DermPath Diagnosis - An outline

Dermpath Diagnosis - An Outline

DermPath Diagnosis - An Outline
Where is the pathology – Epidermis, Dermis, Both or Fat layer

Slide looks like normal skin

Parakeratosis and acanthosis

Parakeratosis with neutrophils

Epidermal acanthosis

Epidermal atrophy

Spongiosis

Acantholysis

Basal vacuolization

Sub epidermal blister or separation

Lichenoid infiltrate

Superficial and deep perivascular infiltrate

Extravasated red cells

Dermal papillary oedema

Nodular dermal infiltrate

Diffuse dermal infiltrate – cells, substances including drugs and organisms

Panniculitis

Tumours

Epidermal cells

Dermal cells

Adnexal structures

Metastases

Where is the pathology – Epidermis, Dermis, Both or Fat layer

Where is the pathology – Epidermis, Dermis, Both or Fat layer When you are examining a slide you hold it up to see the number of cuts and the nature of the specimen. Is it a punch, shave or excision biopsy? You should look at all the cuts but concentrate on the busiest bit!

Conditions showing epidermal pathology are usually to be found in the Red Scaly Mnemonic ie PMs PETAL (The Prime Minister's Pet a little cat called PETAL) . However pustules, vesicles and blisters can also be found in the epidermis so II for pustules and ICI for vesicles and blisters have to be invoked if these are seen either clinically or histologically.

1. Look at the stratum corneum, orthokeratosis or parakeratosis, Granular layer present? Any coronoid lamellae? Any signs of fungus in the stratum corneum? Any neutrophils in the stratum corneum?

2. Is there acanthosis? Or is the epidermis thinned?

3. Do the keratinocytes have a normal morphology? Is there nuclear and cell size variability? Any koilocytes near the granular layer?

4. Any acantholysis? Any vesicles or pustules intra epidermally?

5. Is the basal layer normal? Any proliferation of abnormal melanocytes either individually or in nests?

6. Any spongiosis? What about other cells invading into the epidermis?

7. Any sign of bodies in the epidermal cells eg Orf or Molluscum

8. Are there prominent rete ridges or dermal papillae?

9. Any extravasation of material through the epidermis?

Subconsciously asking yourself these questions when looking at the epidermis will alert you to many diagnoses.

We will look at each of these situations and discuss their significance.

Epidermal changes can be seen with direct damage from applied chemicals or from chronic nutritional deficiencies particularly in zinc deficiency causing acrodermatitis enteropathica, niacin deficiency in pellagra and protein deficiency in marasmus and quashiokor.

The deficiencies cause palor of the superficial layers of keratinocytes and cell death. A similar histological picture is seen in necrolytic migratory erythema from a glucagon producing pancreatic tumour and necrolytic acral erythema in some cytotoxic drug reactions.

View this Virtual Slide of Acrodermatitis Enteropathica

Pellagra

View this Virtual Slide of Pellagra

Necrolytic migratory erythema

View this Virtual Slide of Necrolytic Migratory erythema.

DERMAL PATHOLOGY

Clinically rashes that have a dermal pathology usually are found in the CUL DVA EVIE mnemonic. (See you later at the Dept of Veterans Affairs EVIE where Evie is your girlfriend.)

Histopathologically dermal patterns are due to

1. Infiltrates of cells or substances

2.  Excess or reduction in collagen or elastin

3. Proliferation of nevus cell benign or malignant ,

4. Hair follicle, Apocrine or eccrine gland proliferations,

5.Nerves, lymphatics or blood vessel proliferations

6. Granulomas

7. Perivascular lymphocytic cuffing

8. Vessel damage (Vasculitis)

9. Basal layer infiltrates either Lichenoid or Interface type

When we look at dermal diseases we are looking at anything that is involving the dermal epidermal junction and below as far as the fat layer.   Classically the reaction patterns have then be divided into those that involve a band like infiltrate at the dermal epidermal junction, which is known as a lichenoid infiltrate, those that have more sparse infiltrate but primarily damage to the cells of the dermal epidermal junction, which is then called interface damage and those that have collections of cells in the actual dermis itself.  These cells can be eosinophils, neutrophils, lymphocytes, melanocytes or nevus cells and rarely cells from metastatic disease. 

