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304 North Cardinal St.
Dorchester Center, MA 02124
The skin is commonly affected by a wide range of pathologies. Some of these are cutaneous manifestations of systemic disease processes whilst others are primary disorders of the skin. Common systemic viral illnesses such as measles and chickenpox are associated with characteristic skin rashes and many autoimmune and vasculitic disorders, such as systemic lupus erythematosus, dermatomyositis, scleroderma and Henoch–Schönlein purpura, present with skin manifestations. Primary disorders of the skin are extremely common and the vast majority of these are inflammatory or neoplastic in type.
Skin has a limited repertoire of responses to injury. The most common of these are illustrated in Figs 21.1 to 21.4 . Most stimuli result in a combination of these changes, each with varying degrees of severity. As a result, definitive diagnosis of inflammatory dermatological conditions requires careful correlation of clinical and histological findings. Few skin conditions have pathognomonic histological appearances.
Dermatitis is a common clinical term used to describe a wide variety of inflammatory skin conditions with diverse causes. Histologically, there are changes of acute or chronic inflammation ( Figs 21.5 and 21.6 ). Some disorders have additional histological features that may indicate a more specific diagnosis or aetiology. Two relatively common inflammatory dermatoses with characteristic clinical and microscopic features are lichen planus ( Fig. 21.7 ) and psoriasis ( Fig. 21.8 ).
Systemic viral infections frequently cause skin rashes, some of which have typical histological features, e.g. herpes simplex virus (HSV) infection (see Fig. 5.12 ), chickenpox and shingles. The latter two disorders are different clinical manifestations of infection by the herpes zoster virus and the histological changes closely resemble those of HSV infection. Other viruses give rise to apparently localised skin lesions by causing proliferation of the cells of the epidermis. Common examples include viral warts ( Fig. 21.9 ), which are caused by human papillomavirus infection (see also Ch. 17 ), and molluscum contagiosum ( Fig. 21.10 ), which is due to infection by a poxvirus.
DP dermal papillae G granular layer H hyperkeratosis K keratin O oedema P parakeratosis RP rete peg S stratum spinosum
A acanthosis C chronic inflammation CB Civatte bodies D upper dermis DC dilated capillary DP dermal papilla E epidermis F fluid G granular layer H hyperkeratosis I inflammatory cells M microabscess P pustule PK parakeratosis R rete peg S spongiosis V vesicle
D dermis E epidermis G granular layer H hyperkeratosis K keratin plug N keratin nest P pit PS parakeratotic spires V viral inclusion bodies
Common primary skin tumours may be divided broadly into those arising from epithelial cells, those arising from melanocytes and those arising within dermal and subcutaneous tissues. Much less commonly, skin can be involved by metastatic tumour from other sites (e.g. lung or renal cancer) or by direct invasion from an underlying neoplasm (most commonly breast cancer). Lymphoma may also affect the skin either primarily (e.g. mycosis fungoides , see Fig. 16.11 ) or in cases of systemic lymphoma.
Seborrhoeic keratosis and basal cell papilloma are terms used interchangeably to describe a very common benign skin lesion seen predominantly in elderly patients. Basal cell carcinoma is a low-grade malignant tumour that resembles the basal cells of the epidermis; squamous cell carcinoma is a more aggressive tumour that resembles the cells of the prickle cell layer (stratum spinosum) of the epidermis. Both of these malignant tumours are strongly associated with chronic sun exposure. Chronic sun damage is also associated with premalignant change in the skin in the form of epidermal dysplasia , with disordered maturation of keratinocytes. Severe dysplasia, the skin equivalent of CIN 3 (see Fig. 17.7 ), can be described as carcinoma in situ , intra-epidermal carcinoma or using the eponymous term Bowen’s disease . Lesser degrees of epidermal dysplasia are termed actinic or solar keratosis .
BM basement membrane D dermis K keratin MC microcystic pattern N nodular pattern P palisading cells TM tripolar mitosis S subcutaneous fat
In normal skin, melanocytes are scattered in the basal layers of the epidermis, their fine cytoplasmic processes ramifying between the keratinocytes towards the skin surface ( E-Fig. 21.10 ). Melanocytes are responsible for the synthesis of the brown pigment melanin, which is then transferred to adjacent keratinocytes. There are significant racial and genetic differences in the melanin synthetic activity of melanocytes, resulting in the varying degrees of normal pigmentation seen in the skin. Exposure to sunlight enhances melanin synthesis and transfer into keratinocytes.
