distinguishing these fungi.
  45. 45. CHROMOBLASTOMYCOSIS  4. Serology: There are currently no commercially available serological procedures for the diagnosis of chromoblastomycosis.  5. Identification: Culture characteristics and microscopic morphology are important, especially conidial morphology, the arrangement of conidia on the conidiogenous cell and the morphology of the conidiogenous cell. Cellotape flag and/or slide culture preparations are recommended.
  46. 46. CHROMOBLASTOMYCOSIS Causative agents:  Cladophialophora carrionii, Fonsecaea pedrosoi, Phialophora verrucosa Management:  The treatment of chromoblastomycosis has been exceedingly difficult.  Successful surgical excision requires the removal of a margin of uninfected tissue to prevent local dissemination.  Flucytosine with or without thiabendazole has been extensively used in the past.  However both itraconazole [400 mg/day] and terbinafine [500 mg/ day] for 6 to 12 months have been used successfully for the treatment of chromoblastomycosis.
  47. 47. Histoplasma capsulatum  A dimorphic saprophytic fungus found in soil contaminated with bird or bat feces  Endemic to southeast US (80% of this population may have positive intradermal histoplasmin skin test), Mexico, Africa, Asia  Via inhalation of spores, causing a primary pulmonary pneumonia  Pneumonia is self-limited in immunocompetent patients, but disseminates in immunocompromised (very young, very old, HIV+) to liver, spleen, bone marrow, nodes, lung, rarely to skin  Disseminated disease: strongly associated with AIDS; fever, weight loss, splenomegaly; variable cutaneous lesions
  48. 48. H. CAPSULATUM  Culture: tan-white-brown wooly mold at 25-30C on Sabouraud dextrose agar; organisms have delicate, septate hyphae, 1-2 microns thick, with large rough-walled macroconidia 5-15 microns; revert to yeast at 37C on sheep blood agar; yeast is 2-4 microns, budding, single nuclei, round/oval with thin rigid walls  Treatment: antifungal drugs
  49. 49. H. CAPSULATUM  Gross: cutaneous lesions are nodules, papules, ulcers; less commonly macules, pustules or vesicles  Micro: isolated intracellular organisms, larger aggregates surrounded by chronic inflammatory cells and fibroblasts (but no neutrophils or eosinophils) or epithelioid granulomas with variable caseation; may be narrow based
  50. 50.  Histoplasma capsulatum - a disseminated infection, and the macrophages containing small yeasts appear in multiple organs, particularly those of the mononuclear phagocyte system (lymph node, liver, spleen, marrow).  Liver with H and E stain
  51. 51. HISTOPLASMOSIS  Histoplasma capsulatum organisms in macrophages are seen in liver with PAS stain.
  52. 52.  Histoplasma capsulatum yeast forms fill phagocytes.
  53. 53. MADURAMYCOSIS  Actinomadura is an aerobic actinomycetes, a filamentous bacterium found in soil  Initially believed (incorrectly) to be a fungi, so diagnostic procedures are often performed in mycology laboratories
  54. 54.  MADURA  FOOT
  55. 55. ONCHOMYCOSIS  Spread of fungi to nails  Candida albicans, Scopulariopis brevicaulis, others;  often multiple fungal species
  57. 57. SUPERFICIAL FUNGAL INFECTIONS  Scalp and beard lesions may have superimposed bacterial folliculitis / perifolliculitis  May also be found on neoplastic skin lesions  Infections of stratum corneum are usually caused by dermatophytes  Spores, hyphae and neutrophils usually are present in stratum corneum or hair shafts  Associated with pseudoepitheliomatous hyperplasia
  58. 58. SUPERFICIAL FUNGAL INFECTION  Kerion celsi: superimposed bacterial folliculitis on tinea of scalp  Majocchi’s granuloma: nodular granulomatous perifolliculitis; inflammation of dermis and subcutis by dermatophytes, usually Trichophyton rubrum  Sycosis barbae: tinera barbae with superimposed bacterial follicultis  Tinea corporis: infection of trunk of children and adults, associated with excessive heat and humidity; scaly, red, annular plaques (“ringworm”)  Tinea cruris: "jock itch", infection of inguinal area of obese men during warm weather
  59. 59.  Tinea pedis: "athletes foot", infection causing diffuse erythema and scaling, initially in web spaces, often with bacterial superinfection
  60. 60.  This photomicrograph reveals a number of macroconidia of the dermatophytic fungus Epidermophyton floccosum.  known to be a cause of dermatophytosis leading to tinea corporis (ringworm), tinea cruris (jock itch), tinea pedis (athlete’s foot), and onychomycosis or tinea unguium, a fungal infection of the nail bed.
  61. 61.  Tinea capitis: infection causing hairless patches of skin in scalp, usually in children
  62. 62.  Tinea barbae: infection of beard area of adult men
  63. 63. Tinea versicolor  Infection by Malassezia furfur of upper trunk  Micro: variably pigmented macules of all sizes, with orthokeratotic hyperkeratosis, yeast spores and pseudohyphae within stratum corneum; short hyphae and spores (“spaghetti and meatballs”) with GMS or PAS stains  Presence of fungi does not rule out coexisting inflammatory and neoplastic disorders
  64. 64. Malasse
  65. 65.  Coccidioides immitis infection can often be disseminated to multiple organs, though pneumonia is often present because the infection is acquired via the respiratory tract.  Spherules are seen here in lung with H and
  66. 66.  Spherules of Coccidioides immitis are seen here in liver with H and E staining.  Note the thick wall of the sperules containing endospores. One spherule is rupturing to release the endospores, the yeast phase which grows at body temperature.
  67. 67. HERPES SIMPLEX / VARICELLA ZOSTER  Painful diseases caused by herpes simplex virus or varicella zoster virus (chickenpox)  After primary infection, viral particles reside in sensory ganglia and are dormant until they erupt as recurrent herpes simplex virus or shingles (zoster)  Associated with leukemia and lymphoma  Shingles has dermatomal distribution or severe involvement of trigeminal nerve-first division with corneal ulceration and herpetic keratitis  The two viruses are differentiated by culture or immunologic methods  Gross: grouped vesicles on an erythematous base, later become pustules, then crusts
  68. 68.  Here is the classic lesion of varicella zoster following the dermatome T7 in this 12-year- old boy
  69. 69. HIDRADENITIS SUPPURATIVA  Due to bacterial infection around apocrine glands of axilla, occasionally perineum or vulva  Usually due to anaerobes  May produce fistulas and scarring  Treatment: excision of involved skin if medical therapy fails  Gross: abscesses, sinuses, perianal fistulas with scarring  Micro: heavy neutrophilic or mixed inflammatory infiltrate around apocrine glands with dilated lumina
  71. 71. HIV associated  Dermatitis: interface dermatitis occurs early in HIV infection, with pronounced vacuolization of basal keratinocytes, inflammatory infiltrate is CD3+/CD8+ T cells expressing granzyme B7 and TIA1, and histiocytes; decreased Langerhans cells
  72. 72. HIV ASSOCIATED  Folliculitis: infants and adults; perifollicular chronic inflammatory infiltrate, often with follicular rupture, often with marked eosinophils  Infections: scabies, fungi, mycobacteria, syphilis, bacterial angiomatosis  Maculopapular eruptions: in 25%, in trunk with possible extension to extremities; nonspecific perivascular lymphocytes and histiocytes in upper dermis, variable papulovesicular foci
  73. 73.  Papular neutrophilic xanthoma: foamy macrophages, extracellular nuclear dust, hyaline necrosis of collagen fibers  Papular pruritic eruptions: anywhere on body; may wax and wane; superficial and mid-dermal perivascular lymphocytes with eosinophils, acanthosis, parakeratosis
  74. 74.  Psoriasis  Seborrheic dermatitis: common, usually severe, involves trunk & extremities
  75. 75.  Vasculitis: leukocytoclastic, may be due to HIV directly or CMV  Viruses: herpes simplex (20%; painful perianal or perioral ulcers with large intranuclear inclusions), severe varicella- zoster infection, CMV (ulcerative lesions at mucocutaneous junctions), molluscum contagiosum, hairy leukoplakia, anal warts, bowenoid papulos
  76. 76.  A. widespread maculopapular HIV exanthema.  B. oral enanthema with ulceration.
