Dermatopathology

INFECTIONS AND INFESTATIONS

Warts

Warts are caused by DNA containing papillomavirus. Transmission involves direct contact between individuals, or autoinoculation. Generally, they are self-limited lesions, often regressing spontaneously within six months to two years. The classification includes:

Verruca vulgaris (hands) - white to tan, flat to convex 0.1 to 1.0 cm papules with a rough, pebble-like surface.

Verruca plana (face, dorsal surfaces of hands) - slightly elevated, flat, smooth, tan papules that are generally smaller than V. vulgaris.

Verruca plantaris (sole of foot) and verruca palmaris (palm of hand) - rough, scaly lesions may reach 1 to 2 cm in diameter, coalesce, and be confused with ordinary calluses.

Condyloma acuminatum (venereal) - occurs on the penis, female genitalia, urethra, perianal area, and rectum, may reach several cm's in diameter and are soft, tan and cauliflower like.

Microscopically, the epidermal hyperplasia is often undulating (papillomatous) in character. There is cytoplasmic vacuolization (viral cytopathic effect) that involves the more superficial epidermal layers producing zones of pallor surrounding infected nuclei (koilocytosis). Infected cells can demonstrate prominent condensed keratohyaline granules and jagged eosinophilic intracytoplasmic keratin aggregates as a result of viral cytopathic effects.

A number of descriptive features are present in warts:

Hyperkeratosis - excess keratin formation on the skin surface
Parakeratosis - persistence of cells with keratin on the surface retaining pyknotic nuclei
Acanthosis - an increased thickness of the prickle cell layer of the epidermis, and some areas might show an increase in keratohyaline granules
Spongiosis - intercellular edema of the epidermis
Papillomatosis - finger like elongation of rete ridges
Koilocytosis - enlarged epidermal cells with a pale perinuclear zone
Dyskeratosis - small intracytoplasmic eosinophilic keratohyaline granules are present in layers of the epidermis below the corneal layer

One or more of these features can be present in a variety of infectious and inflammatory conditions of the skin.

Herpetic dermatitis (Herpes simplex virus)

Crops of painful clear vesicles can appear in perineal-genital area (HSV-II) or produce tender lip, tongue, or buccal sores ("Cold sores" from HSV-I). Another pattern produced by herpes zoster (also called varicella zoster virus) is the appearance of painful, clear vesicles on large areas of skin, usually on a dermatomal distribution. This is sometimes called "shingles" and it occurs most often in immunocompromised patients or in the elderly.

Within the lesions on biopsy or cytologic smear are intraepidermal vesicles with dead keratinocytes and multinucleated cells with large nuclei having "inclusions" or at least a change in color of the nucleus on H&E stain (i.e. viral particles inside).

Impetigo

Impetigo is due to bacterial infections (usually Staphylococcus aureus or Group A Streptococcus) of the superficial layers of epidermis of exposed skin (face and hands). It begins as an erythematous macule, but multiple small pustules rapidly supervene. As pustules break, shallow erosions form, covered with drying serum, giving the characteristic clinical appearance of honey-colored crust. If the crust is not removed, new lesions form about the periphery and extensive epidermal damage may ensue. It is mostly seen in children on the face.

The characteristic microscopic feature of impetigo is an accumulation of neutrophils beneath the stratum corneum, often with the formation of a subcorneal pustule. Gram stain reveals the presence of bacteria in these foci. Nonspecific, reactive epidermal alterations and superficial dermal inflammation accompany these findings.

Superficial fungal infections

These are often confined to the stratum corneum, where they are caused primarily by dermatophytes. These organisms grow in the soil and on animals. The genera most often causing dermatophytosis include Epidermophyton, Microsporum, and Trichophyton. The can produce a number of diverse and characteristic clinical lesions according to the area involved:

Tinea capitis (head)
Tinea corporis (body)
Tinea cruris (inguinal areas, "jock itch")
Tinea pedis (athlete's foot)
Tinea versicolor (patchy depigmentation)
Onychomycosis (nails)

Microscopically, fungal cell walls, rich in mucopolysaccharides, stain bright pink to red with PAS stain. A scraping with KOH mount can be utilized to identify these fungi. Involved areas of skin and nails may fluoresce under ultraviolet light. The organisms are present in the anucleate cornified layer of lesional skin, hair, or nails, and scraping of these areas and subsequent culture of organisms will usually produce growth that permits definitive classification of the offending species. Reactive epidermal changes may produce a pattern that mimics a mild eczematous dermatitis.

