Pathology of Skin McKees.5th edition(2020) برای بزرگنمایی عکسها کلیک را روی ان نگه دارید..... ■■■【1】 The structure and function of skin Fig. 1.1.Skin from forearm: there is a fairly thin epidermis. Compare the thickness of the dermis with that from the back (see Fig. 1.5) Fig. 1.2.Skin from palm: note the eosinophilic stratum lucidum clearly separating the granular cell layer from the overlying stratum corneum Fig. 1.3.Skin from palm: there is a conspicuous granular cell layer Fig. 1.4.Spongiosis: the intercellular bridges (prickles) are stretched and more visible in this biopsy from a patient with acute eczema Fig. 1.5.Skin from the lower back: at this site the dermis is very thick and is characterized by broad parallel fascicles of collagen Fig. 1.6.Skin of the nose: there are conspicuous sebaceous glands: at this site, they often drain directly onto the skin surface. These appearances should not be confused with that of sebaceous hyperplasia Fig. 1.7.Skin from the sole of the foot: this is typified by a thickened stratum corneum and prominent epidermal ridge pattern. The dermis is relatively dense at this site. Similar features are seen on the palms and ventral aspects of the fingers and toes Fig. 1.8.Skin from the scalp: there are numerous terminal hair follicles with many of the bulbs in the subcutaneous fat Fig. 1.9.Skin from axilla: apocrine glands as seen at the bottom of the field are typical for this site Fig. 1.10.Skin of areola: there are abundant smooth muscle fibers: lactiferous ducts may also sometimes be present (not shown) Fig. 1.11.Skin from the outer aspect of the lip: note the keratinizing stratified squamous epithelium and skeletal muscle fibers Fig. 1.12.Mucosal aspect of lip: at this site the squamous epithelium does not normally keratinize. Minor salivary glands as shown in this field are not uncommonly present Fig. 1.13.Mucosal aspect of lip: close-up view of the salivary gland shown in Fig. 1.12 Fig. 1.14.Mucosal aspect of lip: the cytoplasm of the keratinocytes is often rich in glycogen Fig. 1.15.Skin from the ear: note the vellus hairs, and a fairly thin dermis overlying the auricular cartilage Fig. 1.16.(A, B) Vulval vestibule: at this site the stratum corneum is absent and there is no granular cell layer. The suprabasal keratinocytes have clear cytoplasm due to abundant glycogen and revealed by the periodic acid-Schiff reaction Fig. 1.17.Variation of skin: sample of skin from the forearm of a 92-year-old female. Note the epidermal thinning and dermal atrophy Fig. 1.18.Stasis change: skin from the lower leg. Although abnormal, the presence of stasis change characterized in this example by papillary dermal lobular capillary proliferation is a very common feature at this site Fig. 1.19 .Stasis: high-power view Fig. 1.20.Variation of normal skin: in dark-skinned races, the presence of inten melanin pigmentation is a normal histologic finding Fig. 1.21.(A, B) Development of normal human fetal skin: (A) at 7 weeks' gestation, the epidermis is only two cell layers thick but the dermis appears very cellular; (B) at 19 weeks' gestation the skin has an outer layer specific to mammals known as periderm. This contains surface blebs which are full of glycogen (G). Also present is a hair peg (H). This downgrowth of the epidermis is the first histologic step in generating a hair follicle. Bar = 25 μm Fig. 1.22.Cytoskeleton of a keratinocyte: the major is keratin, highlighted in green Fig. 1.23.Mid-prickle cell layer of normal epidermis: the abundant keratin filaments (tonofibrils) form a distinct interlacing lattice within the cytoplasm of keratinocytes Fig. 1.24.Normal skin: suprabasal keratinocytes preferentially express keratins 1 and 10 as shown in this picture. Anti-Keratin1 antibody courtesy of I.M. Leigh, MD, Royal London Hospital Trust, London, UK Fig. 1.25.Clinicopathologic consequences of mutations in the keratin 14 gene: (left) typical appearances of generalized severe epidermolysis bullosa simplex which usually results from heterozygous missense mutations in KRT14 or KRT5; (right) ultrastructurally, there is keratin filament disruption and clumping as well as a plane of blistering just above the dermal-epidermal (DE) junction Fig. 1.26.Diagrammatic representation of the location of stem cells in human skin: stem cells are located within the bulge area of hair follicles (where the arrector pili muscle attaches) as well as in the basal keratinocyte layer in the interfollicular epidermis and at the base of sebaceous glands. Stem cells from the bulge area are capable of regenerating all parts of the pilosebaceous unit and interfollicular skin Fig. 1.27.Epidermis contains multiple resident stem cell (SC) compartments and transit- amplifying progeny. Within the bulge area of hair follicles, stem cells are multipotent, residing in the permanent portion of the hair follicle. Interfollicular stem cells reside in the basal layer of the epidermis. Resident progenitors of the hair follicle isthmus and sebaceous gland are located within the hair ORS that is above the bulge and below the sebaceous gland Fig. 1.28.Granular cell layer: note the keratohyalin and membrane coating granules (arrowed) Fig. 1.29.Stratum corneum: keratohyalin granules are present just beneath the keratin lamellae Fig. 1.30.Function of filaggrin in human skin: this is the major component of keratohyalin granules. In the granular layer profilaggrin is cleaved into filaggrin peptides subsequent deamination and degradation provides the skin with mechanical strength and restricts transepidermal water loss. Filaggrin also prevents allergen penetration. In the absence of filaggrin, for example caused by common mutations in the filaggrin gene, external allergens may penetrate the epidermis and encounter Langerhans cells. This may lead to the development of atopic dermatitis as well as other atopic manifestations and systemic allergies Fig. 1.31.Functional consequences of loss-of-function mutations in the filaggrin gene, which can affect up to 10% of the people in some populations Fig. 1.32.Proinflammatory cytokines (IL-1, Fα, etc.) Innate immunity in the skin: the physical barrier is complemented by an innate immune response that targets bacteria, viruses and fungi and prevents them from invading the skin. These peptides include constitutive and inducible substances against a broad range of organisms Fig. 1.33.Langerhans cells express S100 protein: note the conspicuous dendritic processes Fig. 1.34.(A, B) Langerhans cell: (A) note the characteristic lobulated nucleus. Dendritic processes are evident, (B) typical rod forms with the characteristic trilaminar structure Fig. 1.35.(A, B) Normal epidermis: (A)melanocytes are seen along the basal layer of the epidermis. The cytoplasmic vacuolation is a fixation artifact; (B) melanocytes can be highlighted with S100-protein immunohistochemistry. Note the dendritic processes Fig. 1.36.Normal melanocyte: it has abundant pale cytoplasm and scattered solitary melanosomes. Note the absence of tonofibrils and desmosomes Fig. 1.37.Melanosome: note the typical striated internal structure Fig. 1.38.Normal epidermis: this section of black skin has been stained by the Masson- Fontana reaction for melanin. Note the heavy pigmentation, which is present in both melanocytes and keratinocytes Fig. 1.39.Melanin pigment: actinically damaged skin. Note that the melanin pigment is located in a 'cap' overlying the keratinocyte nuclei Fig. 1.40.Macromelanosomes: note the large spherical melanosomes in the cytoplasm of the melanocytes Fig. 1.41.Merkel cells: separated human epidermis showing a striking linear arrangement (troma-1 antibody). By courtesy of J.P. Lacour, MD, and J.P. Ortonne, MD, University of Nice, France Fig. 1.42.Merkel cell: positive labeling for CAM 5.2 identifies Merkel cells in this obliquely sectioned epidermal ridge Fig. 1.43.Merkel cell: a heavily granulated Merkel cell is present in the midfield. This is located immediately adjacent to a small nerve fiber Fig. 1.44.Merkel cell granules: they are membrane bound and measure approximately 150 nm in diameter. By courtesy of A.S. Breathnach, MD (1977) Electron microscopy of cutaneous nerves and receptors. Journal of Investigative Dermatology 69, 8-26. Blackwell Publishing Inc., USA Fig. 1.45.Mid-prickle cell layer of normal epidermis: there are complex interdigitations between adjacent cell membranes with numerous desmosomal junctions Fig. 1.46.Mid-prickle cell layer of normal epidermis showing the stratified nature of the desmosome Fig. 1.47.Protein composition of a desmosome junction between adjacent keratinocytes. The keratin filament network of two keratinocytes is linked by a series of desmosomal plaque proteins and transmembranous molecules to create a structural and signaling bridge between the cells Fig. 1.48.Genetic disorders of desmosomes: autosomal dominant or autosomal recessive mutations in ten different structural components of desmosomes may give rise to specific diseases that can affect skin, hair or heart or combinations thereof Fig. 1.49.Immunobullous diseases of desmosomes: intraepidermal blistering can arise through autoantibody disruption of four separate desmosomal proteins which leads to different clinical variants of pemphigus Fig. 1.50.Genetic disorders of connexins: nine different human connexin molecules are associated with different inherited diseases. Mutations in the four low molecular weight connexins shown at the top of the diagram are associated with a spectrum of skin pathology, as highlighted Fig. 1.51.Sebaceous glands: on the inner aspect of the labia these appear as tiny yellow papules (Fordyce spots). By courtesy of S.M. Neill, MD, Institute London, UK Fig. 1.52 Normal vulva: sebaceous glands are conspicuous, but arise independently of a hair follicle and open directly onto the surface epithelium Fig. 1.53.Nose: sebaceous glands are particularly numerous at this site Fig. 1.54.Nose: multiple sebaceous glands are evident Fig. 1.55.Sebaceous lobule: germinative cells are basophilic and flattened. With maturation the cells acquire their characteristic 'bubbly' cytoplasm Fig. 1.56.Sebaceous duct: this is lined by keratinizing stratified squamous epithelium; it is continuous with the external root sheath Fig. 1.57.Sebaceous gland: the epithelial cells normally strongly express EMA Fig. 1.58.Sebaceous gland: in this field from the center of a sebaceous lobule, the cytoplasm is completely distended with lipid droplets. Germinative cells are evident in the right-lower quadrant Fig. 1.59.Eccrine gland: (A) palmar skin showing numerous eccrine glands located in the deep reticular dermis and subcutaneous fat, (B) the secretory unit is in the lower field. Sections through the coiled duct are evident in the upper field. The epithelium of the duct is more darkly stained than that of the glandular component Fig. 1.60.Eccrine gland: high-power view of eccrine straight duct Fig. 1.61.Eccrine gland: most superficially, the duct coils through the stratum corneum Fig. 1.62.Eccrine gland: excessive glycogen has resulted in vacuolated epithelium Fig. 1.63.Eccrine gland: immunohistochemistry Fig. 1.64.Eccrine gland: low-power electron micrograph showing the lumen in the upper- right quadrant, granular mucous-secreting cells and serous cells Fig. 1.65.Eccrine gland: (left) high-power view of clear cell showing conspicuous mitochondria and numerous electron-dense glycogen granules, (right) high-power view of secretory granules in a dark cell Fig. 1.66.Eccrine gland: (A) lumen of the eccrine dermal duct lined by conspicuous microvilli, (B) high-power view of eccrine dermal duct showing microvilli and circumferentially orientated tonofilaments Fig. 1.67.Apocrine gland: this specimen from normal axillary skin shows apocrine secretory lobules in the subcutaneous fat. Ducts are present in the upper right of the field Fig. 1.68.Apocrine gland: lobules are lined by tall columnar cells with intensely eosinophilic cytoplasm. 