  77. 77.  A. interface dermatitis with individual necrotic keratinocytes, lymphocytic exocytosis.  B. several lymphocytes surrounding one necrotic keratinocyte ("satellite cell necrosis  C. With necrosis and vacuolization of keratinocytes
  78. 78. IMPETIGO  Usually affects hands and face of normal children or adults in poor health  Common, due to Staphylococcus or Streptococcus infection  Gross: erythematous macule  Micro: neutrophils beneath stratum corneum; may have subcorneal pustule
  79. 79. LEPROSY  Also called Hansen’s disease  Most US cases from immigrants  Diagnosis: PCR
  80. 80. LEPROMATOUS LEPROSY  Micro: numerous foamy macrophages (Virchow cells, lepra) stuffed with acid- fast bacilli; granulomas in and around cutaneous nerves or infiltrating and destroying arrectores pilorum muscle; may have subcutaneous nodules (erythema nodosum leprorum)  Positive stains: acid-fast (Ziehl- Neelsen)  DD: fibrous histiocytoma
  81. 81. TUBERCULOID LEPROSY  Micro: bacilli are scanty; granulomas in and around cutaneous nerves or infiltrating and destroying arrectores pilorum muscle
  84. 84. MALAKOPLAKIA  Rare; may occur in HIV+ patients  Micro: Histiocytes have Michaelis-Gutmann bodies, rarely contain gram negative organisms
  85. 85. MOLLUSCUM CONTAGIOSUM  Caused by human molluscum contagiosum poxvirus  Multiple nodules on skin, trunk, anogenital region, due to skin to skin contact; also sexually transmitted Gross:  multiple firm, pruritic, pink-tan nodules, up to 4 mm, with central cores containing white keratinous material  raised, firm, flesh colored nodules Micro:  characteristic findings of sharply delimited dermal lesion containing proliferating epithelium  molluscum bodies present (large cells with cytoplasmic, faintly granular eosinophilic inclusions that displace nuclei; contain viral particles)  may have intense dermal inflammatory infiltrate; rarely metaplastic ossification
  86. 86. MOLLUSCUM CONTAGIOSUM  The features to look for are: ◦ epidermis acanthosis (hyperplasia) which grows into the dermis to form multiple lobule ◦ intracytoplasmic inclusion bodies which are eosinophilic (stianed pink with H & E) at the base but becomes more basophilic (stained blue with H & E) at the superficial layer ◦ central crater into which the inclusion bodies discharge their content
  87. 87.  Lobules of epidermis with inclusion bodies. Note the inclusion bodies are pinker at the base and become progressively darker and bluish towards the crater
  88. 88.  c/s showing nestles of inclusion bodies
  89. 89. MYCOBACTERIA, ATYPICAL  May cause ulcerations, abscesses, rheumatoid-like nodules, histiocytic reactions, panniculitis  Most commonly due to M. kansasii, M. marinum, M. ulcerans
  90. 90. GROSS DESCRIPTION:  The specimens labelled "synovium, left fifth toe" consisted of irregular portions of focally hemorrhagic, fibrofatty tissue, up to 1.0 cm in greatest dimension.  From a 52 y.o.woman with foot infection
  91. 91. Histologic sections revealed fibrovascular and adipose tissue with granulation tissue and focal prominent acute inflammation. Gram stain showed numerous gram positive rods . Acid fast stain revealed several groups of rarely beaded acid fast rods
  92. 92. Aerobic cultures showed rare coagulase negative staphylococcus. Gram positive rods grew on 5% sheep blood agar after four days. The gram positive rods were acid fast positive. Growth of buff colored, nonphotochromogenic, rounded, smooth colonies without filamentous extensions was noted on Lowenstein-Jensen agar at 28oC in four days . Subculture onto Lowenstein-Jensen agar with 5% NaCl and MacConkey agar without Crystal Violet showed growth in 5 days. Growth on tap water agar after 48 hours at 28oC lacked aerial hyphae and showed morphology typical of mycobacterial species. The 3-day arylsulfatase test was positive. The nitrate reduction and iron uptake tests were negative. The organism was identified as Mycobacterium abscessus
  93. 93. Parvovirus B19  skin manifestations are petechial eruption in a glove and stocking distribution, reticular truncal erythema, and "slapped cheek" sign  Manifestation: Fifth’s disease; atypical presentations resemble asymptomatic papular eruption, Sweet’s syndrome, myopathic dermatomyosis, lupus, lower extremity palpable purpura  Due to delayed type hypersensitivity, antibody dependent cellular immunity against microbial antigens in epidermis or endothelium, or circulating immune complexes
  94. 94.  Gross images: slapped cheek appearance  Micro: interstitial histiocytic infiltrate with piecemeal fragmentation of collagen and mononuclear cell- predominant vascular injury pattern; also interface dermatitis, eczematous alterations, papillary dermal edema; occasionally mesenchymal mucinosis, leukocytoclastic vasculitis
  95. 95. PARVOVIRUS B19
  96. 96. SYPHILIS  Secondary lesions are maculopapular, and resemble drug eruption, lichen planus, psoriasis  May present as moth-eaten alopecia on scalp, mucous patches on tongue  Occur on face and trunk
  97. 97. syphilis  Gross: scaly, flesh-colored to erythematous papules or annular plaques; copper macules on palms and soles  Micro: dense perivascular or diffuse plasma cell infiltrate with marked endothelial swelling and proliferation in blood vessels is characteristic; may have noncaseating granulomas, vacuolar interface change, acanthosis, spongiosis, lymphocyte exocytosis
  98. 98.  PRIMARY SYPHILIS  The epidermis is ulcerated, and the underlying tissue is infiltrated by predominantly plasma cells, macrophages, and lymphocytes.  Positive stains: Steiner stain (71% sensitive)
  99. 99. TB-SKIN: LUPUS VULGARIS  Reactivation form of tuberculosis  Chronic cases are associated with squamous cell carcinoma  Diagnosis: culture or PCR  Gross: facial lesions with small, firm nodules in underlying, irregular red patch with elevated borders; nodules become pale and tan when pressed with a glass slide; variable ulceration  Micro: sarcoid-like or necrotic granulomas in dermis; rare acid-fast bacilli
  100. 100.  Lupus vulgaris on the face of an 88 y- o female (gross findings).  The facial skin is the most common site of reinfection tuberculosis of this form.
  101. 101.  Histologic features of lupus vulgaris (HE).  Caseous granuloma is observed in the dermis in the biopsy specimen. Caseation is a relatively rare event and bacilli are usually sparse.
  102. 102.  Fibrosing epithelioid granuloma extends into the subcutaneous tissue. The cytoplasm of the epithelioid cells appears to be foamy (HE). Necrosis is only focally seen.
  103. 103.  A few acid-fast bacilli are identified within the lesion (Ziehl-Neelsen). "Scrofuloderma" is a form of skin tuberculosis showing secondary fistulous extension from the lymph node or bone.