Bites, mites and infestations

Arthropod bites may be urticarial or inflamed papules and nodules, sometimes with ulceration, that may last for several weeks. Extensive necrosis may result from the bite of the brown recluse spider so that radical, surgical excision of the involved area is often necessary.

Scabies (caused by the mite Sarcoptes scabiei) manifests as burrows under the stratum corneum of the hands, periareolar and genital skin.

These lesions are rarely biopsied, but the classic microscopica appearance of an arthropod bite is a wedge-shaped area of perivascular infiltrate composed of lymphocytes, histiocytes, and eosinophils within the dermis. There may be a central zone of exceedingly focal epidermal necrosis, directly under which birefringent insect mouthparts may be found. In some bites, a primarily urticarial reaction is seen histologically, whereas in others the inflammatory infiltrate is so florid and dense that it may superficially resemble a cutaneous lymphoma. Spongiosis, resulting in intraepidermal blisters, is present in some biopsy specimens, and, in certain settings, insect bites even resemble bullous diseases (i.e: pemphigoid).

Careful correlation with a clinical history of exposure to insects and the gross finding of clustered or linear lesions facilitates the clinicopathologic diagnosis.

COMMON BENIGN LESIONS OF SKIN

Nevus (common acquired)

These are usually pigmented, and are tan to brown, uniformly pigmented, small (<1 cm), areas of elevated skin with well-defined, rounded borders. They may be called papules or "moles". Most Caucasians have at least several of them somewhere.

Nevi are histologically composed of round to oval melanocytes forming either round aggregates (nests), columns, or sheets of cells in the epidermis (junctional nevus), dermis (dermal nevus) or both (compound nevus). Individual nevus cells often have no pigment and have a clear cytoplasm with round nuclei. Nucleoli are not prominent and mitotic activity is absent. Intranuclear "vacuolation" - due to invagination of nuclear membrane may be seen. The presence of nevus cells at the dermal-epidermal junction is called "junctional activity". Nevus cell nests can be separated by connective tissue.

"Dysplastic" nevi and the "Dysplastic nevus syndrome"

Patients with the "Dysplastic nevus syndrome" have several dozens to hundreds of melanocytic nevi, predominantely on the trunk and upper extremities. One of the most striking features of dysplastic nevi is their heterogeneity, with great variation in size, shape, and color. Patients with these findings have an increased risk of developing malignant melanoma. Patients with this condition must be vigilant in examining for suspicious changes in any of these nevi.

By light microscopy, dysplastic nevi have the basic features of common nevi but in addition have unusual (or "atypical") microscopic features as seen at low magnification ("architectural" atypia) or at the cellular level ("cytologic" atypia).

Atypical melanocytic hyperplasia, high power microscopic.

Variations in Pigmentation

The amount of pigment in the skin is determined genetically and varies among the various races of humans. The amount of melanin pigment will increase with exposure to sunlight (tanning). An exaggerated increase in pigmentation is seen in some fair-skinned persons, particularly those with red hair, and is known as freckling. The aging process may bring about the appearance of lesions called senile lentigenes. A lentigo senilis is better known as an "age spot" or "liver spot" and is most often observed on the dorsa of the hands. The loss of skin pigmentation is known as vitiligo, and it can appear in a variety of areas. None of these disorders has a great significance other than cosmetic appearance.

It has been common for thousands of years for humans to decorate their bodies with tattoos. Tattooing is the process of introducing an inert pigmented material into the dermis, generally with a sharp instrument such as a needle, where it remains indefinitely. In many human cultures, the tattoos have great significance for both the individual and the group to which he or she belongs.

There are a variety of colors possible, based upon the pigment used, including India ink (black), mercuric oxide (red), cobalt salts (dark blue), manganese salts (light blue), cadmium salts (yellow), chromium salts (green), and titanium dioxide (white). Over time, the colors fade a bit and the sharp borders tend to blur as dermal macrophages engulf and move the pigment particles off via lymphatics to regional lymph nodes. Histologically, pigment appears in small clumps in the papillary and reticular dermis. Rarely, there is a photosensitivity reaction to the colors other than blue or black.

