STRUCTURE OF SKIN, HISTOPATHOLOGIC REACTION PATTERNS,

BASIC CUTANEOUS HISTOPATHOLOGY

ABDUL-GHANI KIBBI, MD

I. INTRODUCTION:

Dermatologists have a relatively unique opportunity to study, with ease, the clinical
and pathologic correlations of disease. With the naked eye, a disease process can be
clinically observed through its course without need of special techniques such as
intubation or use of X-rays. The skin biopsy technique is fast, simple, and done at
little inconvenience to the patient. The entire spectrum of the disease process can be
correlated clinically and pathologically.

In this lecture an attempt will be made to group dermatologic diseases according to

several characteristic histologic patterns occurring in the course of pathologic
reactions or according to pathogenesis. As the patterns and the pathologic processes
that they reflect are described, specific diseases will be discussed to illustrate the
appropriate pathologic reaction. This discussion of histologic patterns, or "reaction
patterns" will begin with those affecting the most superficial layers of the skin and
continue sequentially through the various layers to the deepest portion, the
subcutaneous fat, and will thus present a guided tour of clinicopathologic reactions in
the skin. These clinicopathologic reactions will be grouped according to the clinical
classification of lesions which emphasizes the component of the skin primarily
affected.

II. Anatomic Features important in the Study of the Pathology of the Skin:

The outer portion of the skin, the epidermis, is a stratified squamous epithelium, with
each layer recognizable. The outer layer is the horny layer, or stratum corneum, made
up of biologically dead, but functionally mature, fully keratinized cells. It usually has
an appearance of faintly woven, thick fibers lying parallel to the surface. Beneath the
horny layer, in sequential order, are the granular layer, one-to-three cells thick; the
squamous cell layer, several cells thick, made up of polygonal cells; and, finally, the
basal layer made up of a single row of basal cells that are cuboidal. the epidermal
cells, or keratinocytes, all connect to each other by intercellular bridges, called also
prickles. These prickles are most obvious in the squamous cell layer, which is
therefore also known as the prickle cell layer. Scattered among the basal cells are the
melanocytes, or pigment-forming cells, which, by light microscopy, have an
apparently clear cytoplasm with a dark staining nucleus.

The epidermis sits upon a basal lamina. Basal cells attach to this structure by half-
desmosomes. The basal lamina separates the epithelium from the connective tissue,
or dermis, below. Over much of the body surface, the epidermis, in its lower portions,
forms rete ridges that insert into the upper layer of the dermis. In histologic section of
the skin that are two-dimensional, the rete ridges appear as downward-pointing ridges
that interdigitate with the upper layer of the dermis. The dermal insertions are called
papillae.

The dermis is composed of two layers, the papillary, or the upper, and the reticular, or
the lower. The dermis rests upon subcutaneous fat, which is made up of lobules of
fatty tissue separated by fine fibrous septae that appear continuous with the collagen
of the reticular layer. The fatty tissues irregularly interdigitate with the reticular layer,
especially around the coils of the eccrine glands and the hair follicles.

The upper, or papillary, layer is made up primarily of fine bundles of collagen that lie
in haphazard arrangement and an admixture of reticulum fibers and elastic fibers.

The reticular, or lower, layer consists of dense bundles of collagen organized in

interlacing fashion admixed with thick elastic fibers. (Leather is derived from the
reticular layer of the dermis of animals).

Each dermal papilla is drained by a capillary-venule system. Each venule continues

into a plexus of venules, the superficial venular plexus, that lies parallel to the long
axis of the skin. This plexus lies more or less at the junction of the papillary and
reticular layers of the dermis. The epidermis, papillary layer of the dermis, capillary-
venule system and superficial venular plexus form together a "reactive unit", the "site
of action" of diseases which principally affect the skin, such as psoriasis, or warts, or
seborrheic dermatitis. On the other hand, the reticular layer of the dermis is the "site
of action" of systemic diseases that affect the skin, such as scleroderma. Thus, an
easy rule-of-thumb is that pathological reactions of a principally cutaneous nature
generally occur at or above the superficial venular plexus, whereas pathological
reactions resulting from systemic causes generally affect the reticular layer of the
dermis.