  104. 104. WARTS  Also called verrucae  Cutaneous and mucosal lesions caused by various types of human papillomaviruses (HPV), a type of papova virus  Usually resolve in 6-24 months
  105. 105. Micro:  focal epidermal hyperplasia with hyperkeratosis and parakeratosis, papillomatosis (not verruca plana), may have trichilemmal keratinization  Koilocytes (keratinocytes in upper squamous layer with vacuoles, large cytoplasmic eosinophilic aggregates, pyknotic nuclei)  Tangential sections may show squamous cells surrounded by inflamed stroma  Older lesions may lack cytoplasmic changes  Viral nuclear inclusions are basophilic
  106. 106.  Verruca vulgaris:  A tan rough sessile nontender enlargement is present on the palmar skin.
  107. 107. CAUSE:  HPV  130 known types of HPV  HPV infects the Squamous epithelium, usually of the skin or genitals, but each HPV type is typically only able to infect only a few specific areas on the body.  Many HPV types can produce a benign growth, often called a "wart" or "papilloma", in the area they infect. Many of the more common HPV and wart types are as follows:  Common warts - HPV types 2 and 4 (most common); also types 1, 3, 27, 29, and 57 and others.
  108. 108. WART  Cancers and Genital Dysplasia - "high-risk" HPV types are associated with cancers, ( cervical cancer and can also cause some vulvar, vaginal, penile, anal and some oropharyngeal cancers.  "low-risk" types are associated with warts or other conditions  High-risk: 16, 18 (cause the most cervical cancer); also 58, 33, 45, 31, 52, 35, 39, 59, and others.  Plantar warts (myrmecia) - HPV type 1 (most common); also types 2, 3, 4, 27, 29, and 57 and others.
  109. 109. WART  Anogenital warts (condylomata acuminata or venereal warts) - HPV types 6 and 11 (most common); also types 42, 44 and others.  Low-risk: 6, 11 (most common); also 13, 44, 40, 43, 42, 54, 61, 72, 81, 89, and others.  Flat warts - HPV types 3, 10, and 28.  Butcher’s warts - HPV type 7.  Heck’s Disease (Focal epithelial hyperplasia) - HPV types 13 and 32.
  110. 110. INFESTATIONS
  111. 111. INFESTATIONS  Skin lesions due to direct irritant effects, immediate or delayed hypersensitivity or specific effects of venom  Bites: urticaria, inflamed papules or nodules, variable ulceration Body louse  Causes hyperpigmentation and scratch marks (excoriations)
  112. 112. BODY LOUSE  This is a magnified view of a female body louse with larvae. Lice cause itching and a characteristic excoriated skin rash (looks like a scrape). They may also transmit diseases, including relapsing fever, typhus, and trench fever. (Image courtesy of the Centers for Disease Control and Prevention.)
  113. 113. PEDICULOSIS (LICE)  Causes pruritis, enlarged local lymph nodes  Eggs are attached to hair shaft (nits)
  114. 114. PUBIC LOUSE (CRABS)  A sexually transmitted disease  Gross images:
  115. 115. PUBIC LICE: Phthirus pubis Habitat: Crab or pubic lice lay their eggs on coarse body hair, particularly the hair associated with the pubic regions, perianal region, thighs, abdomen, and armpits, but they will also infest a person's beard and eyelashes. - Much less mobile than head or body lice, they can remain attached with their mouthparts in the skin for days Pubic lice are typically found only on humans and are most often transmitted directly from person to person, particularly during sexual contact.
  116. 116. PUBIC LICE When crab lice feed they can inject saliva into the host, causing pruritus and itching. Scratching the area can increase the irritation. The area can become scaly and hardened with oozing lesions. Painless blue spots can appear after crab lice feed. Other evidence of crab lice includes the occurence of rust-colored insect exretions and darker spots in underwear and flakes similar to dandruff in pubic hair.
  117. 117. SCABIES (MITE)  Produces burrows and extremely pruritic erythematous papules on interdigital skin, palms, wrists  Micro: burrow appears as cleft in upper epidermis containing mite body parts; epidermis exhibits acanthosis, parakeratosis, spongiosis, with dense eosinophilic dermal infiltrate
  118. 118.  Scabies in the young adult - sexually transmitted infection.  Cleaning and disinfection by hot water are needed for the linen to avoid unnecessary transmission  Within the cornified layer, a cut surface of Sarcoptes scabiei hominis with the spiked cuticle and immature and mature eggs is observed (HE)  The epidermis is moderately acanthotic and the dermis is actively inflamed.
  119. 119.  Another case of scabies in the aged (68 y-o M). Itchy papules are seen on the interphalangeal area, focally with burrow formation. The mite burrow formation is pathognomonic of scabies.  Nosocomial infection of scabies is problematic, particularly in the ward of neurosurgery and in the care stations for the aged.  The female mite, Sarcoptes scabiei hominis, eggs and pigmented feces in the unstained skin scratch preparation after potassium hydroxide treatment.  The mite, measuring 0.3-0.45 mm, has four pairs of legs. The mite eats keratinocytes, so that the feces is pigmented by melanosomes and mitochondria.
  121. 121. EPIDERMOLYSIS BULLOSA  At least 12 genetic disorders with site of cleavage in dermis, lower epidermis or at dermoepidermal junction  Blisters form shortly after birth due to pressure, rubbing or trauma  Cause scarring or milia on dorsum of hands, elbows and knees and oromucosal lesions  Dystrophic types: blisters beneath lamina densa (associated with anchoring fibrils), cause scarring  Hallopeau-Siemens recessive dystrophic form associated with aggressive squamous cell carcinoma  Junctional: blisters at lamina lucida, skin appears normal  Simplex: degeneration of basal cell layer causes clinical bullae  Epidermolysis bullosa acquisita: rare autoimmune disorder of antibodies to hemi-desmosomes; rarely occurs following drug therapy, usually unkown cause
  123. 123.  Micro: subepidermal blister with variable inflammation; superficial dermis is fibrotic  Positive stains: linear C3 and IgG deposits along epidermal basement membrane  EM: may be necessary for classification
  124. 124. Epidermolysis Bullosa  An uncommon disorder with a genetic pattern (three types), presenting in children. There is also an acquired form of the disease. Profound scarring of the skin leads to deformities. In the mouth the children present with dental anomalies and fragile blisters. Scarring usually follows. Key Features  Subepithelial separation of the epithelium from the underlying corium  Subepithelial vesicle MICRO:  formation of subepithelial vesicle  subepithelial separation of the epithelium from the underlying corium
  125. 125. ERYTHEMA MULTIFORME  Acute, self limited, hypersensitivity reaction to infections (herpes simplex, mycoplasma, histoplasmosis, coccidioidomycosis, typhoid, leprosy), drugs (penicillin, sulfa, salicylates, phenytoin, phenylbutazone), carcinoma / lymphoma, or collagen vascular disorders  Affects skin (distal extremities, palms, soles) and mucous membranes with target lesions; also sore throat and malaise  Any age  Gross: variable (multiform) lesions – papules, macules, vesicles, bullae, target lesions; commonly in mucous membranes
  127. 127. ERYTHEMA MULTIFORME  Micro: subepidermal bullae with basement membrane in bullae roof due to dermal edema; severe dermal inflammatory infiltrate (includes cytotoxic T cells) with nuclear dust; overlying epidermis often demonstrates liquefactive necrosis and degeneration, dyskeratotic keratinocytes; variable epidermal spongiosis and eosinophils  No microabscesses, no festooning of dermal papillae  Note: erythema multiforme may have variable histologic changes from toxic epidermal necrolysis to dermal disturbances; may also have dermoepidermal bullae with basal lamina at floor of bullae  Positive stains: granular C3 and IgM at basement membrane and in vessels
  128. 128. IMPETIGO CONTAGIOSA  Also called bullous impetigo  Affects face, trunk and extremities of infants and children  Contagious superficial infection of skin, associated with staphylococci  Gross: small vesicles or pustules that rupture easily; may be covered by yellow crust  Micro: vesicles just below keratin layer
  129. 129. STEVEN-JOHNSON SYNDROME  Systemic form of erythema multiforme with fever  Common in children, often involving lips, oral mucosa or other mucosa with erosions and hemorrhagic crusts  Infection of affected areas may cause life threatening sepsis  Toxic epidermal necrolysis: variant with full thickness epidermal necrosis but intact cornified layer, subepidermal bullae and sloughing of skin/mucosal epithelium; analogous to severe burn
  130. 130.  Micro: full thickness epidermal necrosis with separation of epidermis from dermis; necrotic keratinocytes at edge of bullae  DD: staphylococcal scalded skin syndrome (similar clinically, but plane of cleavage is in granular layer), necrolytic migratory erythema (glucagonoma syndrome – has superficial epidermal necrosis)
  131. 131.  Note early cutaneous slough with areas of violaceous erythema.  Extensive sloughing on the face  Note the presence of both 2-zoned atypical targetoid lesions and bullae.