Tattoo pigment is difficult to remove. A small tattoo may be removed by simply making a skin excision. Larger tattoos cannot be excised. Dermabrasion, a process of progressively abrading the epithelium to expose upper dermis and remove the pigment, after which a chemical such as tannic acid is applied to increase inflammation and pigment extrusion, is one arduous process that is complicated by residual scarring. The pigment may also be removed by laser light that vaporizes the pigment granules, but this is also a painstaking process, albeit with minimal scarring, though there may be persistent changes in skin color and texture at the site of removal. Of course, an original tattoo may be revised with a "coverup" tattoo, rather than removing it.

Seborrheic keratosis (SK)

SK's are round, flat, coinlike plaques that vary in diameter from mm to several cm's. They most often occur on middle aged to older individuals. They have a uniformly tan to dark brown in color and usually show a velvety to granular surface. These "stuck on" lesions typically occur on the trunk, extremities, head, and neck. SK's will slowly enlarge and/or increase in number over the years.

Examination of the lesion microscopically will demonstrate an abrupt area of hyperkeratosis, acanthosis, focal hypergranulosis, and papillomatosis appears adjacent to normal epidermis. Squamous and basaloid cells resembling normal epidermal basal cells constitute the bulk of the lesion. Variable melanin pigmentation within basaloid cells is seen as well as pseudo-horn (keratin) cysts.

Fibroepithelial polyp ("skin tag")

This is one of the most common skin lesions seen in middle-aged to older adults. They can be found on the neck, trunk, face, and intertriginous areas as a soft, flesh-colored, baglike tumor attached to the skin surface by a small slender stalk.

Histologically, there is a fibrovascular core covered by benign squamous epithelium.

Keloid

Normal wound healing in response to injury produces a scar. A keloid is an exaggerated response to injury that produces abundant collagenous soft tissue, forming a large nodular scar. This is more likely to occur in dark-skinned persons. They must be excised carefully, avoiding excessive injury, or the same process will recur.

Histologically, keloids are composed of dense bundles of collagen in the dermis.

Acne (non-inflammatory and inflammatory)

This is a problem mainly seen in adolescents and young adults, and it affects mainly the face, upper chest, and upper back. The most common lesion is the "comedo" that involve hair follicles. There are open and closed comedones. An open comedone consists of a distended hair follicle containing a central black keratin plug. This color is due to oxidation of melanin pigment (not dirt). Closed comedones are plugged follicles without a visible central opening. Closed comedones often rupture into the dermis which is followed by inflammation. Inflammatory acne is characterized by erythematous papules, nodules, and pustules.

There is an expanding mass of lipid and keratin within the midportion of the hair follicle seen microscopically. With gradual expansion, the follicle becomes dilated and the follicular epithelium and sebaceous glands atrophy. Inflammation is variable.

Epidermal inclusion cyst (EIC)

The EIC is a subcutaneous, well-circumscribed, firm, and often movable, fluctuant nodule. Sometimes they are incorrectly called "sebaceous cysts" because they are fluctuant. When large, they may be dome-shaped and flesh-colored. They very slowly enlarge and are generally not painful unless traumatically ruptured to elicit a severe inflammatory reaction and often become painful.

A clinically similar lesion seen on the scalp is called a pilar cyst.

Seen on excisional biopsy is a cyst wall lined by epidermis which may contain skin appendages. It is filled with laminated strands of keratin. The pilar cyst lacks a granular layer and is filled with more amorphous material. If ruptured, the keratinaceous debris will be extruded into the surrounding connective tissue and provoke an intense acute and chronic inflammatory reaction that may include foamy macrophages, "cholesterol clefts", and foreign body giant cells in response to the keratin.

Epidermal inclusion cyst, medium power microscopic.

NEOPLASMS OF THE DERMIS

Dermatofibroma

These are tan to brown, firm papules. They are asymptomatic to slightly tender, and their size may increase and decrease slightly over time. They may reach several centimeters. They dimple inward upon lateral compression (nodular melanomas protrude outward when similarly manipulated).

Histologically, the dermatofibroma is composed of benign, spindle-shaped fibroblasts arranged in an ill-defined, non-encapsulated mass within the mid-dermis, with a pushing border into the subcutaneous fat. The overlying epidermis often undergoes hyperplasia with downward elongation of hyperpigmented rete ridges.