Benign pigmented skin lesions are very common and are known colloquially as ‘moles’. This term encompasses a large group of benign lesions called naevi , which are characterised histologically by aggregates of melanocytic cells at various sites within the skin. The three main subtypes, junctional , compound and intradermal naevi , are shown in Fig. 21.15 .
Malignant melanoma is an important and highly malignant tumour of melanocytic cells. Its main features and histological variants are illustrated in Figs 21.16 to 21.19 . There are also melanocytic lesions with features intermediate between a benign naevus and a malignant melanoma. These are described as atypical or dysplastic naevi and may progress to melanoma in some cases.
These are of three main types, defined according to the location of the melanocytic nests:
Junctional melanocytic naevus: Nests of melanocytes are confined to the lower epidermis.
Compound melanocytic naevus: Nests are located in both the lower epidermis and upper dermis.
Intradermal melanocytic naevus: Nests of melanocytes are present in the dermis only.
Benign naevi ( E-Fig. 21.11 ) have a predictable natural history and are illustrated in Fig. 21.15 . Most begin as flat, pigmented junctional naevi , with nests of pigmented melanocytes confined to the lower levels of the epidermis, sitting on the epidermal basement membrane. Purely junctional naevi are most commonly found in children. As the child grows older, some of these junctional melanocytes migrate across the basement membrane into the upper dermis where they lose most of their pigment and the cells become smaller and tightly packed together. There are some remaining pigmented junctional nests in the epidermis and smaller non-pigmented naevus cells in the dermis. At this stage, the naevus is called a compound naevus and the intradermal nests produce a lesion that is raised above the level of skin to form a brown, raised nodule. In early adulthood, most of the junctional nests of melanocytes migrate into the dermis until no more are present in the epidermis. At this stage, the naevus is a completely intradermal naevus . All of these lesions are completely benign but, rarely, a previously benign naevus will transform into a malignant melanoma. This usually occurs by a well recognised route: the junctional nests do not completely migrate into the dermis but proliferate abnormally and show features of cytological and architectural atypia, producing a dysplastic or atypical naevus . If untreated, a proportion of these eventually become superficial spreading malignant melanoma ( Figs 21.16 and 21.17 )
Malignant melanoma ( E-Fig. 21.12 G ) is a malignant tumour of melanocytes, the incidence of which is increasing dramatically in white-skinned people around the world. Excessive sun exposure, particularly sunburning, is believed to be the principal cause. Neglected malignant melanomas have frequently metastasised at the time of presentation, but public awareness is leading to patients presenting earlier, such that many malignant melanomas may now be completely cured by primary excision of the lesion. Malignant melanoma spreads initially via lymphatics to regional lymph nodes and subsequently via the blood-stream, by which time control of the disease is extremely difficult.
AM atypical melanocyte nests B bridging melanocyte nests F fibroplasia H melanophages J junctional nest N intradermal nest SM single melanocytes
The risk of metastasis, and therefore the prognosis, depends mainly on the following factors:
Melanoma in situ indicates that tumour cells have not breached the basement membrane. This indicates that the lesion lacks any metastatic potential and so excision is curative.
Breslow depth is one of the main prognostic indicators in melanoma. This is measured perpendicularly from the granular cell layer of the epidermis down to the deepest invasive tumour cell. Lesions with a Breslow depth of less than 1 mm have an excellent prognosis.
Clark level is an alternative means of assessing the extent of tumour invasion and is most valuable in lesions less than 1 mm in depth. This system identifies the deepest anatomical layer of the skin that is involved, e.g. Clark level 2 indicates that the tumour is limited to the papillary dermis, whilst Clark level 5 describes invasion of subcutaneous tissues.
Radial growth phase describes a lesion with predominantly horizontal (lateral) growth and without evidence of deep dermal infiltration. This pattern of growth is associated with a relatively favourable prognosis and is typically seen early in the development of the superficial spreading form of malignant melanoma. This is one of the common subtypes encountered in clinical practice ( Figs 21.16 and 21.17 ).
Vertical growth phase , in contrast, indicates that the malignant cells show predominantly vertical growth, invading deeper into the dermis. This is typical of nodular malignant melanoma and is associated with an adverse prognosis ( Fig. 21.18 ).
When present, these histological features indicate an adverse prognosis and are associated with a high risk of lymph node and distant metastases.