III. Disorders in which the epidermis is primarily affected:

A. Diseases of the keratinocyte and keratinization:

These disorders are grouped together because they demonstrate, histologically,

abnormalities of the keratinocyte or its end-product, keratin. In disorders of
keratinization, the histological abnormality may be slight and consist of only
increased thickness of the horny layer (hyperkeratosis), as in the various forms of
ichthyosis. In other lesions of the keratinocytes, the pathologic changes may consist
of the formation of vesicles in the epidermis. The intraepidermal vesicles may be
caused by the inability of the keratinocytes to adhere to one another. This change is
known as acantholysis and is typified by pemhigus vulgaris.

Other disorders are the result of more than one abnormality of the keratinocyte. For
example, acute eczema is characterized by epidermal hyperplasia and intraepidermal
vesicle formation due to intercellular fluid accumulation (spongiosis); However, the
chronic forms of eczema typically demonstrate only hyperkeratosis and hyperplasia.

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1. Hyperkeratosis-Ichthyosis Vulgaris:

a. Clinical Manifestations:

Ichthyosis vulgaris is a heritable disease transmitted as an autosomal dominant

trait. It usually begins between the first and fourth year of life but may occur
in adulthood. It produces fine, at times fish-like, scaling of the skin especially
over the extensor or the horny layer of the palms and soles, and results in in-
creased skin markings. The rate of turnover of the epidermal cells is slower
than normal. The disease may be related to impaired shedding of keratin.

b. Histopathology:

The histopathologic changes of ichthyosis vulgaris consist of thickening of the

stratum corneum. The thickened horny layer is densely compacted and it
stains
brightly eosinophilic. The granular layer is decreased in thickness or absent.
The rest of the epidermis may be normal or the rete ridges may be flattened.

2. Blistering Disorders:

a. Blistering disorders caused by acantholysis - Pemphigus vulgaris.

Pemphigus vulgaris describes a blistering disorder in which cells in the

epidermis become acantholytic. Pemphigus comes from the Greek word
for blister, "Pemphyx". Acantholysis refers to the light-microscope
observation that spinous layer cells loose their spines (acanthi) and thus
become rounded,separating from their neighbors, forming a blister and
floating in the blister cavity. The etiology of this disorder is unknown, but
auto antibodies (IgG) tointercellular substance have been demonstrated in this
disorder by immuno-fluorescence methods using monkey esophagus, for
example, as substrate has been useful in diagnosis, and therapeutic assessment
of cases with pemphigus.

l) Clinical Manifestations:

Blisters or bullous lesions occur on urticarial or normal skin, on the scalp,

intertriginous areas, general body skin, and in 95% of cases, on the mucosas.
The blisters are usually flaccid and non-hemorrhagic. Death will ensue in
most cases without therapy which includes treatment with steroids and/or
immuno-suppressant agents.

2) Histopathology:

An intraepidermal blister is formed. The roof of the blister is composed of

upper layers of epidermis, the base of basal cells lining papilli which appear
prominent. These are called villi. The blister itself contains serous material,
sometimes polymorphonuclear leukocytes and acantholytic epidermal cells.

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Characteristically these acantholytic cells appear as rounded up cells with a
rim of cytoplasm about half the width of the nucleus. The nuclear detail may
be obliterated by granular basophilic material, or may be obvious with
nucleolus and chromatin disposed around the periphery of the nucleus.
The acantholytic changes may extend down the external root sheath.

b. Blistering diseases due to viruses - herpes virus varicellae infections -

chicken pox and herpes zoster.

Viruses affect the epidermis in varying ways. On particular DNA- containing

virus, the etiologic agent in herpes zoster and chicken pox, results in striking
abnormalities of the keratinocyte. In herpes zoster and in chicken pox,
vesicles are formed by acantholysis. A different DNA- containing virus, the
cause of the common wart or verruca, results in hyperplasia of the epithelium.
The hyperplastic epidermis exhibits irregular undulation, or papillomatosis.

1) Clinical Manifestations:

Chicken pox, or varicellsa, is present throughout the world and occurs in

epidemics. The majority of persons become infected during childhood. The
incubation period of varicella is about l4 days. Fever and malaise then appear,
followed by transient erythema (pinkness) of the skin, at times, and the
appearance of pink, slightly raised pimples (papules) that rapidly are
surmounted by clear, tense vesicles, each with an umbilicated center. The
clear vesicle surrounded by erythema has been called a "dew - drop on a
rose petal". Within a short time, sometimes hours, the clear blisters become
pustules, and are then yellow and turbid. The pustules last about 3 days, and
then a crust appears that falls off in several days, leaving a pink depression
that heals without scarring. From two to six crops of blisters appear over the
course of three or four days. A hallmark of varicella is the presence,
simultaneously, of lesions in varying stages of development, that is,
papules, blisters, pustules, and crusts. The lesions of chicken pox are
most extensively distributed on the extremities and spread centripetally to
the trunk. Blisters may occur on the mucosas, especially the hard palate.