You can get granulomas occurring and you can obviously get tumours in the dermis where you get hyperproliferation of other tissue cells that are there.  These can be tumours of fibroblasts, nerve or muscle cells and also those derived from hair follicles or eccrine and apocrine glands. 
Most of the pathologies that involve the dermis will give red, non-scaly lesions or skin coloured non-scaly lesions and the fact that they are non-scaly indicates that the epidermis isn't going to be involved. So, if you see that most of the pathology is in the dermis then consider that the clinical morphology is going to be a non-scaly either red or skin coloured lesion. We will show you examples of that when we look at conditions such as granuloma annulare or even some of the atypical mycobacteria or deep fungal infections.  Remember though that sometimes dermal processes can perforate the epidermis.  They can go up through the epidermis as the body tries to get rid of the abnormal tissue.  In those circumstances there will be epidermal involvement and this certainly has to be considered when a predominantly dermal process has an epidermal component as well.

CUL DVA EVIE

Clinically cellulitis presents as a hot red tender spreading plaque on the skin, particularly in the lower legs near the ankles, but it can also occur on the face and other parts of the body.  It is generally due to a staph or strep infection.  There isn't any epidermal involvement and so you would not expect any histological changes there.  What you see histologically is oedema in the dermis and numerous leucocytes interspersed between the collagen bundles in the oedema fluid.  Sometimes the heavy infiltrate of leucocytes will extend deeply even to the septal layer of the fat and give rise to a septal panniculitis.  In the more superficial variant of cellulitis called erysipelas you histologically can see quite a bit of sub epidermal oedema and even a threatening bullous eruption depending on the degree of oedema with a heavy infiltrate of neutrophils.

In urticaria the skin is also red and may be hot but is usually not painful.  It is usually described as being itchy.  It does feel plaque like but histologically this time as well as fluid in between the collagen bundles the cellular infiltrate is mainly eosinophilic.  There are usually also dilated blood vessels and lymphatics associated with this dermal oedema.  The infiltrate of cells isn't as great as an infected process and a large proportion of them are eosinophils, though there may be some neutrophils as well.

 Papular urticaria is a different condition.  Whereas common urticaria is IgE mediated, papular urticaria is generally a Type 4 hypersensitivity reaction to insect bites, particularly fleas and the lesions will arise some hours after the bite reaction. 
Histologically in these circumstances there is both a superficial and deep infiltrate and the infiltrate is of mainly lymphocytes and some eosinophils. Histologically it often has a wedge shaped arrangement.  A similar histological picture may be seen in the pre-bullous phase of bullous pemphigoid which appears to be a dermal hypersensitivity reaction with dermal oedema and eosinophils.  Rarely in early bullous pemphigoid just before the bullae erupt you may see some eosinophilic spongiosis where there is some epidermal involvement, but it is only when an autoimmune attack occurs at the dermoepidermal junction that you get the blisters superimposed on this background of dermal oedema and eosinophils.

The next letter of the mnemonic is L standing for lupus or for polymorphous light eruption.  Now, in these circumstances the damage is going to be at the dermal/epidermal junction with vacuolar damage and some of that damage will extend down the hair follicles.  This is typical in lupus and often you will get some plugging of the hair follicles as well and this is reflected in the carpet tack sign when you remove the scale from the surface of a lesion of lupus.