Other subtypes of melanoma include lentigo maligna (a pre-invasive form of the disease that occurs in sun-damaged skin of older patients, illustrated in Fig. 21.19 ), invasive lentigo maligna melanoma (the invasive form of the same disorder) and acral lentiginous malignant melanoma, which, as the name suggests, occurs at acral sites (sites with thick skin such as the palms and soles). This lesion is uncommon in white-skinned populations, but occurs with relatively greater frequency in black populations owing to the presence of lesser quantities of protective melanin pigment at these sites.
Malignant melanoma usually presents as a new or changing pigmented lesion. On examination, the edge of the lesion is often irregular and rather ill-defined, whilst benign naevi tend to be round and uniform with a sharply defined border. Naevi also tend to be evenly pigmented whereas melanomas typically exhibit variable pigmentation, often with several different shades of black and brown. More advanced tumours can have nodular areas and sometimes show surface ulceration because the expanding mass of tumour cells destroys the overlying epidermis. Occasional lesions are not pigmented and these are termed amelanotic melanomas . These tumours are more difficult to recognise and may be confused with other lesions such as intradermal naevi and basal cell carcinomas. Complete excision is the initial treatment of choice in cases of melanoma.
Management of malignant melanoma is challenging as the disease often responds quite poorly to conventional chemotherapy. Newer drug treatments have been developed that are designed to target specific drivers of tumour growth whilst avoiding effects on normal tissues. An important example is testing for BRAF v600e and v600k mutations as these predict disease response to BRAF inhibitor drugs. In many centres, all cases of locally advanced or metastatic melanoma are tested for these mutations at the point of diagnosis in order to guide patient treatment.
Immunotherapy is also evolving, based upon developments in our understanding of immune tolerance and the key role of PD-1/PD-L1 in a range of tumour types, including non–small cell lung cancer (see Ch. 12 ) and melanoma. PD-L1 has a role in allowing some tumour cells to avoid immune surveillance (so-called immune escape ). New drug treatments are available that can block this pathway and therefore allow the patient’s own immune system to target tumour cells.
Some melanomas harbour mutations in c-KIT (see Fig.13.14 ) and treatment with tyrosine kinase inhibitor drugs such as imatinib may have a role. Pathologists have a key role in determining which patients will benefit from these new treatment options.
Some common skin lesions are difficult to classify because their aetiologies are incompletely understood. Examples include the various cysts commonly referred to as ‘sebaceous cysts’ by clinicians. Common skin cysts fall into two main categories histologically, epidermoid cysts ( Fig. 21.20 ) and pilar cysts ( Fig. 21.21 ). Other lesions such as the pyogenic granuloma ( Fig. 21.22 ) and dermatofibroma ( Fig. 21.23 ) share some features with benign neoplasms, but are considered by others to be reactive proliferations, often occurring after minor injury. Dermatofibrosarcoma protuberans ( Fig. 21.24 ) shows some histological similarities to dermatofibroma, but as the name suggests, this is a malignant soft tissue neoplasm (a sarcoma). Other soft tissue lesions are considered in Ch. 22 .
AM atypical melanocytes D dermis E epithelium G granular layer H hair follicle I inflammatory cells K keratin M melanophages
C collarette of proliferating epidermis E epidermis Ep lining epithelium Ex inflammatory exudate K keratin P basal layer pigmentation V vascular tissue
|Responses of skin to injury|
|Orthokeratosis||Thickened layer of normal keratin. No nuclear fragments. Often associated prominence of granular layer (hypergranulosis).||21.1B|
|Parakeratosis||Abnormal surface keratin with residual flecks of nuclear material. Often associated with loss or diminution of granular layer.||21.1C|
|Acanthosis||Thickening of epidermis, usually associated with increased depth of the rete pegs.||21.2|
|Spongiosis||Intra-epidermal oedema due to acute inflammation, resulting in gaps between keratinocytes and highlighting intercellular junctions.||21.3|
|Vesicle||Small accumulation of oedema fluid within epidermis due to acute inflammation, sometimes containing a few inflammatory cells.||21.4A|