Chicken pox is considered the primary infection with H.varicellae virus.

Herpes zoster is believed to represent predominantly the activation of one or
more latent viruses, probably in the dorsal root-ganglion cells. The factors
that activate herpes zoster are unclear, but, in the presence of certain systemic
diseases such as Hodgkin's disease, there is an increased incidence of herpes
zoster. Whatever the triggering agent, the clinical disease is manifested by the
presence of grouped umbilicated vesicles or an inflamed base in the
distribution of a dermatome.

Contact with persons with herpes zoster has frequently been cited as resulting
in the occurrence of chicken pox in susceptible children or adults. Contact
with patients with chicken pox, however, has rarely been cited as resulting in
the occurrence of herpes zoster in a susceptible person.

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2) Histopathology:

The prominent change in the skin is the formation of an intraepidermal vesicle

that has resulted from the alteration of cells by virus. Initially, virus-laden
cells are typically swollen, forming the so-called balloon cells. Their
cytoplasm is bright pink when stained with eosin, a sign that abnormal
keratinization has occurred. The nuclei of these cells may be large and
irregular or multinucleate, and frequently contain a pink (eosinophilic)
inclusion body that averages about 7.u in diameter, just about as big as a red
cell. The intra-nuclear inclusion bodies are surrounded by a faint clear
halo. The balloon cells, many of which are multinucleate, are round and
float in the vesicle cavity or lie at its base. They are called acantholytic
(they lose adherence to their neighboring cells), i.e., they are dyhesive.

The roof of the vesicle is formed by layers of keratinocytes cells that are often
necrotic. The base is made up of basal cells and virus-infected balloon cells.
The underlying dermis contains an inflammatory infiltrate consisting of acute
and chronic inflammatory cells. Vesicles of herpes simplex, herpes zoster,
and varicella all reveal this same basic histopathologic picture.

3. Hyperplasia and vesiculation - eczema:

Eczema is a clinical and histologic cutaneous reaction pattern provoked by a

wide variety of exogenous (allergic contact), endogenous (drug), and unknown
(atopic, dishydrotic, etc.) stimuli. Eczema is responsible for the highest
incidence of cutaneous morbidity in the USA and is an important cause of
decreased productivity in industry. Approximately 30% of patients seen by
dermatologists are suffering from one of the many forms of eczema.

a. Clinical Manifestations:

Acute eczema is characteristically erythematous, edematous and pruritic.

Intraepidermal vesicles may coalesce to form large bullae. The distribution of
lesions, severity of symptoms and duration of disease varies according to the
provoking stimulus. Chronic eczematous eruptions are always scaly
(hyperkeratotic) and thickened, with accentuation of skin markings
(lichenification).

b. Histopathology:

An acute eczematous lesion will show intra and intercellular edema

(spongiosis ) of the prickle cells, mild to moderate epidermal hyperplasia and
a loose perivascular infiltrate about superficial venules of the papillary
dermis. Intraepidermal spongiotic vesicles form as a result of severe
intracellular edema leading to rupture of cell walls with some retention of
some intercellular attachment. The retained attachments between cells
leave a reticulate vesicular structure.

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 In chronic eczema the epithelium is irregularly thickened, the papillary dermis
is often hyperplastic, and a chronic inflammatory infiltrate is present in the
dermis. Perineural fibrosis is often present in cutaneous nerves in the
superficial portion of these lesions. The reticular dermis is usually unaffected.

B. Disorders of the dermal epidermal interface - epidermolysis bullosa:

The region of the basement membrane, or basal lamina, may be affected in various
ways. There may be striking inflammation of the region and vacuolation, as in lichen
planus, or there may be thickening and vacuolation, as in the epidermolysis-bullosa
group, includes heritable diseases that result in blister formation in the skin in
response to slight trauma. According to ultra structure studies, different types of
epidermolysis bullosa affect different portions of the basement membrane region. The
disorder chosen to illustrate the group, epidermolysis bullosa, dystrophic type
(recessive inheritance), results in a tearing of the epidermis and basal lamina from the
dermis in response to mild trauma. The tear occurs just below the basal lamina in the
upper layer of the papillary dermis. The end result of this tear is the formation of a
subepidermal bulla, the top of which is formed by the epidermis and basal lamina, the
bottom by the dermis.

l. Clinical Manifestations:

Epidermolysis bullosa, dystrophic type (recessive inheritance), results in

perinatal and post-natal shedding of large sheets of epidermis after only the
lightest trauma. The mucosas are involved. Nails are shed. Extensive
scarring results, and, in severe cases, death ensures at an early age.