Neurofibroma

These firm nodules may be solitary and sporadic or multiple and part of von Recklinghausen's disease (neurofibromatosis). There may be overlying hyperpigmentation. With neurofibromatosis, an autosomal dominant condition, there can be multiple cafe-au-lait spots (six or more pale brown pigmented macules each more than 1.5 cm in size).

Microscopically, they are well defined but non-encapsulated masses that are composed of wavy spindle cells with a lot of intervening collagen.

Hemangioma

A hemangioma is a benign neoplasm of blood vessels. Hemangiomas can be variable in size from a few millimeters up to several centimeters in diameter. Characteristically, they are bright red to blue, usually level with the surface of the skin, or slightly elevated. A hemangioma can be a congenital benign neoplasm but may cause serious problems if it is large and poorly resectable.

Histologically, the lesion is usually well defined but unencapsulated. The epidermis above the lesion may show areas of hyperkeratosis with parakeratosis, while in other regions the epidermis appears atrophic. The neoplasm is made up of closely packed aggregations of thin-walled capillaries lined by flattened endothelial cells, usually blood-filled, separated by scant connective tissue stroma. The vascular lumina may be partially or completely thrombosed and organized.

There are two main types of hemangiomata:

Capillary hemangioma: Multiple small endothelially lined spaces are present. The lumina are small and some even collapsed. The connective tissue in between the vessels is loose connective tissue that may contain larger arterioles and venules.
Cavernous hemangioma: The vascular spaces in this type of lesion are very large and dilated, congested with RBC's. The proliferating vascular structures sometimes extend into the subcutaneous adipose tissue to stimulate an invasive tumor.

Kaposi's sarcoma (KS)

KS represents a spectrum of lesions consisting of red-purple coalescent patches, plaques, and/or nodules. The earliest lesions may at first resemble a petechia or may be a red papulonodule. As the lesions enlarge, spongy nodular tumors arise measuring 7 cm or more in diameter.

There are several forms of KS, but the most common nowadays is the "epidemic" form associated with human immunodeficiency virus (HIV) infection. A diagnosis of KS in a patient infected with HIV defines AIDS. KS is far more common in homosexual males than in any other risk group for AIDS. KS is now known to be associated with infection by a herpeslike virus (human herpesvirus-8).

Pathology: KS may be extremely difficult to diagnose histologically. There is formation of irregular and angulated spaces lined by flattened and elongated endothelial cells in close proximity to normal vessels of the superficial dermis and periadnexal connective tissue. In fully developed lesions, there are numerous bland-appearing spindle cells insidiously infiltrating collagen bundles. In some areas these cells form slitlike spaces that may contain rows of red blood cells characteristically arranged in a "boxcar" pattern. Mitoses are common. Individual endothelial cells may contain minute, round, pink cytoplasmic globules.

PREMALIGNANT AND MALIGNANT NEOPLASMS OF THE EPIDERMIS

Actinic keratosis

These lesions are usually less than 1 cm in diameter, are tan-brown to red or skin-colored, and they have a rough, sandpaper-like consistency. Some lesions may produce so much keratin that a "cutaneous horn" develops. Skin sites commonly involved by sun exposure (face, arms, dorsum of hands) are most frequently affected.

On biopsy, the cytologic atypia is first seen in the lowermost layers of the epidermis and may be associated with hyperplasia of basal cells or early atrophy which results in diffuse thinning of the epidermal surface. The dermis contains thickened, blue-gray, abnormal elastic fibers ("elastosis"), the result of years of sun exposure. The stratum corneum is thickened with parakeratosis. An actinic keratosis may be a precursor lesion to squamous cell carcinoma.

Squamous cell carcinoma

This is the most common neoplasm that arises on sun-exposed skin sites of older people. These lesions appear as sharply defined, red scaling plaques (in situ carcinoma) or as nodular, hyperkeratotic, ulcerated lesions (invasive carcinoma). When mucosa is involved, a zone of white thickening is seen, and is referred to clinically as leukoplakia.

Histologically, highly atypical cells are found at all levels of the epidermis. When these cells break through the basement membrane, the lesion has become invasive. Invasive SCC shows variable differentiation, ranging from tumors formed by polygonal cells arranged in orderly lobules and exhibiting numerous large zones of keratinization (squamous pearls) to neoplasms formed by highly anaplastic, rounded cells with foci of necrosis and only abortive, single-cell keratinization (dyskeratosis). These tumors possess a low, but significant, potential for metastasis (<5%).