  133. 133. ACANTHOSIS NIGRICANS  80% are benign type, either autosomal dominant or associated with tissue resistance to insulin, including diabetes, obesity, Cushing’s disease  20% are associated with GI or other internal malignancies; usually age 40+ years Gross: brown, velvety, verrucous plaques in axillae, back of neck and other skin folds Micro: orthokeratotic hyperkeratosis (not actually acanthosis) and papillomatosis of stratum spinosum; hyperpigmentation of basal cell layer, but no melanocytic hyperplasia
  134. 134.  This photograph demonstrates the hyperpigmented, brownish, velvety lesions of acanthosis nigricans.  This skin condition may occur in skin folds such as the axilla (armpit - pictured here), neck, and other areas.  In adults, it may be associated with hormonal problems, internal malignancy, obesity, and drugs.
  135. 135. ACNE ROSACEA  Also called rhinophyma  Erythema of central face, with acneiform pustules and papules, telangiectasia, blepharitis  Micro: perinfundibular lymphocytic or granulomatous inflammation
  136. 136.  Rosacea is a common condition characterized by symptoms of facial flushing and a spectrum of clinical signs, including erythema, telangiectasia, coarseness of skin, and an inflammatory papulopustular eruption resembling acne.
  137. 137. ACNE VULGARIS  Usually teenagers, either gender, although often more severe in males  Due to hormonal variations and alterations in hair follicle maturation  Worsens with drugs (steroids, testosterone, contraceptives), oils/tars, heavy clothing, tropical climates  Noninflammatory acne is due to open and closed comedones  Open comedones: small follicular papules with central black keratin plug (due to oxidation of melanin)  Closed comedones: follicular papules with a deeper plug below the surface  Follicles may rupture and become inflamed Treatment: antibiotics, isotretinoin Micro: lipid (sebum) and keratin within hair follicle; variable lymphocytes and histiocytes
  138. 138.  Severe Acne Vulgaris involving the face & back
  139. 139.  Acne, grade III; papulopustules.  Acne, grade IV; multiple open comedones, closed comedones, and papulopustules, plus cysts.
  140. 140. CAUSES OF ACNE VULGARIS Main underlying cause - a genetic predisposition. - Inherited in an AD pattern with incomplete penetrance. Acne vulgaris may skip a generation. The following aggravating factors are recognized:  Cosmetic agents and hair pomades may worsen acne.  Medications that can promote acne development include steroids, lithium, some antiepileptics, and iodides.  Congenital adrenal hyperplasia, polycystic ovary syndrome and other endocrinological disorders associated with excess androgens may trigger the development of acne vulgaris. Even pregnancy may cause a flare-up.  Mechanical occlusion with headbands, shoulder pads, back packs, or under-wire bras can be aggravating factors  Excessive sunlight may either improve or flare acne. In any case, the ultraviolet exposure ages the skin
  141. 141. ACUTE ECZEMATOUS DERMATITIS  Allergic contact dermatitis:  Atopic dermatitis: unknown cause (not allergic); may be familial (hay fever, asthma, eczema); occurs on flexural surfaces  Drug-related: usually systemic (penicillin), eosinophils present in deep dermis  Eczema: red, papulovesicular, oozing, crusted lesions (spongiotic dermatitis) which evolves to raised, scaling plaques (epidermal hyperplasia and excessive scale)  Irritant contact dermatitis  Photo-dermatitis: due to UV light exposure  Primary irritant dermatitis: due to repeated rubbing  Micro: spongiosis, perivascular lymphocytic infiltrate  DD: drug reaction (prominent eosinophilic infiltrate)
  143. 143. Infancy  Atopic dermatitis is usually noticed soon after birth. Xerosis occurs early and often involves the whole body; the diaper area is usually spared.  The earliest lesions affect the creases (antecubital and popliteal fossae), with erythema and exudation. Over the following few weeks, lesions usually localize to the cheeks, the forehead and scalp, and the extensors of the lower legs; however, they may occur in any location on the body, usually sparing the diaper area. Lesions are ill-defined, erythematous, scaly, and crusted (eczematous) patches and plaques.  Lichenification is seldom seen in infancy
  144. 144. Childhood  Xerosis is often generalized. The skin is flaky and rough.  Lichenification is characteristic of childhood atopic dermatitis. It signifies repeated rubbing of the skin and is seen mostly over the folds, bony protuberances, and forehead.  Lesions are eczematous and exudative. Pallor of the face is common; erythema and scaling occur around the eyes. Dennie- Morgan folds (ie, increased folds below the eye) are often seen. Flexural creases, particularly the antecubital and popliteal fossae, and buttock-thigh creases are often affected.
  145. 145. Adulthood  Lesions become more diffuse with an underlying background of erythema. The face is commonly involved and is dry and scaly.  Xerosis is prominent.  Lichenification may be present.  A brown macular ring around the neck is typical but not always present. It represents localized deposition of amyloid.
  146. 146. ERYTHEMA NODOSUM  Red, painful, subcutaneous lesions on anterior surface of legs that usually involute in days/weeks, leaving depressed pigmented lesions  No ulceration  Immune mediated, but precise mechanism is unknown  May be associated with streptococcus infection, tuberculosis, sarcoidosis, coccidioidomycosis, ulcerative colitis, Behcet’s disease, drug reactions or idiopathic
  147. 147.  Micro: inflammatory infiltrate at junction of dermis and subcutis, extending along fibrous septa separating fat lobules and in dermal vessels; may be neutrophilic, lymphocytic, histiocytic or granulomatous (noncaseating or with occasional giant cells); variable vasculitis  Miescher’s radial granuloma: cluster of small histiocytes arranged around a central cleft  DD: nodular vasculitis or subacute nodular migratory panniculitis (usually septal), Weber- Christian disease associated panniculitis (usually lobular inflammation)
  148. 148. Erythema Nodosum  Deep dermal tissue with inflammatory cells in a perivascular location, between collagen bundles.  Infiltration of inflammatory cells between the adipocytes, typical of a lesion of erythema nodosum.  Represents a common reaction to a variety of insults to the skin.