Lupus also comes up as one of the red scaly diseases, in fact discoid lupus is very scaly, but here we are looking at it under the heading of red non-scaly diseases and so most of the disease process is taking place not in the epidermis but in fact at the dermal/epidermal junction and in the dermis itself.  There is a variant called tumid lupus, particularly affecting the face and upper trunk and this is similar to the histopathology of discoid lupus with vacuolar damage at the dermal/epidermal junction, but there is also a lot of mucin in the dermis and there may be some subepidermal oedema, so there is no real surface scale changes in this variant of lupus.  Jessner's lymphocytic infiltrate looks very similar histopathologically to this condition although the morphology of the lesion is more florid than you see in tumid lupus.  In subacute cutaneous lupus, again the damage is at the dermal/epidermal junction with vacuolar change but this can be more marked in subacute lupus.  There is also a degree of epidermal atrophy, again dermal oedema and mucin and much less of the keratotic epidermal changes that you see in discoid lupus.  There is also a thickening of the basement membrane.  In subacute lupus you may get positive immunofluorescence as well.  Remember that subacute lupus can be due to a variety of drugs as well.  In systemic lupus clinically we see the patient who has a marked erythema, particularly a malar erythema often without much in the way of overlying keratotic changes in the epidermis and histologically this is reflected in the prominent basal layer damage that is occurring.  There may again be dermal oedema and mucin and here you get a lot more damage to blood vessels in the upper parts of the dermis with fibrin deposition in the vessel walls.  As with subacute lupus there is often marked thickening of the basement membrane itself.  Neonatal lupus if you are looking at the biopsy is very similar to subacute lupus.

When you think of lupus in these red non-scaly diseases you also have to consider some of the other collagen disorders such as the dermatomyositis and even scleroderma although morphologically they can look different.  Dermatomyositis can clinically look like lupus and the histopathology also reflects this.  There is the same basement membrane thickening and vacuolar changes at the basement membrane but usually it is only a superficial perivascular infiltrate.  It is not superficial and deep as you tend to get in lupus. You can also get oedema and mucin and a degree of epidermal atrophy and that is reflected later on in the   clinical changes that you will see in dermatomyositis, (poikiloderma) so it can be very difficult histologically to separate dermatomyositis and lupus and in point of fact it is often easier clinically!

Dermal reaction patterns end up causing the red non-scaly skin diseases.

The mnemonic for these is CUL DVA EVIE and the diseases are cellulitis, urticaria, L for lupus usually the subacute tumour type, possible light eruption and Lues or syphilis.  The D is for drug reaction.  The A is for annular erythema. V is viral or bacterial exanthem.  EVIE is E for erythema multiforme, V for vasculitis, I for infiltrates and the other E is for erythema nodosum. 

The thing about all these conditions is that the histological action takes place in the dermis and the epidermis isn't involved to any significant extent at all.  This is true in most of these disorders.  However an exception is where you have damage occurring at the interface of the dermal/epidermal junction.  If enough damage occurs here then the epidermis itself can be damaged and epidermal changes can then occur, ranging from pseudo blister to actual scale.The classic condition that will do this is erythema multiforme.  Other conditions with damage at the dermal/epidermal junction include graft versus-host disease and some of the autoimmune disorders such as dermatomyositis and acute lupus erythematosus.  Lichen planus will also give basal layer damage but there is usually a very marked and significant lichenoid infiltrate of lymphocytes.  This may not be the case in erythema multiforme or lupus. 

However at this stage let's get back to the histopathology of the other red non-scaly disorders and we will slowly work our way through these before looking at the specific histological reaction patterns that we see in the dermis. 

These reaction patterns in the dermis number about seven. 

First of all you have your interface reaction pattern with damage at the dermal/epidermal junction and vacuolar degeneration of the basal keratinocytes.

 Then you have the lichenoid pattern with a thick infiltrate of lymphocytes strongly apposed to the basement membrane. 

Next you have the superficial and deep perivascular reaction pattern as the name implies involving the vessels of the superficial and deep perivascular plexus

 The vasculitic reaction pattern  is more than just the superficial and deep perivascular changes but involves inflammation and damage in and around major vessels and includes conditions such as leukocytoclastic vasculitis and polyarteritis nodosa.. 