'Decapitation secretion' is conspicuous Fig. 1.69.Apocrine gland: immunohistochemistry (CAM 5.2 and EMA) Fig. 1.70.Apocrine gland: immunohistochemistry (S100 protein and SMA) Fig. 1.71.Apocrine gland: close-up view microvilli and decapitation secretion Fig. 1.72.The macromolecular components of the dermal-epidermal junction centered on a hemidesmosome-anchoring filament-anchoring fibril complex. Protein-protein interactions between these molecules secure adhesion between the epidermis and the subjacent dermis Fig. 1.73.Schematic representation of a hemidesmosome-anchoring filament-anchoring fibril complex at the dermal-epidermal junction. A continuum of adhesive proteins extends from the keratin tonofilaments within basal keratinocytes through to dermal collagen. This complex represents the main adhesion unit at the dermal- epidermal junction Fig. 1.74 The basement embrane region stains strongly with periodic acid-Schiff Fig. 1.75.Transmission electron microscopy of the dermal-epidermal junction Fig. 1.76.Genetic disorders of hemidesmosomal proteins. Mutations in components of the hemidesmosome-anchoring filament-anchoring fibril network give rise to specific variants of epidermolysis bullosa (EB) Fig. 1.77.Acquired disorders of hemidesmosomal proteins. Autoantibodies directed against components of the hemidesmosome-anchoring filament-anchoring fibril complex give rise to specific subepidermal autoimmune blistering diseases. SLE, systemic lupus erythematosus; EB, epidermolysis bullosa Fig. 1.78.Laminin-332 is a major adhesion protein at the dermal-epidermal junction: (A) the protein is composed of three polypeptide chains: 03, B3, and 12; (B) Laminin-322 identified by immunofluorescence in a sample of split skin Fig. 1.79.Basement membrane: basement membrane staining with type IV collagen Fig. 1.80.Normal skin: the anchoring fibrils are composed predominantly of type VII collagen as shown in this pre-embedding immunogold electron microscopic preparation Fig. 1.81.Normal skin: this ultrastructural image shows a well-formed dermal microfibril bundle (arrow) Fig. 1.82.Normal skin of forearm: in the papillary dermis the collagen fibers are fine and sometimes have a vertical orientation. Masson trichrome Fig. 1.83.Normal skin of back: broad bundles of collagen typify the reticular dermis. Masson trichrome Fig. 1.84.Collagen: it is characterized by cross-striations with a periodicity of 64 nm Fig. 1.85.Fibrous long-spacing collagen: compare with the adjacent conventional collagen fibers. There is a very different periodicity Fig. 1.86.Collagen of the reticular dermis: note the birefringence when viewed with polarized light. Masson trichrome Fig. 1.87.Reticular dermis: the elastic fibers are long and fairly thick and tend to run parallel to the surface epithelium Fig. 1.88.Papillary dermis: the elastic fibers are delicate and orientated perpendicular to the epithelial surface. Weigert-van Gieson stain Fig. 1.89.Elastic fiber: this consists of microfibrils embedded in an electron-dense matrix called elastin Fig. 1.90.Ground substance: an eccrine gland from the sole of the foot shows an abundance of glycosaminoglycans Fig. 1.91.Relationship of the superficial and deep vascular plexuses Fig. 1.92.Small muscular artery from the deep vascular plexus from the lower leg of an elderly man with endarteritis (intimal thickening): note the thick muscle coat and conspicuous internal elastic lamina, the latter accentuated by the Weigert-van Gieson reaction. (A) Hematoxylin and eosin; (B) Weigert-van Gieson Fig. 1.93.Normal dermal capillary: note the lining of endothelial cells surrounded by a pericyte cell process and adjacent basal lamina. The lumen contains erythrocy (E) Fig. 1.94.(A) Small dermal arteriole: the lumen is compressed to a narrow slitlike space; (B) high-power view of typical Weibel-Palade bodies. These are characteristic of blood vessel endothelium Fig. 1.95.Companion vein to Fig. 1.92: note the wide diameter of the lumen in comparison to the relatively thin muscle coat. There is a little elastic tissue but no discernible internal elastic lamina. (A) Hematoxylin and eosin; (B) Weigert-van Gieson Fig. 1.96.Glomus body: note the arterial and venous limbs connected by a vascular channel rich in glomus cells Fig. 1.97.Lymphatics: these exceedingly thin-walled channels are normally not visible in the dermis. They become readily apparent, however, when obstructed, as in this patient with lymphedema Fig. 1.98.Skin of lower leg: muscular lymphatic trunks can be readily mistaken for arteries. An internal elastic lamina is characteristically absent Fig. 1.99.Pacinian corpuscle: note the characteristic lamellar internal structure Fig. 1.100.Meissner corpuscle within a dermal papilla: with hematoxylin and eosin staining it appears as perpendicularly orientated lamellae of Schwann cells Fig. 1.101.The lipid contents of fat cells are dissolved during processing using conventional (paraffin-embedding) techniques. The cells therefore appear empty and have peripheral compressed nuclei Fig. 1.102.Adult fat in frozen section stained by the Sudan IV technique Fig. 1.103.Typical brown fat showing pink granular cytoplasm Fig. 2.1.Gross representation of pyogenic granuloma (A), with two-color painting of the inferior surface (B). 2-mm- thick gross sections demonstrating the black and blue painting at put-through (C) and in paraffin blocks (D). By courtesy of K. Nargan and K. Lumamba, Africa Health Research Institute, Durban, South Africa Fig. 2.2.A self-contained vacuum infiltration tissue processor of fluid-transfer type Fig. 2.3.Paraffin block containing skin tissue (arrow) on microtome Fig. 2.4.Technical artifact: folds in tissue section because of poor bath floating technique Fig. 2.5.Technical artifact: holes in tissue sections caused by excessively thin sectioning Fig. 2.6.Technical artifact: vertical scores in tissue sections caused by a damaged microtome blade. By courtesy of K. Nargan, Africa Health Research Institute, Durban, South Africa Fig. 2.7.Special stains: Warthin-Starry silver stain demonstrating Donovan bodies Fig. 2.8.Autostainer used for automated immunohistochemical testing Fig. 2.9.Immunohistochemical techniques (A) direct, (B) indirect, (C) streptavidin biotin, (D) polymer chain. By courtesy of K Lumamba, Africa Health Research Institute, Durban, South Africa Fig. 2.10.Technical artifact: HHV8-stained sections demonstrating chromogen entrapment in stratum corneum Fig. 2.11.Technical artifact: suboptimal antibody concentration of CD3 antibody resulting in background staining Fig. 2.12.Technical artifact: poor tissue fixation resulting in incomplete sections, fragmentation, and suboptimal AE1/AE3-stained sections Fig. 2.13.Technical artifact p53 stain: wrinkling and background staining of tissue sections because of erroneously high temperature heat-assisted microwave antigen retrieval exposure of sections in EDTA buffer (pH 8.0) Fig. 2.14.Transmission electron microscope (arrow) with (arrowhead) Fig. 2.15.Cryostat with tissue on freezing stage (arrow) Fig. 2.16.Basement membrane region: protein components at the dermal-epidermal junction and the subtypes of EB that result from mutations in the genes encoding these proteins Fig. 2.17.Clinical appearances of neonates with different forms of inherited EB. All three cases have similar blisters and erosions but their respective prognoses differ considerably. (A) Severe, generalized recessive dystrophic EB; (B) Dowling-Meara EB simplex; (C) Herlitz junctional EB. Skin biopsy is fundamental to establishing the subtype of severe forms of EB Fig. 2.18.Optimal skin biopsy for diagnosing EB: following local anesthesia, the normal- appearing skin is gently rubbed, and then a superficial shave biopsy is taken. The skin sample can then be subdivided for immunolabeling of frozen sections as well as being processed for transmission electron microscopy Fig. 2.19.Antigen mapping to diagnose the subtype of inherited EB: this picture shows immunolabeling of rubbed skin from an individual with EB (case illustrated in Fig. 2.17A) with an anti-type IV collagen antibody. Rubbing the skin induces microsplits at the dermal-epidermal junction (asterisk). The type IV collagen reactivity maps to the roof of the dermal-epidermal junction (arrows). This indicates a sublamina densa plane of cleavage and establishes a diagnosis of dystrophic EB. (Bar = 25 μm.) Fig. 2.20.Specific antibody probes to subtype inherited EB: (A) immunostaining of normal control skin with an antibody to type VII collagen shows bright linear labeling at the dermal-epidermal junction; (B) in contrast, the complete absence of labeling in skin from an individual with EB (case illustrated in Fig. 2.17A) indicates a diagnosis of severe, generalized recessive dystrophic EB. (Bar = 50 μm.) Fig. 2.21.Transmission electron microscopy of skin in Dowling-Meara EB simplex (case illustrated in Fig. 2.17B): within the basal keratinocyte cytoplasm the keratin filaments are condensed and form clumps and there is cytolysis that occurs just above the dermal-epidermal junction. (Bar = 1 μm.) Fig. 2.22.Genetics of clear cell sarcoma: (A) this complicated karyotype shows derivative chromosomes 12 (blue box) and 22 (orange box). While recurrent translocation-associated karyotypes are initially simple, they can become more complex with tumor progression. (B) The mechanism of chromosomal translocation involves breaks in chromosomes 12 and 22 that recombine to produce novel derivative chromosomes 12 and 22. The active fusion gene (EWSR1-ATF1) is produced on der(22). The fusion genes can be produced by a variety of breakpoints within the introns of the involved genes making multiple exon combinations (C). This complicates the design of PCR-based detection methods, as does substitution of the CREB1 gene for ATF1 on occasion Fig. 2.23.Four-color FISH to two interface nuclei and metaphase chromosomes: the upper portion shows two interface nuclei with the hybridization signals for the four colors detectable as discrete spots. In the metaphase spread underneath, the hybridization signals can be seen to map to chromosome 6p (purple), 6 centromere (light blue), 6q (yellow), and chromosome 11q13 (green) Fig. 2.24.FISH to tissue sections of a melanoma (left panel) and nevus (right panel): the panels show 400-fold magnifications of two nests of melanocytes with the nuclei stained in blue. The green probe for chromosome 11q13 shows amplification in the melanoma as evident by a marked copy number increase compared to the