  149. 149. EXFOLIATIVE DERMATITIS & ERYTHRODERMA  Total body erythema and scaling  Due to drug reaction, allergic contact dermatitis, psoriasis, pityriasis rubra pilaris, malignancy  Associated with dermatopathic lymphadenitis  Micro: nonspecific changes; may have lichenoid dermatitis  DD: Sezary’s syndrome / mycosis fungoides
  150. 150.  Diffuse skin involvement  90% or more scaling of the cutaneous surface  Exfoliative dermatitis onset usually occurs in persons older than 40 years, except when the condition results from atopic dermatitis, seborrheic dermatitis, atphylococcal scalded skin syndrome a hereditary ichthyosis.  Age of onset primarily is related to etiology.
  151. 151. ICHTHYOSIS  Disorder of epidermal maturation; skin resembles fish scales  Associated with excessive keratin buildup due to desquamation defect, leading to retention of abnormally formed scale  Usually apparent at birth; in adults, is associated with malignancies  Ichthyosis vulgaris: common type  Lamellar ichthyosis: rare, inherited skin condition of newborn with shedding of plate-like layers of skin  X linked variant: deficiency in steroid sulfatase, which removes proadhesive
  152. 152.  Gross: skin resembles fish scales; rough scaly patches and plaques  Micro: increased stratum corneum with loss of normal basket weave pattern, little inflammation; loss of granular layer in ichthyosis vulgaris
  153. 153. Lamellar ichthyosis  The abnormal stratum corneum has produced what appears as very thick scale on the skin, and with an abnormal barrier layer these patients commonly get secondary staphylococcal and yeast infections.  Note that there are other associated ectodermal problems such as the teeth, hair, and eyelids.  X-LINKED
  154. 154. LICHEN PLANUS  Purple, pruritic, polygonal papules of unknown origin  Usually flexor arms and legs, glans penis and mucous membranes; may be confined to oral mucosa  Self limiting lasting 1-2 years, although longer for oral lesions; may have zone of hyperpigmentation after resolution  Wickham straie: white dots or lines within papules  Koebner phenomenon: new lesions at sites of trauma  Lichen planopilaris: primary site of involvement is epithelium of hair follicles, causing alopecia
  155. 155.  Micro: classic example of a lichenoid dermatitis; hyperkeratosis and acanthosis; prominent granular cell layer, sawtoothing of rete pegs, band like chronic inflammatory infiltrate (T cells and macrophages) that destroys the dermoepidermal junction; Civatte bodies (apoptotic basal cells, PAS+); artifactual cleft formation between epidermis and papillary dermis; occasional subepidermal bullae; no atypia  Variants: bullous, pemphigoid, hypertrophic, atrophic, follicular  Positive stains: immunoglobulins along dermoepidermal junction  DD: lichenoid dysplasia (atypia present), lichenoid dermatitis
  156. 156.  hyperkeratosis and acanthosis; prominent granular cell layer, sawtoothing of rete pegs, band like chronic inflammatory infiltrate
  157. 157. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)  Due to anti-DNA antibodies  Usually women  Fatigue, fever, arthritis, erythematous bilateral butterfly (malar) rash of face, renal disease, lymphadenopathy, serositis  Exacerbated by sunlight  Discoid lupus-type lesions in 1/3  Gross images: Malar rash of the face
  158. 158.  Micro: fibrinoid necrosis at dermoepidermal junction with liquefactive degeneration and atrophy of epidermis; more mucin deposition in reticular dermis than discoid lupus  Positive stains: IgG, IgM, C5b-C9 (by direct immunofluorescence) in clinically involved skin as irregular band at dermoepidermal junction; IgG and IgM only in 50% in normal skin  DD: polymorphous light eruption, Jessner’s lymphocytic infiltration of skin
  159. 159.  This is a picture of a systemic lupus erythematosis rash on the face. Lupus erythematosis often produces a "butterfly rash" or malar rash.  Typically, the rash also appears on the nose.
  160. 160. MILIARIA  Obstruction of sweat gland ducts during high heat and humidity
  161. 161. MYXEDEMA  Often in pretibial skin  Due to accumulation of mucopolysaccharides in dermis, similar to that in orbital tissues, caused by excess TSH secretion or hypothyroidism  Skin is thick, dry, waxy  Elephantiasis: extreme disease  Gross: large nodular lesion in patients with thyrotoxicity or euthyroid  Micro: eccrine sweat glands contain aggregates of mucoprotein that separates collagen strands  Positive stains: mucicarmine, Hale’s colloidal iron, PAS+ diastase resistant
  162. 162.  Bilateral erythematous infiltrative plaques in the pretibial areas.
  163. 163. NECROBIOSIS LIPOIDICA  Usually on legs of diabetic patients  Gross: atrophic, yellow depressed plaques  Micro: ill defined areas of disintegrating dermal collagen, surrounded by palisading lymphocytes and histiocytes, with thick walled vessels, usually in reticular dermis  Negative stains: lysozyme, mucin  DD: granuloma annulare (mucin+, lysozyme+, no association with diabetes), necrobiotic xanthogranuloma (head and neck of patients with paraproteinemia, not associated with
  164. 164. Necrobiosis lipoidica diabeticorum  is a chronic skin disease characterized by shiny plaques that vary in color from light yellowish to reddish- tan.  It is seen more commonly in women.  Although the name implies diabetes and the majority of cases occur in diabetics, this condition can occur in individuals without diabetes.
  165. 165. PITYRIASIS ROSEA  Initially a single large “herald” patch, then a generalized rash 1-2 weeks later, lasting 2-6 weeks  Self-limited, benign  Children, young adults  Micro: subacute spongiotic dermatitis with papillary dermal microhemorrhage and discrete mounts of parakeratosis  DD: secondary syphilis (usually plasma cells in dermis)
  166. 166.  Pityriasis rosea is a skin disease that produces oval spots (papules) over the trunk. The rash is frequently preceded by a "herald patch" (pictured here) lasting 1 to 2 weeks. The rash is usually rose red to brownish red with fine scales and central clearing. Itching (pruritus) occasionally occurs. Spontaneous remission occurs in 2 to 8 weeks. It is probably caused by an infectious agent, most likely a virus.
  167. 167.  HERALD PATCH
  168. 168. PSORIASIS  Also called psoriasis vulgaris  Common, affects 1% of population, all ages  Chronic, bilaterally symmetric, nonpruritic lesion of elbows, knees, umbilicus, lower back, scalp, glans penis; may be generalized  Associated with arthritis, myopathy, enteropathy, spondylitic heart disease, AIDS  30% have nail discoloration and onycholysis
  169. 169.  Pustular psoriasis: rare; prominent small pustules in plaque; either localized (hands/feet) or generalized and life threatening with fever, leukocytosis, diffuse infections, secondary infections and electrolyte disturbances  Auspitz sign: bleeding when scale is lifted from the plaque  Koebner phenomenon: new lesions form at site of trauma  Parapsoriasis: similar morphologically but no pain or itching; small plaque variants are considered benign; large plaque variants and parapsoriasis variegata are consistered early stages of cutaneous T cell lymphoma
  170. 170. PSORIASIS  Treatment: photochemotherapy (psoralen) and ultraviolet A light (PUVA) – associated with increased risk of melanoma and squamous cell carcinoma  Gross: well demarcated erythematous plaques covered by fine, loosely adherent, silvery-white scales  Micro: parakeratosis but usually no hyperkeratosis, acanthosis with downward elongation of rete ridges (resembles a comb), thin/no granular cell layer, suprapapillary thinning (attenuated layer of epidermal cells above tips of dermal papillae), Munro microabscesses (neutrophils in parakeratotic scale); increased mitotic figures above basal layer; prominent dermal capillaries, mixed dermal infiltrate of lymphocytes, macrophages and neutrophils  DD: psoriasiform lesions - lichen simplex chronicus, florid seborrheic dermatitis, pityriasis rubra pilaris, mycosis fungoides, Reiter’s syndrome
  171. 171. PSORIASIS  This is a picture of guttate (drop- shaped) psoriasis on the arms and chest.  Guttate psoriasis is a rare form of psoriasis.  It frequently follows a streptococcal infection, appears rapidly and affects the face, chest, and nearest limbs.  The patches are small and round or oval and have the typical appearance of psoriasis.  This photograph shows the diffuse and widespread coverage on the arm and chest
  172. 172. SEBORRHEIC DERMATITIS  Nummular eczema (silver dollar-sized patches) to generalized exfoliative dermatitis (severe atopic dermatitis) to large vesicles on palms and soles (dyshidrosis)  Not due to any known agents, although associated with irritant contact dermatitis  Micro: acute, subacute or chronic spongiotic dermatitis
  173. 173.  This is seborrheic dermatitis on the face. Note the redness (erythema) and mild scaling. Individuals with AIDS frequently develop seborrheic dermatitis or other types of skin rashes, as seen in this person who is HIV positive.  his is a close-up of seborrheic dermatitis. Note the redness (erythema) and mild scaling. Individuals with AIDS frequently develop seborrheic dermatitis or other types of skin rashes, as seen in this person.