2. Histopathology:

A subepidermal bulla is formed. The roof of the bulla is the epidermis, and
the base of the bulla is the dermis. If the section is stained with PAS stain (the
periodic-acid-Schiff reaction), the basement membrane is clearly delineated in
scarlet red as lying above the bulla attached to the epidermis.

IV. Disorders of the Dermis:

A. Disorders of the superficial vascular plexus - erythema multiforme

Inflammatory disorders of the superficial vascular plexus are principally mediated by

lymphocytes and histiocytes. Acute disorders include eosinophils and at times
polymorphonuclear leukocytes, but the principal cell in all instances, both in acute and
chronic inflammatory disorders, is the lymphocyte admixed with other mononuclear
cells.

Alterations in the SVP occurring in the course of acute inflammatory disorders may
vary from slight increases in permeability that result in the accumulation of fluid in
the papillary dermis that can be reabsorbed within hours, to marked increase in
permeability of vessels with exudation of fibrin, red blood cells, various inflammatory
cells with embarrassment of oxygen of the epidermis and resulting focal infarction

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and/or bulla formation. Any inflammatory reaction that is present for several hours
and involves the SVP will have some effect on the epidermis. Epidermal alterations
range from mild spongiosis to frank necrosis and bullae formation.

l. Clinical Manifestation:

The etiology of EM is manifold; some of the various agents and conditions

noted to produce this reaction are listed in the following Table which is taken
from Fitzpatrick, T.B. et al Dermatology in General Medicine.

Circumstances Blamed for Precipitating Erythema Multiforme

Infections: Physical agents:

Acute serous ,meningitis Exposure to: Cold, x-ray, sunlight

Adenovirus
Cholera Endocrine states:
Cat-scratch disease Menstruation
Dermatophytosis Pregnancy
Hemolytic streptococci
Herpes simplex Reaction to drugs including:
Hepatitis Antibiotics, especially penicillin
Histoplasmosis Antimalarials
Infectious mononucleosis Antipyretics
Influenza type A Arsenic
Mumps Barbiturates
Orf Hydantoins
Ornithosis Mercury
Primary typical pneumonia Phenolphthalein
Salmonella typimurium Phenylbutazone
Sonne dysentery Sulfonamides
Tuberculosis
Vaccination Miscellaneous:
Variola Carcinoma, dental extraction,
beer drinking, Reiter's and Bechet's
syndromes

B. Disorders of the reticular dermis - Scleroderma

As already pointed out, when systemic diseases affect the skin, they involve
principally the reticular layer of the dermis and spare the "reactive unit" involved in
diseases that are primarily cutaneous, that is, the unit consisting of the epidermis and
the papillary layer of the dermis and its capillary and venule.

l. Clinical Manifestations:

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 Scleroderma occurs in two forms: a localized form and a systemic form. The
localized type, called morphea, affects the skin and the subcutaneous tissue

below the involved skin. The lesions are usually well circumscribed. They are
smooth -surfaced and shiny, and they frequently have a grey-white color
surrounded by a violaceous halo. They are typically firm, and the skin feels
taut. A linear form of morphea occurs.

Systemic scleroderma, or progressive systemic sclerosis, usually has

cutaneous involvement associated with widespread involvement of the viscera
including the heart, lungs, and gastrointestinal tract. The skeletal
musculature is also involved. The skin in progressive systemic sclerosis is
more diffusely involved than in morphea, and the lesions are not well
demarcated. Involvement may begin on the trunk or it may start on the
hands and face. The skin is shiny, smooth, and indurated and, with
associated atrophy of subcutaneous fat, it appears bound down to
underlying structures.

2. Histopathology:

Biopsies taken from ivory-colored areas of morphea and from areas of the skin
involved in progressive systemic sclerosis show similar finding. The dermis
appears thickened. There is hypertrophy of the collagen bundles. Hair
follicles and sebaceous glands are absent; however, sweat glands, which
are normally surrounded by fat, persist and are completely entrapped by
broad collagen fibers. Broad collagen bands streak into the
subcutaneous fat, which may appear atrophic. In systemic scleroderma, many
of the visceral changes are related to extensive fibrosis of the organs.