Lastly there is a granulomatous reaction pattern in the dermis.  This is deep and can be infective or non-infective.

 Each of these reaction patterns has to be looked at in their own right, but we will do that in passing. 

Before we start that, the other thing that can obviously happen in the dermis is that you can have hyperproliferation of cells that are normally found there such as fibroblasts or adnexal structures such as hair follicles or sweat glands and this can give rise to a multitude of tumours that can arise in the dermis. Tumours can also arise from the nerves, both the nerve sheaths and the nerve axonal  structure itself.  Also from muscle, both the smooth muscle of the erector pili muscles and the deeper striated muscle, and also from the blood vessels. 

There are a wide variety of tumours that can occur from each of these structures both benign and malignant and we will look at those in some detail later on.  It will be obvious when you look under a microscope which of these structures you are dealing with, except if you have a lot of spindle cells which can be derived from melanocytes, keratinocytes, nerve cells and muscle cells. Special immunoperoxidase stains are required to determine the cell of origin.  

When we look at dermal diseases we are looking at anything that is involving the dermal epidermal junction and below as far as the fat layer.   Classically the reaction patterns have then be divided into those that involve a band like infiltrate at the dermal epidermal junction, which is known as a lichenoid infiltrate, those that have more sparse infiltrate but primarily damage to the cells of the dermal epidermal junction, which is then called interface damage and those that have collections of cells in the actual dermis itself.  These cells can be eosinophils, neutrophils, lymphocytes, melanocytes or nevus cells and rarely cells from metastatic disease. 

You can get granulomas occurring and you can obviously get tumours in the dermis where you get hyperproliferation of other tissue cells that are there.  These can be tumours of fibroblasts, nerve or muscle cells and also those derived from hair follicles or eccrine and apocrine glands. 
Most of the pathologies that involve the dermis will give red, non-scaly lesions or skin coloured non-scaly lesions and the fact that tyey are non-scaly indicates that the epidermis isn't going to be involved. So, if you see that most of the pathology is in the dermis then consider that the clinical morphology is going to be a non-scaly either red or skin coloured lesion. We will show you examples of that when we look at conditions such as granuloma annulare or even some of the atypical mycobacteria or deep fungal infections.  Remember though that sometimes dermal processes can perforate the epidermis.  They can go up through the epidermis as the body tries to get rid of the abnormal tissue.  In those circumstances there will be epidermal involvement and this certainly has to be considered when a dermal process has an epidermal component as well.

FAT Layer Pathology

Inflammation in the fat layer usually gives rise to a septal or lobular panniculitis histological picture or a mixture of both.

Infiltrates of cells and sustances can also occur in the fat layer and some deep infections with deep fungii or atypical mycobacteria can mainly be found in the fat layer.

We will discuss each of these below. The Clinical Mnemonic is PMLE ( Pancreatic, Metabolic and Mycobacterial, Lupus erythematosus and Erythema nodosum)

Slide looks like normal skin

Slide looks like normal skin

Parakeratosis and acanthosis

Parakeratosis and acanthosis Parakeratosis

Parakeratosis refers to retained keratinocytic nuclei in the stratum corneum. It is seen in proliferating keratinocytic disorders such as psoriasis, and in keratinocytic malignancies and premalignant conditions such as Bowen's disease and Solar keratosis. The nuclei are flattened and run  parallel to the epidermal surface.
When you see it look carefully at the underlying epidermis. You may see hyperkeratosis, hypogranulosis and acanthosis.  Histological parakeratosis usually equates to surface scale so think of the mnemonic for the red scaly diseases PMs PETAL for likely diseases.