  175. 175. FIBROEPITHELIAL POLYP  Also called acrochordon, squamous papilloma, skin tag, soft fibroma  Common, non-neoplastic, no clinical significance  Ages 40+ years; usually face, neck, trunk, intertriginous areas  Associated with diabetes, intestinal polyposis; increase during pregnancy  May be a common endpoint of various processes, including seborrheic keratosis or warts
  176. 176. Gross: soft, flesh-colored, baglike tumor, attached to skin by slender stalk Micro: papillary, fibrovascular cores covered by squamous epithelium; may have ischemic necrosis due to torsion
  177. 177. SEBORRHEIC KERATOSIS  Common; usually age 40+ years  Benign, although may coexist with malignancy  Usually affects trunk, head and neck, extremities; only hair bearing skin  Not HPV related, although HPV present in morphologically similar cases of epidermodysplasia verruciformis and bowenoid changes  Dermatosis papulosa nigra: in blacks  Leser-Trelat sign: sudden appearance or increase in number and size of seborrheic keratoses, associated with internal malignancy  Treatment: superficial curettage, freezing
  178. 178.  Gross: exophytic, sharply demarcated, pigmented lesions that protrude above surface of skin, appear to be stuck to skin, single or multiple, soft, tan-black  Micro: basal keratinocyte proliferations
  179. 179. SEBORRHEIC KERATOSIS Patterns:  acanthotic – most common, rounded verrucous surface; thick layer of basal cells mixed with horn cysts (contain keratin) and pseudohorn cysts (downgrowth of keratin into tumor mass); no prominent granular layer; some cells contain melanin due to transfer from neighboring melanocytes  irritated – pronounced squamous metaplasia with abundant eosinophilic cytoplasm and whorled squamous eddies; often atypia and mitotic figures; resembles carcinoma  inverted follicular keratosis – irritated seborrheic keratosis that grows downward and involves hair follicles  Also hyperkeratotic, adenoid, acantholytic and desmoplastic patterns  Positive stains: low molecular weight keratin  Negative stains: high molecular weight keratin (usually), HPV  DD: squamous cell carcinoma (particularly desmoplastic pattern)
  180. 180. VERRUCOUS HYPERPLASIA  Papillomatosis associated with hyperkeratosis  Benign  Nonspecific change, associated with various entities  Epidermal nevus: if present since birth or early childhood; higher risk for basal cell carcinoma or adnexal tumors  Nevus sebaceous of Jadassohn: associated with malformed adnexal structures  Verruca vulgaris: exophytic growth with marked hyperkeratosis, focal parakeratosis, papillomatosis resembling church spires, prominent granular layer, koilocytosis, dilated vessels within papillary dermis
  181. 181. DERMOID CYST  Resemble keratinous cysts of epidermal type, but also have hair adnexae  Usually face of children along embryonic closure lines
  182. 182. HIDROCYSTOMA  Usually face, solitary or multiple  Lined by two rows of sweat duct-like epithelium which may have apocrine features
  183. 183. ECCRINE ACROSPIROMA  Also called solid-cystic or nodular hidradenoma  Arises from sweat gland distal excretory duct  Gross: nodules with cystic foci high in dermis  Micro: nests/lobules of cells resembling eccrine poroma with either clear cytoplasm or prominent squamous metaplasia; may have marked vascularity; small and large lumina are lined by cuboidal ductal cells or columnar secretory cells; cystic spaces may be due to degeneration of tumor cells  Positive stains: keratin, EMA, CEA, S100, vimentin  DD: glomus tumor (different staining pattern)
  184. 184. BASAL CELL CARCINOMA  The most common cancer affecting humans  Slow growing  At least 75% first tumours are on the face  Relatively ‘benign’ in most cases – but if left untreated can be disfiguring and life threatening
  185. 185. ETIOLOGY  The most important risk factor is solar ultraviolet radiation  Type 1 skin  Episodes of painful sunburn in early life  Mechanism of injury by UV radiation is complex: direct DNA damage damage to repair mechanisms immune dysregulation mutations in p53 suppressor genes
  186. 186. TYPES OF BCC (1) NODULAR  Usually begin as a small pink ‘pearly’ papule  Develop a depression in the centre  Rolled edge  Overlying telangiectasia
  187. 187. TYPES OF BCC (2) SUPERFICIAL  Usually found on the trunk  May be multiple  Flat red patches  Usually have typical beaded edge
  188. 188. TYPES OF BCC (3) MORPHOEIC  White or waxy  Always on face  Presents as a spontaneous ‘scar’  Margins are usually much wider than what is clinically visible
  189. 189. TYPES OF BCC (4)  Multifocal  Bowenoid – usually found on lower legs of women with sun damaged skin. Diagnosis by biopsy  Poorly differentiated
  190. 190. MANAGEMENT  Surgical excision – with 4mm margins – complete excision of 98% tumours less than 2cm in diameter  Moh’s micrographic surgery – immediate histological analysis. If residual tumour – further surgery. Ensures precise and conservative tumour removal. Usually reserved for high risk lesions – eyelids, nose, lips, ears. 5 year cure rate 99%  Photodynamic therapy  Radiation therapy  Topical therapy – imiquimod (aldara) – immune modulator
  191. 191. FOLLOW UP POLICY  Overall recurrence rate for BCC is around 5%  Thus patients are followed up for 2 years – at least 6 monthly  However risk of second primary – 5 years after excision 36% patients develop a second primary and 20% develop multiple new BCCs
  192. 192. SQUAMOUS CELL CARCINOMA  Less common than BCC but more aggressive  The incidence is rising  Most important aetiological agent is UV radiation – total life time exposure
  193. 193. SCC: ETIOLOGY  Sunlight exposure  Therapeutic radiation  Chemical carcinogens – arsenic  Immunosuppressio n  Viral infection  Scars and chronic inflammation  Premalignant lesions  Genetic syndromes
  194. 194. CLINICAL FEATURES  May be seen at any body site  Disorganised keratin  Keratin horn on a fleshy tumourous base  Surface tends to ulcerate
  195. 195. CLINICAL FEATURES  SCC on lower leg - Marjolin’s ulcer  Failure to respond to nursing care  Heaped up margin
  196. 196. METASTASES SCC may spread in several ways:  Local invasion  Along tissue plains, between muscles, over periosteum  Along nerves and blood vessels  Distant mets
  197. 197. RISK FACTORS FOR METASTASES  Most SCCs behave in a relatively benign fashion  SCC arising from sun-damages skin has a low propensity to metastasize – 0.5% compared to 2% of all SCCs  SCCs arising in certain situations have a much higher rate of spread: >2cm poorly differentiated scars and ulcers immunosuppression perineural invasion recurrent lesions
  198. 198. DIFFERENTIAL DIAGNOSIS  Solar keratosis  Bowen’s disease  Viral warts  Cutaneous horn  Keratoacanthoma  Basal cell carcinoma  Leg ulcers
  199. 199. MANAGEMENT  Intention to cure primary lesion and prevent recurrences  No one treatment has been shown to be effective in all patients  Thus treatment should be tailored to the individual as much as possible  Ideally – multidisciplinary oncology team – clinical oncologist, dermatologist, pathologist, appropriate surgeon