purple signals representing chromosome 6p. By contrast, the melanocytes of the nevus in the right panel do not significant differences for these two loci Fig. 2.25.Break-apart FISH technique: the 12;22 translocation associated with clear cell sarcoma is depicted. (A) When the EWSR1 locus is intact, the probes hybridize to the centromeric (red) and telomeric (green) regions flanking the gene. The spectral overlap of the two signals in juxtaposition produce a yellow signal. Thus in cell lacking rearrangement of this locus, two yellow signals are present, representing the two copies of chromosome 22 lacking rearrangement (right); (B) When rearrangement occurs, such as the balanced translocation with chromosome 12 depicted here, the centromeric probe (red) is retained by the derivative chromosome 22 while the green probe is transferred to the derivative chromosome 12. Thus in the nuclei one yellow signal indicates the intact chromosome 22 while the derivative 12 and 22 chromosomes segregate freely as single green and red signals, respectively (right) Fig. 2.26.Multiple translocations involve EWSR1 and the homologous gene, FUS: both EWSR1 and FUS can often substitute for one another and both are involved in balanced translocations with multiple genes resulting in a variety of neoplasms. Since FISH only indicates that a single locus, such as EWSR1, is rearranged and nothing about the fusion partner, results must be interpreted carefully within the clinical and morphologic context of a tested case. Sometimes techniques such as RT-PCR must be used to verify the fusion partner Fig. 2.27.Comparative genomic hybridization (CGH) on a metaphase chromosome spread (upper panels) and a microarray (lower panels): the regions of the chromosomes (upper panel) that appear red are affected by deletions, whereas the regions that appear green are affected by gains or amplifications (bright green). Yellow indicates an area with normal DNA complement-no gain or loss. The lower panel on the right shows a DNA microarray with approximately 2500 targets printed as triplicates spots. Triplets that appear green indicate gains whereas those that appear red indicate loss. The array targets are not printed in order of their genomic position which can help control for technical variations. The precise genomic location of the DNA copy number changes detected by the measurement only becomes apparent after plotting the average ratios of red to green fluorescence intensities corresponding to their genomic position as illustrated in Fig. 2.28 Fig. 2.28.DNA copy number changes as detected by array comparative genomic hybridization of an acral melanoma: the graph shows the log2 of the ratio of the fluorescence intensity ratios of tumor to reference DNA plotted according to their genomic position on the x-axis. The numbers at the top and at the bottom indicate the chromosomes. A log2 ratio of zero corresponds to normal copy number. As can be seen, multiple contiguous chromosomal regions showed losses and gains. The arrow corresponds to an amplification of chromosome 11913 interval containing the gene that encodes cyclin D1 Fig. 2.29.Use of RT-PCR to detect fusion transcripts: this technique uses reverse transcription to convert RNA to cDNA that can then be amplified by PCR. This step is necessary as the breakpoints in the usually large intronic regions of genomic DNA within a gene are essentially random, making it extremely difficult to amplify such large regions to identify the breakpoints using genomic DNA as the template. When the gene is transcribed to RNA, the introns are removed during splicing and introns are directly juxtaposed (Fig. 2.220) allowing more ready detection of the novel juxtaposition of exons from two different genes. When primers are designed for the exons of each of the two genes involved in a translocation, amplification only occurs of the cDNA of the fusion transcript as these introns would not be adjacent in normal tissue. This product will have a specific size and can be detected on a gel, but direct DNA sequencing or other methods should be used to confirm its identity. Amplification of normal housekeeping gene transcripts are used to ensure the quality of the cDNA Fig. 2.30.Multiple modalities for detection of recurrent translocations. Traditional karyotypes use metaphase chromosomes spreads to detect translocations and other structural genetic aberrations using banding (staining) techniques. FISH uses less condensed interphase chromosomes to detect rearrangements or amplifications. RT-PCR can detect the precise exons involved in a fusion RNA transcript. Each is a valid method for demonstrating chromosomal translocations, but each has applicability to different sample types and provides different information Fig. 2.31.Integrated genome viewer (IGV) depiction of a BRAF V600E mutation inmelanoma. Note that the display shows individual DNA strands sequenced in both directions (forward and reverse strands, blue and red) by NGS sequencing. Thus the precise variant allele frequency can be determined Fig. 2.32.Mycosis fungoides: TCR gene rearrangement (photo of 2 gels from different patients, A and B). Red asterisks indicate dominant clonal T-cell gene rearrangement shown as discrete bands rather than a smear demonstrating numerous clones and non-rearranged receptors Fig. 2.33.Structure of IG. The two epitope binding sites are formed primarily by the two variable domains Fig. 2.34.B-cell lymphoma: IG gene rearrangement (photo of gel). The upper bands arrowed in lanes two and three indicate non-rearranged IG with the asterisk in lane two indicating a polyclonal IG population. The lower band in lane three shows a dominant IG clone Fig. 3.1.(A, B) Severe generalized ichthyosis: this was an incidental finding at autopsy. Ichthyosis can be very disfiguring and a considerable social disadvantage. (A,B) By Courtesey Ph. McKee Fig. 3.2.(A) Ichthyosis vulgaris: fine scaling, particularly involving the extremities and characteristically sparing the flexures. (B) Palms show typically increased markings Fig. 3.3.(A, B) Ichthyosis vulgaris: there is orthohyperkeratosis with characteristic absence of the granular cell layer Fig. 3.4.X-linked recessive ichthyosis: many patients show large, confluent, and dark scales. By courtesy of the Institute of Dermatology, London, UK Fig. 3.5.X-linked ichthyosis: involvement of the flexures is a feature that allows differentiation form ichthyosis vulgaris. By courtesy of the Institute of Dermatology, London, UK Fig. 3.6.X-linked recessive ichthyosis: some patients show light-gray scales Fig. 3.7.(A) Sex-linked ichthyosis: characteristic linear opacities at the level of Descemet membrane. Slit-lamp photograph. (B) Same lesion viewed by specular microscopy. By courtesy of R.J. Buckley, MD, Moorfield's Eye Hospital, London, UK Fig. 3.8.(A, B) X-linked recessive ichthyosis: there is orthohyperkeratosis a acanthosis. The granular cell layer is normal Fig. 3.9.Autosomal recessive congenital ichthyosis: the collodion membrane is best seen on the forehead. There is scaling and erythema on the trunk. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 3.10.Autosomal recessive congenital ichthyosis: note the erythema. The skin is shiny, taut, and shows fissuring around the anterior aspect of the ankle. By courtesy of D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK Fig. 3.11.Autosomal recessive lamellar ichthyosis: note the widespread and prominent large dark brown scales. By courtesy of D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK Fig. 3.12.Autosomal recessive lamellar ichthyosis: in this infant, there is gross ectropion and eclabion. By courtesy of D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK Fig. 3.13.Autosomal recessive congenital ichthyosis: there is intense erythema and fine scaling is also present. The scalp hair is sparse and the eyebrows are absent. By courtesy of D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK Fig. 3.14.Autosomal recessive congenital ichthyoses: there is marked erythema with severe scaling. Blistering is not seen in this variant of ichthyosis. By courtesy of D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK Fig. 3.15.Autosomal recessive congenital ichthyosis: there is intensive erythema and fine scaling. By courtesy of the Institute of Dermatology, London, UK Fig. 3.16.Autosomal recessive congenital ichthyosis: there is severe palmar involvement and constriction bands are evident. By courtesy of the Institute of Dermatology, London, UK Fig. 3.17.Bathing suit ichthyosis: areas with higher skin temperature are severely affected giving a bathing suit-like appearance; those with lower skin temperature are almost completely spared Fig. 3.18.Autosomal recessive congenital ichthyosis: (A) there is very marked orthohyperkeratosis and the epidermis shows papillomatosis; (B) the stratum granulosum is preserved. Note a mild lymphocytic infiltrate Fig. 3.19.(A, B) Harlequin ichthyosis: the most extreme form of congenital ichthyosis. The scales are very thick and are often referred to as armor-plating. By Courtesey of Sabine Köhler, Stanford University Fig. 3.20.Harlequin ichthyosis: there is massive hyperkeratosis and papillomatous and pale staining epidermis with thinning of the granular cell layer. The dilated spaces in the stratum corneum represent affected hair follicles and sweat ducts. By courtesy of S. Köhler, MD, Stanford University, USA Fig. 3.21.Autosomal dominant lamellar ichthyosis: large, dark-gray scales on the entire body. By courtesy of H. Traupe, MD, Münster, Germany Fig. 3.22.(A, B) Autosomal dominant lamellar ichthyosis: there is a marked compact hyperkeratosis with parakeratosis and a prominent granular cell layer Fig. 3.23.Congenital bullous ichthyosiform erythroderma: close-up view of an infant showing intense erythema and blistering. By courtesy of M. Liang, MD, The Children's Hospital, Boston, USA Fig. 3.24.Epidermolytic ichthyosis: hyperkeratosis and scales follow re-epithelialization of widespread blistering Fig. 3.25.Epidermolytic ichthyosis: adult showing very generalized scaling, particularly severe on the legs. By courtesy of Institute of Dermatology, London, UK Fig. 3.26.Epidermolytic ichthyosis: same patient as Figure 3.25, showing elbow involvement with verrucous hyperkeratosis. By courtesy of the Institute of Dermatology, London, UK Fig. 3.27.Epidermolytic ichthyosis: the hands are particularly affected. By courtesy of the Institute of Dermatology, London, UK Fig. 3.28.Epidermolytic ichthyosis: blistering may sometimes be seen in adulthood. By courtesy of the Institute of Dermatology, London, UK Fig. 3.29.Epidermolytic ichthyosis: (A) there is massive hyperkeratosis and acanthosis. The epidermis shows conspicuous superficial vacuolation, which has resulted, in vesiculation; (B) there is intracellular vacuolation, and irregular eosinophilic granules (representing dense abnormal aggregates of keratin filaments) are present in the superficial layers of the epidermis Fig. 3.30.Epidermolytic ichthyosis: striking perinuclear keratin clumping is evident. By courtesy of R.A.J. Eady, MD, Institute of Dermatology, London, UK Fig. 3.31.Annular epidermolytic ichthyosis: migrating, polycyclic, gray hyperkeratotic plaques with a peripheral erythematous border. By courtesy of H. Traupe, MD, Münster, Germany Fig. 3.32.Superficial epidermolytic ichthyosis: flexural hyperkeratosis with early blister formation. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.33.Superficial epidermolytic ichthyosis: dark lichenified hyperkeratosis and characteristic superficial peeling with a molting-like appearance (Mauserung phenomenon). By courtesy of H. Traupe, MD, Münster, Germany Fig. 3.34.Linear epidermolytic epidermal nevus: (A) low-power view showing massive hyperkeratosis and papillomatosis; (B) high-power view showing epidermolytic hyperkeratosis Fig. 3.35.Epidermolytic acanthoma: the lesion is papillomatous with massive hyperkeratosis. There is a superficial perivascular chronic inflammatory cell infiltrate Fig. 3.36.Epidermolytic acanthoma: there is superficial cytoplasmic vacuolation and eosinophilic inclusions are conspicuous Fig. 3.37.Incidental epidermolytic hyperkeratosis: focal expression of epidermolytic hyperkeratosis in the periphery of a melanocytic nevus Fig. 3.38.Ichthyosis hystrix Curth-Macklin: the epidermis is acanthotic and orthohyperkeratotic. The suprabasal keratinocytes are vacuolated but lack eosinophilic intracytoplasmic inclusions and some are binucleated. By courtesy of S. Fraitag, MD, Paris Fig. 3.39.Congenital reticular ichthyosiform erythroderma: patches of normal skin appear to be enclosed by erythrokeratotic and hyperpigmented areas in a reticular arrangement Fig. 3.40.Congenital reticular ichthyosiform erythroderma: (A) there is hyperkeratosis and well-developed psoriasiform hyperplasia; (B) parakeratosis with prominent nuclei and absence of a granular layer are also observed. Note the cytoplasmic vacuolation and binucleated keratinocytes. Eosinophilic intracytoplasmic inclusions are absent Fig. 3.41.Comèl-Netherton syndrome: ichthyosis linearis circumflexa. Note the serpiginous lesions with characteristic double border. By courtesy of M. Judge, MD, Institute of Dermatology, London, UK Fig. 3.42.Comel-Netherton syndrome: (A) hyperkeratotic lesions may sometimes be prominent; (B) note the focal loss of the polycyclic pattern Fig. 3.43.Comèl-Netherton syndrome: (A) there is profound erythema with scaling; (B) the hair is dull and appears short and thin. The eyebrows are deficient. (A) By courtesy of M. Judge, MD, Institute of Dermatology, London, UK. (B) By courtesy of A. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.44.Comèl-Netherton syndrome: bamboo hair (trichorrhexis invaginata). By courtesy of M. Judge, MD, Institute of Dermatology, London, UK Fig. 3.45.Comèl-Netherton syndrome: (A) scanning view showing a detached thickened stratum corneum and psoriasiform hyperplasia; (B) note the marked parakeratosis and dilated vessels mimicking psoriasis vulgaris Fig. 3.46.Peeling skin syndrome type B: erythematous lesions show peeling of the skin leaving superficially denuded red patches. By courtesy of H. Traupe MD and V. Oji MD, Department of Dermatology, Münster, Germany Fig. 3.47.Peeling skin syndrome type B: the biopsy is taken from the edge of the lesion. Note that the stratum corneum is clearly separated from the underlying epidermis Fig. 3.48.Acral peeling skin syndrome type C: the skin of the backs of hand and feet shows reddish scaly patches. By courtesy of H. Traupe MD and V. Oji MD, Department of Dermatology, Münster, Germany Fig. 3.49.Keratosis linearis-ichthyosis congenita-sclerosing keratoderma (KLICK): diffuse palmoplantar keratoderma and keratotic papules arranged in parallel lines on the wrist Fig. 3.50.Keratosis linearis-ichthyosis congenita-sclerosing keratoderma (KLICK): immunostaining for filaggrin shows broad immunoreactivity in the upper epidermis that characteristically extends into the horny layer Fig. 3.51.Sjögren-Larsson syndrome: brownish-yellow color and a cobblestone-like pattern of lichenification is typical. By courtesy of M. Willemsen, MD, University Medical Center, Nijmegen, Belgium Fig. 3.52.Sjögren-Larsson syndrome: characteristic macular crystals. By courtesy of M. Willemsen, MD, University Medical Center, Nijmegen, Belgium Fig. 3.53.Sjögren-Larsson syndrome: there is hyperkeratosis, with focal parakeratosis, hypergranulosis, and mild papillomatosis. A mild superficial perivascular lymphocytic infiltrate is present Fig. 3.54.Trichothiodystrophy: (A) polarizing microscopy of a hair shows an alternating light and dark banding ('tiger-tail pattern'). (B) The same hair without polarizing Fig. 3.55.Conradi-Hünermann-Happle syndrome: scaly erythema follows the whorled lines of Blaschko. By courtesy of H. Traupe MD, Dept of Dermatology, Münster, Germany Fig. 3.56.Conradi-Hünermann-Happle syndrome: (A) there is hyperkeratosis, acanthosis, and a reduced granular cell layer. Note the basophilic deposits within the thickened stratum corneum; (B) the basophilic deposits represent von Kossa preparation Fig. 3.57.Ichthyosis follicularis with alopecia and photophobia: (A) the skin is dry and ichthyosiform; (B) on the scalp a nonscarring alopecia with follicular hyperkeratosis is characteristic. By courtesy of H. Traupe MD, Dept of Dermatology, Münster, Germany Fig. 3.58.Ichthyosis follicularis with alopecia and photophobia: The hair follicle is atrophic and lacks a hair shaft; the opening contains a keratotic plug Fig. 3.59.Ichthyosis follicularis with alopecia and photophobia: there is hyperkeratosis centered on an acrosyringium Fig. 3.60.Acquired ichthyosis: (A) cutaneous manifestations most often resemble ichthyosis vulgaris; (B) close-up view of the scale. By courtesy of the Institute of Dermatology, London, UK Fig. 3.61.Acquired ichthyosis: there is intense erythema and scaling. This patient also suffered from graft-versus-host disease. By courtesy of B. Solky, MD, Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, USA Fig. 3.62.Acquired ichthyosis: this patient developed ichthyosis in a background of mycosis fungoides. Low-power view showing marked focally compact hyperkeratosis and acanthosis Fig. 3.63.Acquired ichthyosis: high-power view to emphasize the thinned granular layer. Mycosis fungoides as defined by an atypical lymphocyte population and epidermotropism with retraction artifact Fig. 3.64.Pityriasis rotunda: characteristic lesion showing circumscription, scaling, and hyperpigmentation. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 3.65.Keratosis pilaris: (A) typical follicular papules and pustules on the thigh; (B) note the conspicuous plugged follicles. (A) By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK. (B) By courtesy of the Institute of Dermatology, London, UK Fig. 3.66.Keratosis pilaris: (A) there is follicular dilatation and plugging; (B) note the atrophy of the infundibular epithelium Fig. 3.67.Ulerythema ophryogenes: there is intense erythema with loss of follicles. The eyebrow is a commonly affected site. By courtesy of the Institute of Dermatology, London, UK Fig. 3.68.Ulerythema ophryogenes: the cheek is also frequently involved. By courtesy of the Institute of Dermatology, London, UK Fig. 3.69.Keratosis pilaris atrophicans: (A) low-power view showing gross follicular hyperkeratosis and dilatation of the ostium; (B) high-power view. Note the perifollicular fibrosis extending into the reticular dermis Fig. 3.70.Erythrokeratoderma variabilis: (A) annular erythematous lesions showing scaling; (B) migration within days Fig. 3.71.Erythrokeratoderma variabilis: fixed geographical, reddish-yellow-brown greasy hyperkeratotic plaques Fig. 3.72.Erythrokeratoderma variabilis: (A) low-power view showing hyperkeratosis, acanthosis with an undulating skin surface and a very mild superficial perivascular chronic inflammatory cell infiltrate; (B) high-power view showing marked parakeratosis overlying a thickened orthokeratotic stratum corneum. Note the presence of a granular cell layer Fig. 3.73 Erythrokeratoderma varia scattered dyskeratotic keratinocytes are sometimes seen Fig. 3.74.Progressive symmetric erythrokeratodermia: erythematous scaly plaques gradually appear on the extensor surfaces on the extremities and then persist Fig. 3.75.KID syndrome: there is marked scaling of the scalp with alopecia. Note the facial erythema and dark plaques on the cheeks. By courtesy of R.J.G. Rycroft, MD, St John's Dermatology Centre, London, UK Fig. 3.76.HID syndrome: verrucous and hyperkeratotic, brownish-yellow sharply circumscribed plaques Fig. 3.77.KID syndrome: scanning magnification view showing mild hyperplasia of the epidermis. In this example the eccrine sweat glands are normal Fig. 3.78.HID syndrome: verru errucous and pseudoepitheliomatous hyperplasia of the epidermis Fig. 3.79.KID syndrome: high-power view emphasizing the basket-weave keratin overlying a zone of compact keratin. There is focal parakeratosis and vacuolization of the granular layer Fig. 3.80.HID syndrome: the nuclei of the keratinocytes are surrounded by empty spaces reminiscent of a bird's eye, (A) in the granular layer and (B) the horny layer Fig. 3.81.Porokeratotic adnexal ostial nevus (PAON): (A) filiform keratoses, protrude from the dilated ostia of hyperplastic sweat glands and hair follicles; (B) the underlying epithelium reveals vacuolated epithelia with pyknotic nuclei and lacks keratohyalin granules Fig. 3.82.Diffuse palmoplantar keratoderma Vörner-Unna-Thost: there is hyperkeratosis affecting the entire sole of the foot. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.83.Diffuse palmoplantar keratoderma Vörner-Unna-Thost: in this patient the palms of the hands were also affected. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.84.Diffuse palmoplantar keratoderma Vörner-Unna-Thost: the border of the lesion is marked by a linear zone of erythema. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London Fig. 3.85.Diffuse palmoplantar keratoderma Vörner-Unna-Thost: scanning view showing massive hyperkeratosis, papillomatosis, and acanthosis Fig. 3.86.Diffuse palmoplantar keratoderma Vörner-Unna-Thost: high-power view demonstrating the features of epidermolytic hyperkeratosis Fig. 3.87.Mal de Meleda: (A) hyperkeratosis is severe, waxy, diffuse, and appears macerated; (B) it extends on to the dorsal surfaces of hands and feet ('glove-and- socks' distribution) Fig. 3.88.Greither keratoderma (progressive palmoplantar keratoderma): (A) diffuse hyperkeratosis with fissures progressively extends to the back of the hands and feet; (B) affects the region of the Achilles tendon Fig. 3.89.Greither keratoderma (progressive palmoplantar keratoderma): patchy hyperkeratosis develops on the knees Fig. 3.90.Mal de Meleda: there is orthohyperkeratosis, hypergranulosis, and prominent papillomatosis, the latter feature is characteristic for Mal de Meleda Fig. 3.91.Diffuse non-epidermolytic palmoplantar keratoderma: there is massive hyperkeratosis, hypergranulosis, and acanthosis. Absence of epidermolytic hyperkeratosis rules out diffuse palmoplantar keratoderma Vörner-Unna-Thost Fig. 3.92.Diffuse non-epidermolytic palmoplantar keratoderma: (A) in this example, there is massive hyperkeratosis with an undulating growth pattern. Intraepidermal vesiculation is apparent; (B) high-power view showing signs of spongiosis Fig. 3.93.Diffuse non-epidermolytic palmoplantar keratoderma: fungal hyphae are apparent in the thickened stratum corneum (PAS stain) Fig. 3.94.Huriez syndrome: (A) the main features are sclerodactyly, hypotrophic and dystrophic nails; (B) there is diffuse, mild palmar keratosis Fig. 3.95.Huriez syndrome: there is mild acanthosis, orthohyperkeratosis and a well- developed granular cell layer Fig. 3.96.Vohwinkel syndrome: there is marked palmoplantar keratoderma. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.97.Vohwinkel syndrome: in this example there is very disfiguring keratoderma, hence the alternative title, keratoderma hereditarium mutilans. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.98.Loricrin keratoderma: (A) there is a generalized fine scaling; (B) palmoplantar keratoderma with a yellowish papular and honeycomb-like appearance but less mutilating than in classical Vohwinkel syndrome Fig. 3.99.Loricrin keratoderma: there is hyperkeratosis and mild acanthosis Fig. 3.100.Loricrin keratoderma: the stratum granulosum is prominent and scattered cells (on the right side of the field) show perinuclear vacuolization. The parakeratotic keratinocytes in the lower horny layer represent transitional cells. In the upper horny layers small roundish residual nuclei are preserved Fig. 3.101.Clouston syndrome: the keratoderma shows a typical 'pebbled' appearance Fig. 3.102.Clouston syndrome: there is nail dystrophy accompanied by hyperkeratosis of the fingertips, thereby accentuating the epidermal surface ridges. By courtesy of D. Atherton, MD, the Children's Hospital at Great Ormond Street, London, UK Fig. 3.103.Clouston syndrome: verruciform hyperplasia and papillomatosis of the epidermis are characteristic and should not be misdiagnosed as verruca vulgaris. The ducts of sweat glands are associated with a fibrovascular stroma Fig. 3.104.Olmsted syndrome: in this variant, the lesions are very disfiguring. Constriction bands and autoamputation are important complications. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.105.Papillon-Lefèvre syndrome: (A) there is marked hyperkeratosis affecting the soles of the feet; (B) in this patient, the dorsal aspects of the hands, particularly the knuckles are also affected. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.106.Papillon-Lefèvre syndrome: a scaly psoriasiform plaque is present over the elbow. By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK Fig. 3.107.Papillon-Lefèvre syndrome: gingival inflammation and swelling with the characteristic irregular positioning of the teeth which, as a result of destruction of supporting tissues, have shifted under the forces of mastication. This patient is a 12-year-old child, but the severity of the periodontal destruction is what might be expected in a person aged 60 years. By courtesy of R.A. Cawson, MD, Guy's Hospital, London, UK Fig. 3.108.Papillon-Lefèvre syndrome: there is hyperkeratosis, hypergranulosis and acanthosis Fig. 3.109.Howel-Evans syndrome: (A) focal autosomal dominant palmoplantar keratoderma is associated with an increased risk of esophageal squamous carcinoma; (B) in this patient, the palms were also severely affected. By courtesy of the Institute of Dermatology, London, UK Fig. 3.110.Schöpf-Schulz-Passarge syndrome: diffuse keratoderma on palms and fingers is associated with nail dystrophy Fig. 3.111 Schöpf-Schulz-Passarge syndrome: multiple yellowish and bluish cysts on the eyelids Fig. 3.112.Schöpf-Schulz-Passarge syndrome: the cysts on the eyelids represent apocrine hidrocystomas Fig. 3.113.Striate palmoplantar keratoderma: (A) linear hyperkeratotic bands along the palms and flexural side of the fingers; (B) island-like areas of hyperkeratosis on the soles over pressure points Fig. 3.114.Striate palmoplantar keratoderma: (A) histology reveals massive orthohyperkeratosis, hypergranulosis, and acanthosis; (B) loss of cohesion of keratinocytes leads to characteristic widening of the intercellular spaces Fig. 3.115.Carvajal-Huerta syndrome: patients are born with wooly hair Fig. 3.116.Carvajal-Huerta syndrome: (A) massive orthohyperkeratosis, acanthosis, and papillomatosis; (B) partial dehiscence of suprabasal keratinocytes and characteristic widening of the intercellular spaces Fig. 3.117.Pachyonychia congenita: (A) there is gross nail deformity with transverse arching of the distal portion. Although the nail plate appears to be thickened, most of the changes are, in fact, due to massive hyperkeratosis of the nail bed, resulting in elevation and bending of the nail plate; (B) in this view, the subungual hyperkeratosis is more obvious Fig. 3.118.Pachyonychia congenita: circumscribed, yellow, hyperkeratotic plaques on the soles of the feet are a common manifestation. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 3.119.Pachyonychia congenita: leukoplakia of the buccal mucosa is a frequent accompanying feature. By courtesy of R.A. Marsden, MD, St George's Hospital London, UK Fig. 3.120.Pachyonychia congenita: (A) volar skin showing massive hyperkeratosis, hypergranulosis, and acanthosis; (B) suprabasal keratinocytes have a characteristic pale cytoplasm and eosinophilic inclusions Fig. 3.121.Pachyonychia congenita: follicular lesion showing keratin plugging of the ostium with adjacent hyperkeratosis and associated acanthosis Fig. 3.122.Pachyonychia congenita: (A) scanning view of the oral mucosa showing massive acanthosis with large blunt rete ridges; (B) high-power view showing focal parakeratosis and vacuolization of superficial keratinocytes. A single dyskeratotic cell is evident (arrowed) Fig. 3.123.Punctate palmoplantar keratoderma: there are tiny keratotic papules over the entire palms. The central keratotic core is (A) translucent and opaque or (B)verrucous Fig. 3.124.Punctate palmoplantar keratoderma: discrete yellow keratotic papules over pressure areas coalesce into larger plaques Fig. 3.125.Punctate palmoplantar keratoderma: there is massive orthohyperkeratosis overlying an epidermal depression Fig. 3.126.Punctate palmoplantar keratoderma: elongated and curved rete ridges may be seen and are often misdiagnosed as verruca vulgaris Fig. 3.127.Keratosis punctata of the palmar creases: minute punctate lesions are localized solely to the palmar creases. There is often a history of manual labor. By courtesy of the Institute of Dermatology, London, UK Fig. 3.128.Spiny keratoderma: multiple tiny keratotic spines project from palms, soles, and fingers Fig. 3.129.Spiny keratoderma: a keratotic spike develops over a depressed epidermis Fig. 3.130.Marginal papular acrokeratoderma: pearly papules predominantly affecting sides of the hands, wrists, fingers Fig. 3.131.Marginal papular acrokeratoderma, variant acrokeratoelastoidosis: (A) focal areas orthohyperkeratosis overlying crateriform dells lined by acanthotic epidermis; (B) Weigert elastic staining reveals diminution of the dermal elastic tissue Fig. 3.132.Acquired palmoplantar keratoderma: acquired disease may be a manifestation of underlying malignancy. By courtesy of the Institute of Dermatology, London, UK Fig. 3.133.Keratoderma climactericum: there is massive hyperkeratosis with fissuring over the heels. By courtesy of the Institute of Dermatology, London, UK Fig. 3.134.Mechanic hands: patients with dermatomyositis, in particular dermatomyositis- systemic scleroderma-overlap syndrome may develop circumscribed hyperkeratoses on palms Fig. 3.135.Transient aquagenic keratoderma: (A) shortly after immersion of the right hand in water thickening and 'pebbly' changes developed on the palm. Left hand is the control; (B) the papular lesions show widely dilated ostia Fig. 3.136.Transient aquagenic keratoderma: note the wide opening of an acrosyringeal ostium, and the pale staining of an orthohyperkeratotic stratum corneum, otherwise there are no other histologic changes Fig. 3.137.Clavus: massive hyperkeratosis overlies an epidermal depression Fig. 3.138.Keratolytic winter erythema: palmoplantar erythema is followed by centrifugal peeling. By courtesy of W. Grayson, MD, University of the Witwatersrand, Johannesburg, South Africa Fig. 3.139.Keratolytic winter erythema: there is hyperplasia and spongiosis of the epidermis. The stratum granulosum is absent. Keratinocytes show a pale cytoplasm,perinuclear vacuoles, and pyknotic nuclei. A parakeratotic wedge is seen within the hyperkeratotic stratum corneum. By courtesy of W. Grayson, MD, University of the Witwatersrand, Johannesburg, South Africa Fig. 3.140.Circumscribed palmar or plantar hypokeratosis: (A) on the thenar area a well- circumscribed, depressed, erythematous lesion is present; (B) a closer view reveals a scaly border Fig. 3.141.Circumscribed palmar or plantar hypokeratosis: (A) there is a sharply circumscribed loss of the cornified layer and some psoriasiform hyperplasia of the epidermis; (B) higher view from the edge of the lesion Fig. 3.142.Acrokeratosis verruciformis: numerous brown flat-topped papules are symmetrically distributed over the dorsal aspects of the hands. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 3.143.Acrokeratosis verruciformis: there is hyperkeratosis and church-spire papillomatosis Fig. 3.144.Flegel disease: (A) there are characteristic disseminated erythematous scaly lesions; (B) the lower legs are commonly affected. Lesions are small, multiple and show irregular margins covered by a well-developed scale ('cornflake sign'). By courtesy of M. Price, MD, Institute of Dermatology, London, UK Fig. 3.145.Flegel disease: (A) scanning view of an established lesion showing focal hyperkeratosis, and a superficial bandlike infiltrate; (B) there is hyperkeratosis, focal epidermal atrophy, vacuolization of the dermal-epidermal junction with many colloid bodies, below a dense lymphocytic infiltrate Fig. 3.146.Porokeratosis of Mibelli: the lesions are erythematous, atrophic and scaly, with a sharply defined and slightly raised keratotic rim Fig. 3.147.Disseminated superficial actinic porokeratosis: (A) there are numerous small, reddish or brownish keratotic macules on sun damaged skin; (B) squamous cell carcinoma developed in the crusted and hyperkeratotic lesion Fig. 3.148.Linear porokeratosis: in this variant, the lesions have a half-sided linear and reticulated nevoid distribution Fig. 3.149.Porokeratosis ptychotropica: brownish to reddish macules or plaques appear symmetrically distributed on the buttocks and natal cleft Fig. 3.150.Porokeratosis of Mibelli: (A) on the right side the diagnostic features is a keratin-filled epidermal invagination with an angulated keratotic tier, the cornoid lamella. The center of the lesion is atrophic. (B) The epidermis below the cornoid lamella expresses large, vacuolated, and pleomorphic keratinocytes and does not form a granular layer. (C) The corneocytes of the cornoid lamella are parakeratotic and express characteristic PAS-positive granules Fig. 3.151.Disseminated superficial actinic porokeratosis: in this example, the cornoid lamella has arisen overlying an acrosyringium. The epidermis towards the center of the lesion appears atrophic and the papillary dermis contains ectatic blood vessels Fig. 3.152.Porokeratosis of Mibelli: (A) there is central orthohyperkeratosis with two well- developed cornoid lamellae on both sides. Note the epidermal depression at their bases. (B) The cornoid lamella can be seen to be composed of a column of parakeratosis Fig. 3.153.Porokeratosis ptychotropica: there is no solitary keratotic rim on the lateral side but multiple parakeratotic tiers above epidermal invaginations (arrows), characteristic feature of the punctate type of porokeratosis Fig. 3.154.Digitate hyperkeratosis: in this familial variant disseminated spiny keratosis developed on trunk and extremities. By courtesy of H. Traupe, Münster, Germany Fig. 3.155.Digitate hyperkeratosis: an orthohyperkeratotic spicule arises from a pointed epidermal elevation Fig. 3.156.Granular parakeratosis: (A) in the axilla of a middle-aged woman erythematous, hyperpigmented and hyperkeratotic papules develop in a reticulated fashion; (B) a few of these lesions are erosive Fig. 3.157.Granular parakeratosis: (A) there is marked thickening of the horny layer with parakeratosis; (B) high-power view showing retention of keratohyalin granules Fig. 3.158.Granular parakeratosis: (A) this example arose against a background of lymphomatoid papulosis; (B) high-power view Fig. 4.1.Classification of subepidermal blisters: lesio poor and (B) cell-rich variants Fig. 4.2.Basement membrane constituents: blisters can be classified into those that develop within the lamina lucida (LL) and those that arise below the lamina densa (LD). (AF, anchoring fibrils; AP, anchoring plaque; CM, cell membrane.) Fig. 4.3.Split skin immunofluorescence Fig. 4.4.