Keratoacanthoma

A keratoacanthoma (KA) is a flesh-colored, dome-shaped nodule with a central, keratin-filled plug, imparting a crater-like topography. The lesions can vary in size from 1 cm to several cm's. They have a predilection for appearance on the cheeks, nose, ears, and dorsa of hands. They can develop rapidly, reaching a maximum size in 3 to 6 weeks, and can mimic squamous cell carcinoma. However, a KA heals spontaneously, without treatment, and disappears. Most patients with a KA are Caucasians (males > females) over 50 years of age.

There is a central, keratin-filled crater, surrounded by proliferating epithelial cells that extend upward in a liplike fashion over the sides of the crater and downward into the dermis as irregular tongues or nests of squamous cells. The epithelium is composed of enlarged, often cytologically atypical, cells that have a characteristically "glassy" eosinophilic cytoplasm and produce keratin abruptly (without the development of an intervening granular cell layer).

Basal cell carcinoma (also called basal cell epithelioma)

A basal cell carcinoma is a common, slow-growing tumor that rarely metastasizes. These lesions can occur at sites subject to chronic sun exposure and in lightly pigmented people. They present as pearly papules often containing prominent, dilated subepidermal blood vessels (telangiectasias). Some contain melanin pigment and appear similar to nevi or melanomas. Advanced lesions may ulcerate, and extensive local invasion of facial tissues, including bone may occur (hence the old term "rodent ulcer" for this kind of carcinoma).

Histologically, the neoplastic cells resemble those in the normal basal cell layer of the epidermis growing as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix and often surrounded by a fibroproliferative dermal response. The cells forming the periphery of the tumor islands tend to arrange themselves radially with their long axes in a parallel alignment ("palisading"). The tumor cells arise from the basal layer of the epidermis or follicular epithelium and do not occur on mucosal surfaces. Multiple patterns are seen ranging from multifocal growths originating from the epidermis and extending over several square centimeters or more of skin surface, to nodular lesions growing downward deeply into the dermis.

Malignant melanoma

Multiple factors play a role in development of this lesion (mainly sun exposure, but pre-existing dysplastic nevi, heredity, and carcinogen exposure) can also be factors. Four different clinico-pathologic variants of malignant melanoma are recognized:

Superficial spreading
Acral-lentiginous
Lentigo maligna
Nodular

ABC's of melanoma:

A= Asymmetry of lesion
B= Border Irregularity
C= Color change (red, white, blue and black)

The microscopic examination of pigmented lesions is very important. Melanoma cells are usually considerably larger than nevus cells. They contain large nuclei with irregular contours having chromatin characteristically clumped at the periphery of the nuclear membrane and prominent red (eosinophilic) nucleoli. All melanomas start as "In Situ" lesions, involving only the epidermis. At this stage melanoma cells grow as poorly formed nests or as individual cells at the dermo-epidermal junction. With time, cells spread upward to involve all layers of the epidermis ("epidermal tropism", or "Pagetoid spread"). As melanoma cells expand laterally (so called "radial growth phase"), the area of involved skin enlarges. Eventually, melanoma cells invade the dermis and the so-called "vertical growth phase" begins (which indicates the progression from "in-situ" to "invasive" melanoma).

Staging Criteria

Depth of invasion is the most important factor that determines the biologic behavior (prognosis) of a melanoma. Therefore, accurate measurement of resected melanoma lesions must be performed by the pathologist. There are two methods of evaluating depth:

Clark's Levels:

With an H&E stained slide, the depth of penetration of the melanoma is assessed according to the histologic structures involved. Prognosis based on the Clark level is well known:

Clark's Levels	Criteria	% Disease-free at 5 years
Level I	Melanoma cells still confined to epidermis (i.e: in-situ)	100%
Level II	Melanoma cells present in the papillary dermis	100%
Level III	Melanoma cells filling completely the papillary dermis	88%
Level IV	Melanoma cells invading the reticular dermis	66%
Level V	Melanoma cells invading the adipose tissue	15%

Breslow's Micrometric Measurement:

With the aid of an ocular micrometer a measurement (in mm) of the depth of invasion is recorded from the granular layer to the deepest invading melanoma cell. Prognosis based on thickness is well known:

Breslow's thickness	5 year disease-free	Risk
Less than 0.75 mm	98%	low risk
0.75 - 1.5 mm	50-90%	intermediate risk
More than 1.5 mm	50%	high risk

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