|Bulla||Large collection of fluid within or beneath epidermis, sometimes containing inflammatory cells and fibrin.||21.4B|
|Pustule||Collection of neutrophil polymorphs and some fluid within or beneath the epidermis. May be subcorneal, intra-epidermal or subepidermal.||21.4C|
|Acute dermatitis ( E-Fig. 21.3 G )||Intra-epidermal oedema resulting in spongiosis and vesiculation. Some inflammatory cells in epidermis. Later, chronic inflammation in dermis.||21.5|
|Chronic dermatitis ( E-Fig. 21.4 G )||Acanthosis and hyperkeratosis with chronic inflammation around vessels in superficial dermis.||21.6|
|Lichen planus||Irregular acanthosis with chronic inflammation blurring dermo-epidermal junction. Basal cell vacuolar damage and apoptotic keratinocytes.||21.7|
|Psoriasis ( E-Fig. 21.5 G )||Regular acanthosis with thinning of suprapapillary epidermis and dilated capillaries in oedematous papillary dermis. Munro micro-abscesses.||21.8|
|Viral wart (verruca vulgaris)||Exophytic papillary lesion of epidermis with parakeratotic spires, hypergranulosis and occasional koilocytic cells. HPV infection.||21.9|
|Molluscum contagiosum||Inverted lobules of proliferating epithelium with viral inclusions (molluscum bodies) and a central plug of keratin. Poxvirus infection.||21.10|
|Seborrhoeic keratosis (basal cell papilloma) ( E-Fig. 21.6 G )||Benign proliferation of bland cells resembling basal cells of epidermis. Hyperkeratosis and nests of keratin. Usually exophytic.||21.11|
|Basal cell carcinoma ( E-Figs 21.7 G and 21.8 G )||Low grade malignant tumour. Small, hyperchromatic cells resembling basal cells of epidermis. Peripheral palisading. Mitotic. Various patterns.||21.12|
|Squamous cell carcinoma ( E-Fig. 21.9 G )||More aggressive than BCC. Larger cells with eosinophilic cytoplasm. Keratinisation. May arise from carcinoma in situ (Bowen’s disease).||21.13|
|Intra-epidermal carcinoma (carcinoma in situ, Bowen’s)||Full thickness dysplasia of epidermis. Disordered architecture and cytological atypia. Basement membrane intact.||21.14|
|Actinic keratosis (solar keratosis)||Mild to moderate epidermal dysplasia. Associated with chronic sun damage.|
|Junctional naevus||Nests of uniform and bland pigmented melanocytic cells at dermo-epidermal junction. No naevus cells in dermis.||21.15A|
|Compound naevus ( E-Fig. 21.11 )||Nests of naevus cells at dermo-epidermal junction and in dermis. Dermal nests smaller, less pigmented and showing maturation.||21.15B|
|Intradermal naevus||No remaining junctional melanocyte nests. Mature naevus cells only within dermis.||21.15C|
|Atypical naevus (dysplastic naevus)||Cytological and architectural atypia of melanocyte nests. Often more spindle- shaped cells and superficial desmoplasia.||21.15D|
|Superficial spreading malignant melanoma in situ||Nests of severely atypical melanocytes with Pagetoid spread of single cells within epidermis. Basement membrane remains intact.||21.16|
|Invasive superficial spreading malignant melanoma ( E-Fig. 21.12 G )||Atypical melanocytes in epidermis and also invading into dermis. Breslow depth and Clark level important for prognosis.||21.17|
|Nodular malignant melanoma||Tumour in vertical growth phase with nodule of tumour cells in dermis and minimal junctional activity. Adverse prognosis due to lesional depth.||21.18|
|Lentigo maligna||Form of melanoma in situ found on face of elderly patients. Linear proliferation of atypical melanocytes at dermo-epidermal junction.||21.19|
|Lentigo maligna melanoma||Invasive malignant melanoma arising from long-standing lentigo maligna. Often nodule forms within flat, pigmented patch.|
|Epidermoid cyst (epidermal cyst)||Clinical term sebaceous cyst. Cyst filled with lamellated keratin. Lined by stratified squamous epithelium. Granular layer present.||21.20|
|Pilar cyst (tricholemmal cyst)||Clinical term sebaceous cyst. Usually scalp. Firm, amorphous keratin. Squamous lining without granular layer.||21.21|
|Pyogenic granuloma (lobular capillary haemangioma)||Often after minor penetrating injury. Lobules of capillary size vessels. Collarette of epidermis at base.||21.22|
|Dermatofibroma (benign fibrous histiocytoma) ( E-Fig. 21.13 G )||Probably reactive lesion. Fibroblasts and collagen, ill-defined edge. Scattered histiocytes. Overlying epidermal hyperplasia.||21.23|
|Dermatofibrosarcoma protuberans||Low-grade sarcoma of skin. Resembles dermatofibroma but deeply invasive and locally aggressive. May rarely metastasise.||21.24|