  200. 200. TREATMENT METHODS  Excision – margins 2-10mm  Moh’s micrographic surgery  Curretage and cautery  Cryotherapy  Laser  Photodynamic therapy  Retinoids  Radiation therapy
  201. 201. FOLLOW UP POLICIES  75% SCCs recur within 2 years  95% recurrences are within 5 years  Most clinicians follow up for at least 4 years  3 monthly for first year then every 6 months  Close examination of the scar site and draining lymph node areas is recommended
  202. 202. MELANOCYTIC TUMORS MELANOMA IN SITU Definition ● Malignant melanocytes in epidermis, without dermal invasion ● Variants include lentigo maligna, superficial spreading, and acral melanoma
  203. 203. MELANOMA IN SITU Clinical ● Cases in sun damaged skin may resemble benign lichenoid keratosis ● Characterized by pagetoid spread, confluence, and nesting of atypical melanocytes ● May be associated with invasive malignant melanoma ● Hutchinson's sign: periungual extension of brown-black pigmentation from longitudinal melanonychia [pigmented stripe within length of nail bed] onto the proximal and lateral nailfolds ● Large, pigmented lesions, irregular margins, irregular pigmentation
  204. 204. MELANOMA IN SITU Treatment and prognosis ● Excision with negative margins ● Evaluation of entire margin is recommended - not by classic Mohs surgery, slow Mohs may be used ● Imiquimod cream 5% is a nonsurgical alternative
  205. 205.  Figure 1. Representative images of longitudinal melanonychia prior to biopsy.  Note the positive Hutchinson sign in panel B. Scales indicate millimeters
  206. 206. MELANOMA IN SITU Micro description ● Atypical melanocytes in epidermis with no dermal invasion ● Usually epidermal effacement (absences of rete ridges in some foci ● Predominance of individual unit melanocytes over nests ● Confluent growth of melanocytes along the dermo-epidermal junction ● Pagetoid spread ● Involvement of the adnexal structures
  207. 207.  A 28-year-old man consulted for a pruritic pigmented lesion of his right shoulder. Dermoscopy revealed an asymetric pattern with blue-gray globules and focal structureless areas. The lesion was excised and pathology revealed a melanoma in situ.
  208. 208. DERMOSCOPY M-IS
  209. 209.  Case 2, an 80-year-old man. A Broad, irregularly pigmented macule 24 mm in maximum diameter on the sole of his foot.  B. Dermoscopic image showing the typical parallel ridge pattern  C. Histopathologic image showing proliferation of atypical melanocytes in the epidermis, consistent with the diagnosis of melanoma in situ.  D. Fluorescence in situ hybridization image showing multiple red CCND1 signals with 2 green reference signals in an atypical melanocyte (white arrow).
  210. 210. Case 10, a 60-year-old woman. A. Light brown macule on the sole of her foot. Maximal diameter of this lesion is only 6 mm. B. Dermoscopic image showing the typical parallel ridge pattern C. Histopathologic image showing a very slight increase of healthy-looking melanocytes along the basal layer D. Fluorescence in situ hybridization image showing the CCND1 amplification in a melanocyte (white arrow) within the basal cell layer of the epidermis. Clustered and multiple red CCND1 signals are seen (inset).
  211. 211.  Shave biopsy of mid-back shows usual features of hyperkeratotic seborrheic keratosis with co-existing melanoma in- situ.
  212. 212.  High magnification of melanoma in-situ component, with nests of atypical melanocytes along dermal-epidermal junction.
  213. 213. MELANOMA  Third most common skin cancer  Caused by severe intermittent bouts of sun exposure  Found on sun exposed and non- exposed sites  Second most common cancer to affect young women  High metastatic potential - local, lymph nodes, lung, liver and brain
  214. 214. MELANOMA  30% arise in a pre-existing mole ◦ Features to look out for are asymmetry of the mole, irregular shape and irregular colour  Most commonly arise in normal skin in renal transplant patients
  215. 215. MELANOMA
  216. 216. Methods of Preventing Long Term Skin Damage  Avoid sun  Avoid midday sun  Use photo- protective clothing, hats etc  Use sunblocks
  217. 217. MELANOMA, INVASIVE Epidemiology ● Incidence increasing worldwide ● 48,000 cases and 9,200 deaths in US in 2000 ● Usually due to sun (UV light) exposure Populations at higher risk: ● Whites with fair skin, red hair, tendency to burn or freckle from sun exposure, large number of melanocytic nevi, xeroderma pigmentosum, familial dysplastic nevi, melanosis, vitiligo, frequent sunburns at any age 5-10% familial, possibly neurofibromatosis type I ● Blacks and Hispanics in US have low risk, their common melanoma sites are palms, soles, nail beds or mucous membranes; often poorer prognosis ● Usually occurs after puberty, occasionally children - all have same morphology
  218. 218. MELANOMA, INVASIVE Sites ● Head and neck, back, lower extremities (particularly in women) ● Also oral and anogenital mucosa, esophagus, meninges, eye ● Rarely subungual (“melanotic whitlow”), palm, sole Clinical warning signs ● Change in color of pigmented lesion ● Enlargement of existing mole ● Itching or pain in preexisting mole ● Development of new pigmented lesion in adult life ● Irregular borders in pigmented lesion ● Variegation of color in pigmented lesion
  219. 219. MELANOMA, INVASIVE Clinical features ● 5% are multiple, although prognosis is related to type and stage of largest lesion, not number of lesions ● Must distinguish multiple lesions from “hot nevi” / nevus activation ● Self assessment often inaccurate Physiology ● Cytotoxic T lymphocytes have difficulty killing melanoma cells due to delayed or ineffective apoptosis Regression ● Partial regression is common, total regression may occur
  220. 220. MELANOMA,INVASIVE Metastases ● Regional lymph nodes, liver, lungs, GI tract, bone, CNS, heart, skin (satellite tumors are considered intralymphatic metastases within 2 cm of primary tumor, termed in transit metastases if >2 cm from primary tumor but before the first echelon of regional lymph nodes), other sites ● Metastasis are occasionally S100 negative, but can still be identified as melanoma due to (a) negative workup for carcinoma, lymphoma and sarcoma, (b) HMB45+, MART1+, (c) clinical history of melanoma ● Metastases may arise from unrelated clones ● Molecular analysis can distinguish a second primary from metastatic disease
  221. 221. MELANOMA, INVASIVE Survival ● Overall 5 year survival is 60%, but behavior is variable, with occasional late deaths or long survival even with widespread satellite nodules Poor prognostic factors ● Breslow (vertical) thickness in primary tumor ● Clark’s level ● Vascular invasion ● High stage (TNM) ● Male gender ● High mitotic rate ● Ulceration ● Microscopic satellites (tumor nests 50 microns or larger and separated from main tumor mass) ● Deeper level of invasion for T1 tumors ● Higher % tumor area/volume in sentinel node ● Positive nonsentinel lymph nodes ● Regression ● Tumor-infiltrating lymphocytes