Patterns of parakeratosis can be helpful.
Confluent in Bowen's disease and Psoriasis         Virtual Slide

Alternating in Solar keratosis                              Virtual Slide

Parakeratosis in a heaped up column in the cornoid lamellae of DSAP   Virtual Slide

Checkerboard parakeratosis in PRP   Virtual Slide

Sandwich parakeratosis over orthokeratosis in Tinea        Virtual Slide

There is also the unusual axillary granular parakeratosis with granules in the stratum corneum. See Virtual Slide

View the Video of this Topic

Acanthosis

This usually results from keratinocyte hyperplasia and features acanthosis of the epidermis. Often there is associated hyperkeratosis.

Check it to see if there is any cytological atypia of the keratinocytes to indicate Bowen's disease.

 Otherwise a lot of chronic diseases eg Lichen simplex and Psoriasis will show a thickened epidermis but look out for some Deep fungal infections, TB of the skin and Reactive perforating collagenosis and the much rarer halogenodermas.

Parakeratosis with neutrophils

Parakeratosis with neutrophils Neutrophils in the Stratum Corneum

Whenever I see this I think of Impetigo, Fungi or Pustular psoriasis and would order a PAS stain.
Munro microabscesses are collections of neutrophils in the stratum corneum.

Other causes include AGEP acute generalised pustular dermatosis, Subcorneal pustular dermatosis and sometimes also in pemphigus foliaceous.
Acropustulosis of infancy and Neonatal scabies can also show subcorneal pustules without the scabetic organism.

View this video on Sub Corneal Pustules

  View this virtual slide of pustular psoriasis

Neutrophils in the epidermis can be seen in a variety of inflammatory conditions but remember Acne and folliculitis, Gonococcemia, Necrolytic migratory erythema, Pemphigus erythematosus or foliaceous, Neonatal pustular melanosis, Scabies and Halogenodermas.


If you see Pustules in the epidermis the mnemonic is II

I - Infective  Viral, Bacterial, Fungal, Rickettsial, Protozoa
I Inflammatory eg Drugs, Pustular psoriasis, Rare ( Scabies, Necrolytic migratory erythema, Subcorneal pustular dermatosis, Neonatal pustular melanosis, Erosive pustular dermatosis, Acrodermatitis enteropathica, Halogenodermas)

Epidermal acanthosis

Epidermal acanthosis

Epidermal atrophy

Epidermal atrophy Thinned Epidermis

This suggests epidermal destruction as occurs in erythema mutiforme , lupus erythematosus, dermatomyositis and in lichen sclerosus. Epidermal consumption can also be a feature of melanoma.

The commonest cause of epidermal thinning is ageing and sun damage but remember the regional differences in the body with eyelid skin epidermis being particularly thin relative to other areas.

Spongiosis

SPONGIOSIS:

Spongiosis is the accumulation of fluid between the keratinocytes in the epidermis causing the desmosomes to stretch.  This is most obvious in the prickle layer of the skin in the stratum spinosum.  If the amount of fluid between the keratinocytes increases then sometimes intraepidermal vesicles can be seen. 

The next thing that you should look for if you spot spongiosis is to see if there are any cells infiltrating the epidermis and are these cells neutrophils, lymphocytes or eosinophils.  If they are neutrophils then look to see where they are accumulating.  If they are accumulating in the stratum corneum then consider that the patient has early psoriasis which may well have a little bit of spongiosis.  Look to see though if they have any evidence of fungal hyphae in the stratum corneum because it may be that this is a dermatophyte infection and also look to see if there is any bacteria with signs of secondary infection of eczema, particularly staphylococci. 

If instead the cells are eosinophils, then consider the potential causes of eosinophilic spongiosis.  These include a spongiotic drug reaction, particularly with the thiazide diuretics but also conditions such as pemphigus or pemphigus  vegetans.  Now as well as having spongiosis in these conditions you also should have acantholysis, in other words separation of the keratinocytes.  Bullous pemphigoid can also give some eosinophilic spongiosis early on as can allergic contact dermatitis and even arthropod bites.  A rare type of eosinophilic spongiosis can occur in Ofugi's disease where the eosinophils are associated with follicles, particularly in the infundibulum.  There is also the rare inherited disorder of Incontinentia pigmenti particularly the very first stage where there can be spongiosis with intra epidermal vesicles which are packed with eosinophils.  There is usually some evidence of dyskeratotic cells as well in Incontinentia pigmenti.