(A, B) Split skin immunofluorescence: the split is through the lamina lucida, the lamina densa lining the floor of the artificial blister cavity Fig. 4.5.Split skin immunofluorescence: type IV collagen lines the floor of the split skin artificial blister which therefore forms within the lamina lucida. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK Fig. 4.6.Split skin immunofluorescence: (left) linear IgG at the basement membrane; (middle) in epidermolysis bullosa acquisita (EBA), the antibody binds to the floor of the blister cavity; (right) in bullous pemphigoid (BP), the antibody binds to the roof of the blister. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK Fig. 4.7.Paraffin-embedded immunoperoxidase antigen mapping: in bullous pemphigoid, type IV collagen is present along the floor of the blister Fig. 4.8.Paraffin-embedded immunoperoxidase antigen mapping: in epidermolysis bullosa acquisita, type IV collagen is present along the roof of the blister cavity Fig. 4.9.Schematic representation of the major adhesive proteins within hemidesmosome adhesion complexes at the dermal-epidermal junction and their involvement in different types of EB. (AD = autosomal dominant; AR = autosomal recessive) Fig. 4.10.Localized EB simplex: typical acral lesions affecting the toes. The pale color is due to the marked thickness of the roof of the blister. By courtesy of St John's Institute of Dermatology, London, UK Fig. 4.11.Acral peeling skin syndrome: signs instep extending to the toes Fig. 4.12.Generalized severe EB simplex: showing characteristic grouping of blisters and erosions. By courtesy of R.A.J. Eady, MD, St John's Institute of Dermatology, London, UK Fig. 4.13.EB simplex with mottled pigmentation: diffuse hyper- and hypopigmentation with minor small patches of erythema and occasional tiny vesicles. By courtesy of J.E. Mellerio, St John's Institute of Dermatology, London, UK Fig. 4.14.Generalized severe junctional EB: newly born infant with blistering and nail involvement. By courtesy of J. McGrath, MD,of Dermatology, London UK Fig. 4.15.Generalized severe junctional EB: infant showing granulation tissue at the edge of a healing blister. By courtesy of the Institute of Dermatology, London, UK Fig. 4.16.Junctional EB with pyloric atresia: widespread blistering with deep ulceration. By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK Fig. 4.17.(A, B) Junctional EB with pyloric atresia: pyloric canal obliterated by fibrous connective tissue Fig. 4.18.Generalized dominant dystrophic EB: scarring, milia and nail dystrophy. By courtesy of St John's Institute of Dermatology, London, UK Fig. 4.19.Dominant dystrophic EB-acral: predominantly acral blisters and scarring as well as nail dystrophy. By courtesy of St John's Institute of Dermatology, London, UK Fig. 4.20.Dominant dystrophic EB-pretibial: linear erosions with scarring localized to the front of both shins. By courtesy of St John's Institute of Dermatology, London, UK Fig. 4.21.Bullous dermolysis of the newborn: (A) blisters on the heel; (B) blisters on the fingers; (C) type VII collagen is present at the dermal-epidermal junction but there is also striking punctate staining within the epidermis; (D) ultrastructurally, in this basal keratinocyte there are numerous pale gray stellate bodies (dilated Golgi apparatus containing type VII collagen). This form of dystrophic EB usually tends to improve spontaneously during the first few months of life Fig. 4.22.Generalized severe recessive dystrophic EB: in addition to the gross mitten deformity, there is very severe scarring and scaling. By courtesy of St John's Institute of Dermatology, London, UK Fig. 4.23.Generalized severe recessive dystrophic EB: in this patient, numerous large keratoses are evident. Many of these progress to squamous cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK Fig. 4.24.Generalized intermediate recessive dystrophic EB: this individual has atrophic scarring and recent erosions overlying both knees Fig. 4.25.Kindler syndrome: the hands of this 14-year-old girl show poikiloderma (hyperpigmentation, hypopigmentation, atrophy, and telangeictasias) Fig. 4.26.Ultrastructural appearances of a hemidesm at the dermal-epiderma junction in normal human skin Fig. 4.27.Ultrastructural appearances of a desmosome between two keratinocytes in normal human skin Fig. 4.28.Generalized severe EB simplex: numerous tonofilament clumps are present in the adjacent clinically normal skin (arrowed). By courtesy of J.A. McGrath, John's Institute of Dermatology, London, UK Fig. 4.29.Generalized severe EB simplex: (A) electron micrograph showing intrakeratinocyte splitting; (B) close-up view of tonofilament clumps. By courtesy of J.A. McGrath, MD, and R.A.J. Eady, MD, St John's Institute of Dermatology, London, UK Fig. 4.30.EB simplex: the earliest histologic feature in the development of a blister is marked vacuolation of the basal keratinocytes, so-called cytolysis Fig. 4.31.EB simplex: old lesion; the features are those of a cell-free subepidermal blister and are not specific Fig. 4.32.Schematic representation of the transmembranous and intracellular components of desmosomes that provide a bridge between the keratin filament networks in adjacent keratinocytes Fig. 4.33.Desmosomal EB simplex: pan-epidermal cell-cell detachment within the epidermis, here resulting from autosomal recessive mutations in desmoplakin Fig. 4.34.Desmosomal EB simplex: the ultrastructural plane of cleavage leading to cell separation occurs through the intracellular desmosomal plaque consistent with the localization of the mutant desmoplakin in this case Fig. 4.35.Junctional EB: the level of blister formation at the through the lamina lucida (asterisk) Fig. 4.36.Anchoring fibrils in normal skin: fibrillar structures with a fan-shaped appearance, central cross-banding and insertion into the lamina densa represent the ultrastructural hallmarks of anchoring fibrils in the superficial dermis (arrows) Fig. 4.37.Generalized severe recessive dystrophic EB: complete absence of anchoring fibrils below the lamina densa with onset of sub-lamina densa blistering (asterisks) Fig. 4.38.Generalized severe recessive dystrophic EB: in addition to obvious subepidermal blistering there is dermal scarring and chronic inflammation Fig. 4.39.(A, B) Generalized severe recessive dystrophic EB: biopsy from the forearm of a 30-year-old patient showing a cell-free subepidermal blister. In addition, a well- differentiated squamous cell carcinoma extends into the subcutaneous fat Fig. 4.40.Bullous pemphigoid: classification Fig. 4.41.Erythrodermic BP: blistering has developed against a background of generalized erythroderma. By courtesy of the Institute of Dermatology, London, UK Fig. 4.42.BP: early tense blister arising on an erythematous base. By courtesy of the Institute of Dermatology, London, UK Fig. 4.43.BP: tense, dome-shaped blisters. The flexures are typically affected. By courtesy of the Institute of Dermatology, London, UK Fig. 4.44.BP: widespread, fluid-filled, hemorrhagic blisters on the arms of an elderly female. By courtesy of the late M. Beare, MD, Royal Victoria Hospital, Belfast, N. Ireland Fig. 4.45.BP: new blisters arising at the edge of a healing lesion ('cluster of jewels' sign). Although typically seen in childhood linear IgA disease, this is sometimes a feature of bullous pemphigoid. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.46.BP: oral erosions are an occasional finding. Intact blisters are rare. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.47.BP: conjunctival injection is present. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.48.Bullous pemphigoid: occasionally erythematous urticarial lesions may be the presenting feature. Blisters may not evolve until several weeks later. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.49.Bullous pemphigoid: close up view. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.50.(A, B) Pemphigoid vegetans: presentation as verrucous lesions in the flexures may result in considerable diagnostic difficulties. By courtesy of R.K. Winkelmann MD, The Mayo Clinic, Scottsdale, Arizona, USA Fig. 4.51.Pemphigoid nodularis: in addition to bullous lesions, this patient also developed these pruritic nodules. By courtesy of H. Shimizu, MD, Keio University School of Medicine, Tokyo, Japan Fig. 4.52.Childhood BP: very rarely this disease affects young children and infants.There is a widespread distribution of bullae, which characteristically arise on an erythematous base. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.53.Childhood BP: plantar involvement is sometimes the only site of disease. courtesy of M. Liang, MD, The Children's Hospital, Boston, USA Fig. 4.54.Childhood BP: note the perineal scarring and isolated blister. By courtesy of M. Liang, MD, The Children's Hospital, Boston, USA Fig. 4.55 Localized pemphigoid, nonscarring variant: lesions are found particularly on the lower legs of females. The prognosis is usually good, but occasionally the condition can become generalized. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.56.Desquamative gingivitis: note the intense gingival erythema and retraction. Such features may also be seen in mucous membrane pemphigoid and pemphigus. By courtesy of P. Morgan, FRCPath, London, UK Fig. 4.57.Prebullous pemphigoid: there is upper dermal edema and a perivascular lymphohistiocytic infiltrate with conspicuous eosinophils Fig. 4.58.Prebullous pemphigoid: there are numerous eosinophils Fig. 4.59.BP: an established lesion showing a subepidermal tense, dome-shaped blister containing edema fluid, fibrin, and inflammatory cells Fig. 4.60.BP: the blister cavity contains large numbers of eosinophils Fig. 4.61.BP: preservation of the dermal papillary outline (festooning) is a characteristic feature Fig. 4.62.BP: the presence of eosinophil microabscesses in the dermal papillae is a useful although rare diagnostic marker Fig. 4.63.BP: eosinophilic spongiosis is sometimes seen in the epidermis adjacent to the blister Fig. 4.64.Cell-poor pemphigoid: this is a very uncommon variant and is most often seen if a very early lesion is sampled. The blister contains only a little edema fluid and there is a light chronic inflammatory cell infiltrate in the superficial dermis Fig. 4.65.Vesicular pemphigoid: (A) low-power view showing a multilocular blister; (B) the blister contains a neutrophil-rich infiltrate Fig. 4.66.Vesicular pemphigoid: (A) neutrophil microabscesses in the adjacent dermal papillae heighten the resemblance to dermatitis herpetiformis. It would be impossible to establish the diagnosis of bullous pemphigoid without appropriate immuno-fluorescent findings; (B) preservation of the dermal papillae may be a clue to the correct diagnosis of pemphigoid Fig. 4.67.Pemphigoid nodularis: this is a biopsy of a pruritic nodule showing hyperkeratosis, irregular acanthosis, dermal chronic inflammation, and scarring Fig. 4.68.Pemphigoid nodularis: this subepidermal blister comes from the same patient as shown in Fig. 4.67. Pemphigoid nodularis is of particular importance because the nodular lesions may precede clinical evidence of blistering Fig. 4.69.BP: electron micrograph showing the lamina densa lying along the floor of the blister cavity Fig. 4.70.BP: high-power view of the lamina densa Fig. 4.71.BP: direct immunofluorescence of perilesional skin showing intense linear basement membrane zone staining (IgG) Fig. 4.72.BP: direct immunofluorescence showing C3 deposition (left), no staining is seen in the negative control (right). By courtesy of B. Boghal, FIMLS, Institute of Dermatology, London, UK Fig. 4.73.BP: direct immunoperoxidase reaction using frozen tissue substrate showin electron-dense deposits in the lamina lucida Fig. 4.74.BP: immunogold electron microscopic preparation. Note that the immunoreactant to BP180 and BP230 is particularly located on the hemidesmosomes (open arrows). However, deposits are also present within the lamina lucida, black arrows. (BC, basal cell; DER, dermis.) By courtesy of H. Shimizu, MD, Keio University School of Medicine, Tokyo, Japan Fig. 4.75.BP: Western blot demonstrating the two quite separate bullous pemphigoid antigens. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK Fig. 4.76.A schematic representation of the BP180 molecule showing the globular intracellular NH2 domain, the membrane proximal NC16A domain and the flexible rod-like interrupted collagenous structure of the extracellular domain. (HD, hemidesmosome). Collagen XVII/BP180: a collagenous transmembrane protein and component of the dermal-epidermal anchoring complex. (Powell AM, Sakuma-Oyama Y, Oyama N, Black M.M. Department of Immunodermatology, St John's Institute of Dermatology, St Thomas' Hospital, London, UK.) Fig. 4.77.Pemphigoid gestationis: prebullous phase showing erythema and small papules. By courtesy of the Institute of Dermatology, London, UK Fig. 4.78.Pemphigoid gestationis: the blisters are tense and dome-shaped. By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK Fig. 4.79.Pemphigoid gestationis: slightly raised erythematous lesions with a propensity to cluster on the abdomen. By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK Fig. 4.80.Pemphigoid gestationis: umbilical involvement is a common mode of presentation. By courtesy of the Institute of Dermatology, London, UK Fig. 4.81.Pemphigoid gestationis: early erythematous lesion showing marked edema of the papillary dermis and conspicuous eosinophils Fig. 4.82.Pemphigoid gestationis: early erythematous lesion showing eosinophilic spongiosis Fig. 4.83.Pemphigoid gestationis: established subepidermal blister Fig. 4.84.Pemphigoid gestationis: the blister cavity contains a heavy eosinophil infiltrate Fig. 4.85.Pemphigoid gestationis: indirect complement immunofluorescence showing linear deposition of IgG Fig. 4.86.Pruritic papules and plaques of pregnancy: note the erythematous papules particularly related to the abdominal striae, and characteristic umbilical courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK Fig. 4.87.Pregnancy prurigo: there are erythematous papules and excoriations. Blisters are not a feature of this condition. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.88.Lichen planus pemphigoides: typical lichenoid papules are present on the anterior aspect of the wrist. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK Fig. 4.89.Lichen planus pemphigoides: note the blisters and erosions arising on an erythematous base. Atypical target lesions are present. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK Fig. 4.90.Lichen planus pemphigoides: note the intact dome-shaped tense blister. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK Fig. 4.91.Lichen planus pemphigoides: the lichenoid papules show typical features of lichen Fig. 4.92.Lichen planus pemphigoides: there is a subepidermal blister Fig. 4.93.Lichen planus pemphigoides: the blister contains eosinophils Fig. 4.94.Mucous membrane pemphigoid: there is erosion of the buccal mucosa. By courtesy of P. Morgan, FRCPath, London, UK Fig. 4.95.Mucous membrane pemphigoid: in addition to erosions, intact blisters are evident. By courtesy of P. Morgan, FRCPath, London, UK Fig. 4.96.Mucous membrane pemphigoid: there is a dense fibrous adhesion (symblepharon) between the conjunctiva lining the eyelid and that covering the globe. By courtesy of the Institute of Dermatology, St Thomas' Hospital, London, UK Fig. 4.97.Mucous membrane pemphigoid: in this advanced case, there is entropion and trichiasis (inwardly directed eyelashes). By courtesy of D. Kerr-Muir, MD, St Thomas' Hospital, London, UK Fig. 4.98.Mucous membrane pemphigoid: here there is dense corneal scarring with complete opacification. By courtesy of D. Kerr-Muir MD, St Thomas' Hospital, London, UK Fig. 4.99.Mucous membrane pemphigoid: in addition to erosions, marked scarring of the vulva is present. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.100.Mucous membrane pemphigoid: note the localized blistering and erosion with scarring on the lower leg of an elderly female. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.101.Brunsting-Perry localized pemphigoid: there is extensive alopecia in addition to multiple erosions with scarring. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.102.Mucous membrane pemphigoid: in this example of a recurrent lesion, the subepidermal blister is cell free nd there is dermal scarring Fig. 4.103.Mucous membrane pemphigoid: high-power view of a similar lesion Fig. 4.104.Mucous membrane pemphigoid: oral lesion showing an intact subepithelial blister Fig. 4.105.Mucous membrane pemphigoid: note the preservation of the papillae Fig. 4.106.Mucous membrane pemphigoid: in this example, the infiltrate consists of lymphocytes and histiocytes. Eosinophils are not a feature Fig. 4.107.Mucous membrane pemphigoid: this specimen of conjunctiva shows complete squamous metaplasia. Neovascularization of the lamina propria is evident. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK Fig. 4.108.Mucous membrane pemphigoid: section of cornea. The overlying pannus shows squamous metaplasia, chronic inflammation, and neovascularization. Blood vessels are also present in the cornea. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK Fig. 4.109.Mucous membrane pemphigoid: this section shows iris impaction with anterior synechiae. Iritis and posterior synechiae are also present. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK Fig. 4.110.Mucous membrane pemphigoid: this field shows anterior uveitis. There is inflammation of the iris and ciliary body. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK Fig. 4.111.Mucous membrane pemphigoid: postmortem specimen showing laryngeal erosion, ulceration, and scarring Fig. 4.112.Epidermolysis bullosa acquisita: there is a tense fluid-filled blister on the ankle. An old lesion is also evident. By courtesy of the Institute of Dermatology, London, UK Fig. 4.113.Epidermolysis bullosa acquisita: conspicuous milia are present on the back of the hand. By courtesy of the Institute of Dermatology, London, UK Fig. 4.114.Epidermolysis bullosa acquisita: in this patient with the dermatitis herpetiformis- like inflammatory variant, blisters, erosions, and erythematous plaques are evident on the elbow. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.115.Epidermolysis bullosa acquisita (classical variant): there is a cell-free subepidermal vesicle. Note the dermal scarring Fig. 4.116.Epidermolysis bullosa acquisita (classical variant): high-power view. There is fibrin along the floor of the blister cavity. Note the absence of inflammatory cells Fig. 4.117.(A, B) Inflammatory epidermolysis bullosa acquisita: in this bullous pemphigoid-like variant, subepidermal blistering is associated with an eosinophil-rich infiltrate Fig. 4.118.Inflammatory epidermolysis bullosa acquisita: dermatitis herpetiformis-like variant,with a neutrophil-rich infiltrate Fig. 4.119.(A, B) Epidermolysis bullosa acquisita: electron micrograph showing the lamina densa in the roof of the blister. (BC, blister cavity.) Fig. 4.120.Epidermolysis bullosa acquisita: occasional deposits of finely granular electron- dense material (immunoreactant) as seen in this field may be a useful diagnostic pointer Fig. 4.121.Epidermolysis bullosa acquisita: (left) direct immunofluorescence shows linear IgG deposition along the basement membrane region; (right) with split skin the immunoreactant lines the floor of the induced lesion. By courtesy of Department of Immunofluorescence, Institute of Dermatology, London, UK Fig. 4.122.Epidermolysis bullosa acquisita: direct immunoelectron microscopy showing reactant deposition below the lamina densa Fig. 4.123.Epidermolysis bullosa acquisita: immunogold preparation showing localization of the immunoglobulin to the anchoring fibrils. By courtesy of H. Shimizu, MD, Keio University School of Medicine, Tokyo, Japan Fig. 4.124.Epidermolysis bullosa acquisita: there are two distinct antigens: one the 290-kD major antigen; the other the 145-kD minor antigen. By courtesy of I. Leigh, MD, Royal London Hospital Trust, London, UK Fig. 4.125.Bullous systemic lupus erythematosus: West Indian female with perioral blistering. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.126.Bullous systemic lupus erythematosus: in this example, there is a conspicuous inflammatory background. By courtesy of the Institute of Dermatology, London, UK Fig. 4.127.Bullous systemic lupus erythematosus: numerous erosions are present over the chest, shoulders, and upper arms. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.128.Bullous systemic lupus erythematosus: tense bullous pemphigoid-like lesions. By courtesy of the Institute of Dermatology, London, UK Fig. 4.129.Bullous systemic lupus erythematosus: this shows the typical features of a subepidermal, neutrophil-rich vesicle Fig. 4.130.Bullous systemic lupus erythematosus: the presence of a neutrophil abscess in the papillary dermis increases the histologic similarity of this condition to dermatitis herpetiformis Fig. 4.131.Bullous systemic lupus erythematosus: this scanning view shows a central focus of subepidermal vesiculation. Striking inflammatory changes outline the dermal vasculature Fig. 4.132.Bullous systemic lupus erythematosus: this view shows florid leukocytoclastic vasculitis Fig. 4.133.Bullous systemic lupus erythematosus: this is a close-up view of the subepidermal vesicle shown in Fig. 4.131 Fig. 4.134.Dermatitis herpetiformis: excoriations are present on the elbow and back of the arm. Intact blisters are uncommon in dermatitis herpetiformis because of the inense pruritus. By courtesy of the Institute of Dermatology, London, UK Fig. 4.135.Dermatitis herpetiformis: the buttocks are frequently affected. By courtesy of the Institute of Dermatology, London, UK Fig. 4.136.Dermatitis herpetiformis: direct immunofluorescence showing (A) deposits of granular IgA in the dermal papillae; (B) fibrin deposition in the dermal papillae. By courtesy of the Department of Immunofluorescence, Institute of Dermatology, London, UK Fig. 4.137.Dermatitis herpetiformis: biopsy from an early lesion showing conspicuous neutrophil microabscesses Fig. 4.138.Dermatitis herpetiformis: in this early lesion, there are thin strands of fibrin visible above the neutrophilic infiltrate Fig. 4.139.Dermatitis herpetiformis: an established subepidermal blister. Although early lesions are usually multilocular, by 24-48 hours the lesion becomes unilocular Fig. 4.140.Dermatitis herpetiformis: floor of the blister in Fig. 4.139 Showing an intense neutrophil infiltrate Fig. 4.141.Dermatitis herpetiformis: nuclear debris (karyorrhexis) within the dermis is a characteristic feature Fig. 4.142.(A, B) Dermatitis herpetiformis: in this example acantholysis may result in diagnostic confusion with pemphigus. Note that the blister is subepidermal Fig. 4.143.Adult linear IgA disease: in this example, the clinical appearances of excoriated lesions are suggestive of dermatitis herpetiformis. By courtesy of the Institute of Dermatology, London, UK Fig. 4.144.Adult linear IgA disease: there is marked conjunctival injection and blepharitis. By courtesy of the Institute of Dermatology, London, UK Fig. 4.145.Childhood linear IgA disease: in this case widespread erosions on an erythematous background are present on the buttocks and legs. Occasional intact vesicles are also evident. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.146.Childhood linear IgA disease: groups of blisters are present on the vulva and inner thighs. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.147.Childhood linear IgA disease: the arrangement of blisters called the 'cluster of jewels'. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 4.148.(A, B) Linear IgA disease: in this example, the features are those of a neutrophil-rich subepidermal vesicle reminiscent of dermatitis herpetiformis Fig. 4.149.(A, B) Linear IgA disease: in this field, the presence of eosinophils is more suggestive of bullous pemphigoid Fig. 4.150.Linear IgA disease: direct immunofluorescence showing linear IgA deposition. By courtesy of the Department of Immunofluorescence, Institute of Dermatology,London, UK Fig. 4.151.Linear IgA disease: direct immunoperoxidase reaction using frozen tissue substrate. There is an abundance of granular IgA beneath the basal lamina Fig. 5.1.Acantholysis: the keratinocytes are rounded and separated from each other to form an intraepidermal blister. Villi formed from the underlying dermal papillae typically project into suprabasal cavities Fig. 5.2.Pemphigus vulgaris: painful erosions are present on the buccal mucosa. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 5.3.Pemphigus vulgaris: in this patient, there is an intact blister on the floor of the mouth. Pemphigus commonly presents in the mouth. By courtesy of the Institute of Dermatology, London, UK Fig. 5.4.Pemphigus vulgaris: since the blisters are superficial, erosions are more commonly encountered. By courtesy of the Institute of Dermatology, London, UK Fig. 5.5.Pemphigus vulgaris: extensive erosions and blisters are present on the shin. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 5.6.Pemphigus vulgaris: umbilical lesions showing intact blisters as well as raw erosions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 5.7.Pemphigus vulgaris: extensive trauma-induced blisters. By courtesy of the Institute of Dermatology, London, UK Fig. 5.8.Pemphigus vulgaris: extensive disease can be very disfiguring. By courtesy of the Institute of Dermatology, London, UK Fig. 5.9.Pemphigus vulgaris: direct immunofluorescence. By courtesy of the Institute of Dermatology, London, UK Fig. 5.10.Pemphigus vulgaris: established blister showing marked acantholysis and scattered neutrophils. The dermal papillae project into the cavity as villi Fig. 5.11.Pemphigus vulgaris: (A) perianal mucosa showing acantholysis and villi; (B) high-power view Fig. 5.12.Pemphigus vulgaris: cell-free example showing a linear palisade of intact basal keratinocytes - the so-called 'tombstone' appearance Fig. 5.13.Pemphigus vulgaris: follicular involvement distinguishes pemphigus from Hailey-Hailey disease in which it is not a feature Fig. 5.14.Pemphigus vulgaris: electron photomicrograph of an early lesion showing suprabasal, intraepidermal vesiculation. Residual cytoplasm of basal keratinocytes lines the floor of the blister. The lamina densa is clearly visible Fig. 5.15.Pemphigus vulgaris: electron photomicrograph of an early lesion showing marked dilatation of the intercellular space. Cytoplasmic 'villus' formation is conspicuous and only occasional desmosomes are apparent Fig. 5.16.Formshiaus vegetais: ille ulceration and vegetative lesion. From the side collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK Fig. 5.17.Pemphigus vegetans: the epidermis is hyperplasic and there are scattered abscesses Fig. 5.18.Pemphigus vegetans: follicular involvement is seen on the right Fig. 5.19.Pemphigus vegetans: there are numerous eosinophils. Note the acantholysis Fig. 5.20.Pemphigus foliaceus: multiple erosions are present with background erythema and postinflammatory hyperpigmentation. Courtesy of the Institute of Dermatology, London, UK Fig. 5.21.Pemphigus foliaceus: crusted lesions are evident on the back of this young male.From the collection of the late Smith, MD, the Institute of Dermatology London, UK Fig. 5.22.Pemphigus foliaceus: (A) there are numerous crusted lesions on the lower abdomen and in the groin; (B) high-power view. From the slide collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK Fig. 5.23.Pemphigus foliaceus: in this patient, there is generalized erosion with scaling and erythroderma. By of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 5.24.Pemphigus foliaceus: (A) in this patient, the eruption was induced by penicillamine therapy; (B) close-up view of intact blisters, erosions, and crusting. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK Fig. 5.25.Pemphigus foliaceus: (A) in this example, there is a cell-free, subcorneal blister; (B) occasional acantholytic cells are present adjacent to the roof Fig. 5.26.Pemphigus foliaceus: in this example, there is spongiosis resembling a spongiotic dermatitis and only subtle, focal acantholysis Fig. 5.27.Pemphigus foliaceus: in this example, the blister cavity contains numerous neutrophils. Acantholytic cells are conspicuous Fig. 5.28.Brazilian pemphigus foliaceus: this woman with chronic disease shows very severe scaling. Blisters are not apparent. By courtesy of S.A. Pecher, MD, Amazonas, Brazil Fig. 5.29.Brazilian pemphigus foliaceus: in this example of an early lesion, the features of eosinophilic spongiosis are evident Fig. 5.30.Brazilian pemphigus foliaceus: there is superficial dermal edema anda perivascular inflammatory cell infiltrate with conspicuous eosinophils Fig. 5.31.Pemphigus erythematosus: there is scaliness and erythema affecting both cheeks. By courtesy of the Institute of Dermatology, London, UK Fig. 5.32.Pemphigus erythematosus: typical intercellular immunofluorescence with granular staining (IgG) at the basement membrane region. By courtesy B. Bhogal, FIMLS, Institute of Dermatology, London, UK Fig. 5.33.Pemphigus erythematosus: immunoelectron micrograph showing immunoreactant beneath the lamina densa in addition to occupying the intercellular space. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK Fig. 5.34.Paraneoplastic pemphigus: there are numerous erosions and crusted lesions. Courtesy of the Institute of Dermatology, London, UK Fig. 5.35.Paraneoplastic pemphigus: IgG is evident in an intercellular distribution Fig. 5.36.Paraneoplastic pemphigus: this medium-power view shows suprabasal acantholysis and interface change. Note the hyperkeratosis and hypergranulosis. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA Fig. 5.37.Paraneoplastic pemphigus: higher-power view of acantholysis with suprabasal cleft formation. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA Fig. 5.38.Paraneoplastic pemphigus: note the basal cell hydropic degeneration and cytoid bodies. There is an intense lymphohistiocytic infiltrate. A single eosinophil is evident. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA Fig. 5.39.IgA pemphigus: erythematous lesions and an intact vesicle are present. From the slide collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK Fig. 5.40.IgA pemphigus: high-power view showing pus-filled intact blisters and an erosion. From the slide collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK Fig. 5.41 .IgA pemphigus: this biopsy is from the edge of an established blister. Note the heavy inflammatory cell infiltrate and focal acantholysis Fig. 5.42 .IgA pemphigus: the blister cavity contains neutrophils and eosinophils Fig. 5.43 .Hailey-Hailey disease: erythematous and scaly lesions are present in the groin and on the labia majora. From the slide collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK Fig. 5.44 .Hailey-Hailey disease: lesions are most often seen in the flexures as a consequence of friction. By courtesy of the Institute of Dermatology, London, UK Fig. 5.45 .Hailey-Hailey disease: close-up view of keratotic warty lesions. By courtesy of the Institute of Dermatology, London, UK Fig. 5.46 .Hailey-Hailey disease: early lesion showing the characteristic 'dilapidated brick wall' appearance Fig. 5.47 .Hailey-Hailey disease: in this example, there is marked hyperkeratosis, parakeratosis, and acanthosis. Villi project into the blister cavity Fig. 5.48 .Hailey-Hailey disease: in contrast to Darier disease, dyskeratosis is usually minimal or even absent Fig. 5.49 .Darier disease: in this patient, keratotic brown papules are present on the back of the neck. From the slide collection of the late N.P. Smith. MD, the Institute of Dermatology, London, UK Fig. 5.50 .Darier disease: close-up view of keratotic papules. From the slide collection of the late N.P. Smith, MD. the Institute of Dermatology, London, UK Fig. 5.51 .Darier disease: this patient shows a striking symmetrical distribution. From the slide collection of the late N.P. Smith. MD. the Institute of Dermatology London, UK