  222. 222. MELANOMA, INVASIVE Possible poor prognostic factors: ● Patient age ● Site of primary melanoma ● Angiotropism (migration of melanoma cells along external surface of blood vessels ● Tumor lymphangiogenesis ● Increased density of dendritic leukocytes in nodal paracortex ● For patients with localized melanoma, most important prognostic factors are tumor thickness and ulceration ● For patients with nodal metastases, most important prognostic factors are number of metastatic nodes, microscopic versus macroscopic tumor and presence or absence of ulceration of primary melanoma ● Note: there is excellent agreement between pathologists in assessing tumor thickness, ulcerative state and tumor mitotic rate
  223. 223. MELANOMA, INVASIVE Diagnosis and Treatment ● Initial biopsy should attempt to remove the entire lesion ● Punch biopsies for diagnosis are discouraged, since determination of depth may be inaccurate but may be useful to define margins ● Initial excision is usually down to subcutis with narrow margins, but then need wide local re- excision with 1-2 cm margins ● Frozen sections for margins only ● Lymphatic mapping and sentinel node biopsy for tumors with depth > 1mm ● Nodal block dissection
  224. 224. MELANOMA, INVASIVE Note: minimal metastatic risk if radial growth phase only; metastatic behavior occurs with vertical growth phase Treatment for metastatic disease: Interleukin-2 and dacarbazine; possibly adoptive cell therapy with autologous antitumor lymphocytes in lymphodepleted hosts variable results for adjuvant radiotherapy
  225. 225. MELANOMA, INVASIVE  Scaly erythematous crusty pigmentation and thickened plaques on the nipple, spreading to surrounding areola
  226. 226. MELANOMA, INVASIVE Micro description ● Features of melanoma in situ + dermal involvement of atypical melanocytes with cytologic atypia and no maturation ● Classic features are junctional activity with obscured dermoepidermal junction and pagetoid spread individually and in clusters throughout epidermis ● Prominent melanin pigmentation, invasion of surrounding tissue ● Large cells with abundant eosinophilic and finely granular cytoplasm ● Nuclear pseudoinclusions, folds or grooves ● Marked atypia with pleomorphic nuclei with large eosinophilic nucleoli ● Frequent mitotic figures
  227. 227. MELANOMA, INVASIVE 4 major subtypes ● Acral lentiginous ● Lentigo maligna ● Nodular ● Superficial spreading (described separately)
  228. 228. MELANOMA INVASIVE: MICRO ● Lack of a junctional component suggests a metastases, although epidermal component may have regressed or not been sampled, or melanoma may have developed from an intradermal nevus ● Consumption of epidermis: usually (86%) present; thinning of epidermis with attenuation of basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes; variable clefts separating epidermis and dermis, edema, telangiectasias; is associated with increased Breslow depth and ulceration ● Lymphatic invasion identified in 5% on H&E but 33% using D2-40/podoplanin and S100
  229. 229. MELANOMA, INVASIVE ● Subepidermal cleft present in 24% ● Angiotropism is suggestive of epidermotropic metastatic disease versus recurrent disease ● Rarely paradoxical maturation occurs, but still have areas of cells with abundant cytoplasm and large nuclei, more mitotic figures, more confluence, high Ki-67 rate ● Rarely CD68+ osteoclast-like giant cells, signet-ring cells, lipoblast like
  230. 230. MELANOMA, INVASIVE Other microscopic features ● Growth patterns: pseudoglandular, pseudopapillary, peritheliomatous (around blood vessels), hemangiopericytoma-like, Spitz nevus- like, trabecular, verrucous, nevoid ● Cell type: epithelioid, spindled or bizarre ● Size: lymphocytes to multinucleated giant cells ● Cytoplasm: eosinophilic, basophilic, foamy, signet ring, rhabdoid, oncocytic or clear ● Stroma: desmoplastic, myxoid, bone or cartilage, osteoclast-like giant cells ● Epithelium: pseudoepitheliomatous hyperplasia ● Other differentiation: Schwann cells, ganglion cells, other neural structures
  231. 231.  Thin and thick melanoma
  233. 233. Satellite metastasis Tumor infiltrating lymphocytes
  235. 235. Pagetoid extension
  236. 236. Follicular growth
  237. 237. POSITIVE STAINS MELANOMA, INVASIVE Distinguish melanocytes from non- melanocytes, but not malignant cells from benign cells: ● S100: nuclear and cytoplasmic staining, 90%+ sensitive but not specific (although usually negative in tumors considered in the differential) ● HMB45: cytoplasmic and weak nuclear staining , less sensitive but more specific than S100; negative in desmoplastic melanoma ● MelanA/Mart1: sensitive, but also stains steroid-producing cells in ovary, testis, adrenal cortex ● Tyrosinase: sensitive, but also stains
  238. 238. MELANOMA, INVASIVE ● Microphthalmia transcription factor: sensitive, but also stains dermatofibroma and smooth muscle tumors; negative in spindle cell / desmoplastic melanoma ● NKI-C3 and NSE: nonspecific ● PHH3 and Ki-67: may distinguish melanoma from nevi ; another marker is SM5-1 ● Azure blue counterstaining may be preferable to bleaching ● Other positive stains: Fontana-Masson (detects melanin granules), vimentin; variable staining for Cam 5.2, CEA, EMA, alpha-1-antichymotrypsin, CD68 ● some melanomas, especially when metastatic, may stain with simple keratins (CK8)
  239. 239. MELANOMA, INVASIVE Electron microscopy ● Melanosomes and premelanosomes ● May be useful if stains are not confirmatory ● May have well developed microvilli similar to adenocarcinoma
  240. 240. MELANOMA-MOLECULAR / CYTOGENETICS ● Main altered pathways include RAS-RAF- MEK-ERK, p16(INK4A)-CDK4-RB and ARF- p53 ● 20% of melanoma prone families have point mutation in CDKN2A locus at 9p21 which encodes p16(INK4a) and p14(ARF) ● 10% of cases may be familial due to CMM1 gene at 1p36 ● Microsatellite instability seen in pediatric melanoma (43%), adult melanoma (30%), nevi (9%) ● Most melanomas have multiple chromosomal gains and losses, features that can be used to differentiate them from nevi, which do not have chromosomal alteration
  241. 241. MELANOMA: DD ● Nevi - particularly Spitz nevi-desmoplastic type, halo nevi, activated and dysplastic nevi, vulval nevi and recurrent nevi after incomplete excision; features relatively specific for melanoma include absence of maturation, suprabasal melanocytes; also atypia, size >6 mm, mitotic figures, dermal lymphocytes and asymmetry, necrosis, asymmetrical melanin and melanin in deep cells ● Benign fibrous histiocytoma ● Hemangioma ● Pigmented seborrheic keratosis ● Pigmented basal cell carcinoma ● Atypical fibroxanthoma - HMB45, MelanA and S100 are usually negative ● Granular cell tumor - negative for HMB45 and MelanA ● Amelanotic tumors resemble pyogenic granuloma
  242. 242. Helpful features of melanoma that differentiate from benign lesions ● Poor circumscription of intraepidermal component ● Lateral extension of individual melanocytes ● Transepidermal migration of melanocytes ● Pleomorphism of tumor cells ● Asymmetry ● Lack of maturation of dermal tumor cells ● Atypia ● Mitotic figures in melanocytes (particularly atypical ones) ● Melanocytes with clear cytoplasm and finely dispersed chromatin, individual melanocyte necrosis (compared to eosinophilic hyaline bodies in Spitz nevi) ● Band like chronic inflammatory infiltrate in dermis ● Presence of chromosomal gains or losses