C. Granulomatous Dermatitis:

Granulomatous dermatitis affecting the skin, regardless of the etiologic agent, be it

sarcoidosis, leprosy, berylliosis, silicosis or others are all disorders that result in
dermal nodules. In these lesions, granulomas are present throughout the reticular
dermis and sometimes extend into the fat.

V. Disorders affecting the Panniculus

A. Disorders in which blood vessels are primarily affected but where the major
change is in the panniculus - erythema nodosum.

l. Clinical Manifestations:

Erythema nodosum describes a syndrome that includes the appearance of

brawny-red contusiform lesions on the extensor aspects of the limbs,

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especially the lower extremities and is usually associated with fever, some
malaise, and sometimes with arthralgias. The course of erythema nodosum
is usually circumscribed and the syndrome is generally considered to be
an allergic or reactive process occurring either idiopathically or in response
to a variety of systemic illnesses, infections or drugs. More exactly, the
lesions vary in size from l to 5 centimeters. They are present on the
anterior aspects of the legs, occasionally on the extensor aspects of the
arms, and have been noted as well on the trunk. They are bright to deep
red, and at times hemorrhagic. They may be slightly elevated or
nodular and are often surrounded by a zone of erythema. The lesions
may last anywhere from a week to several months. The systemic symptoms
associated may include arthralgias, malaise, gastro-intestinal disturbances,
and fever, sometimes as high as l03 -l05 F. The different illnesses that
may be associated with this disorder are: sarcoidosis, coccidior mycosis,
tuberculosis, streptococcal infection, "collagen" diseases and others. The
lesions may occur in response to drugs, especially sulfonamides or halides.

2. Histopathology:

Erythema nodosum is typically a septal panniculitis. The septa are the site of
marked edema, infiltration with acute and chronic inflammatory cells and a
deposition of fibrin in the collagen. The venules are involved with a
perivascular inflammatory infiltrate, and there may be fibrin deposited about
these vessels. At times, medium sized veins may also be involved with
inflammation and exhibit fibrin deposited in their walls. Hemorrhage
accompanies these changes. The lobules of fat are principally spared in
erythema nodosum, save for a few foci of infiltration by lymphocytes along
the septa. Fat necrosis is not a prominent feature of this disorder. In
addition, erythema nodosum is frequently associated with a perivenular
lymphosytic infiltrate in the dermis.

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General References:

Wolff K, Kibbi A-G, and Mihm Mc, Jr.: Basic pathologic reactions of the skin. In
TB
Fitzpatrick, et. al. (Eds) Dermatology in General Medicine. New York: McGraw-Hill
Co., l986.

Rook, A., Wilkinson, D.S., Ebling, F.J.G. Textbook of Dermatology . Blackwell,

Oxford and Edinborough, l973.

Moschella, S.L. et al. Dermatology. W.B. Saunders Co., l975.

Lever, W.F., & Schaumburg-Lever, G. Histopathology of the skin. 5th edition. J.B.
Lippincott Co., l975.

Icthyosis:

Feinstein, A., Ackerman, A.B. & Ziprkowski, L. Histopathology of dominant

icthyosis vulgaris and X-linked icthyosis. Arch. Derm. l0l : 529, l970.

Frost, P. Ichthyosiform dermatoses. J. Invest. Derm. 60 : 541, l973.

Pemphigus:

Elias, P.M., et al. Childhood pemphigus vulgaris. NEJM 287: 758 -760, l972.

Lever, W.F., Pemphigus. Medicine, 32: l, l953.

Eczema:

Mihm, M.C. Soter, N.A., Dvorak, H.F. and Austen, K.F. The structure of normal skin
and the morphology of atopic eczema. J. of Invest. Derm. 67: 305-312. 1976.

Prose, P.H., Pathologic changes in eczema. J. Pediat. 66: 178 - 199, l965.

Epidermolysis Bullosa:

Lowe, L.B. Hereditary Epidermolysis Bullosa. Arch. Derm. 95: 587-595, l967.

Erythema Multiforme:

Orfanos, C.E., Schaumber-Lever, G., Lever, W. Dermal and epidermal types of

erythema multiforme. Arch. Derm. 1 682, l974.

Scleroderma

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Fleischmajer, R., Damiano, V. and Nedwick, A. Alteration of subcutaneous tissue in
systemic scleroderma. Arch. Derm. l05: 59, l972.
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