Neutrophilic spongiosis we have talked about as being a feature of psoriasis and also of dermatophyte infections and possibly secondary bacterial infection, but it may also be part of an acute generalised eczematous pustulosis or AGEP which is usually a drug reaction to drugs such as Tegretol or some of the sulphonamide antibiotics.  Rarely IgA pemphigus can also give rise to neutrophils high in the epidermis under the stratum corneum, but most cases of pemphigus will show you an eosinophilic infiltrate with eosinophilic spongiosis.

If you primarily see lymphocytes and spongiosis, look at the lymphocytes and see if they are atypical.  If they are atypical and especially if they are small congregations of them then these may be Pautrier microabscesses and they are a feature of early T-cell lymphoma of the skin.  This can be a difficult diagnosis to make early on.  One of the variants of T-cell lymphoma is what is called small plaque parapsoriasis and in this condition there may be mainly a spongiotic pattern with mild individual atypical lymphocytes in the adjacent epidermis.  This is usually reported as chronic superficial dermatitis, but over time the lymphocytes congregate into small Pautrier microabscesses and become more atypical and the areas of skin will thicken and look more like the plaquestage of T-cell lymphoma.

I think it is always important to remember the mnemonic for the clinical diseases that are associated with these red scaly disorders and that is the PMs PET with his little cat called PETAL.  PET is for psoriasis eczema tinea, the A for annulare erythema and the L for lupus or perhaps early lichen planus.  The initial P is for pit rosea, pityriasis versicolor, pityriasis rubra pilaris and the M is for mycosis fungoides, the S is for solar damage, syndromes and perhaps scabies.  These will all give rise to red scaly disorders.

Certainly eczema is the most common cause of spongiosis but we have already said that spongiosis can be seen in some early forms of psoriasis and it also can be seen in pityriasis rosea and in dermatophyte infections.  The A stands for annulare erythema and erythema annulare centrifugum is the commonest of the annulare erythemas.  The primary feature you notice histologically is usually a superficial and deep perivascular lymphocytic infiltrate, but many cases will show a degree of spongiosis as well.  Those that do will clinically have scale whereas there are forms of erythema annulare centrifugum without any scale and these won't show the same degree of spongiosis.

View this Virtual Slide of EAC

Atopic dermatitis is obviously one of the commonest dermatitic disorders that we will see that shows some degree of spongiosis.  The more acute and weeping the condition is clinically the more likely the spongiosis is going to be significant and it is when small accumulations of the spongiotic fluid break out on the surface of the skin that you have the small erosions that are so typical of the dermatitic process.  Drier forms and the more chronic lichenified forms of dermatitis though won't show the same degree of spongiosis, but will show epidermal acanthosis and some hyperkeratosis.  In contrast acute contact dermatitis can show marked spongiosis and often  intraepidermal vesiculation.  This is particularly likely with a plant contact dermatitis.

View this Virtual Slide of Acute Contact Dermatitis

Seborrhoeic dermatitis will also show a degree of spongiosis but it is centred around some hair follicles and these also show the phenomenon of parakeratosis with parakeratosis around the ostial openings.  There may be overlying crust that has neutrophils in it, but again the crust is centred around follicles.  This is reflected in the greasy clinical appearance of seborrhoeic dermatitis.

View this Virtual Slide of Seborrhoeic Dermatitis

Pompholyx eczema also gives rise to prominent vesicles in the epidermis but this is because of the overlying fixed stratum corneum not allowing the fluid to escape easily.  Pompholyx eczema is particularly seen on the sides of the fingers and toes.

View this Virtual Slide of Pompholyx Eczema

Stasis dermatitis is mainly seen in the elderly with an impaired venous or lymphatic circulation and it is most prominent around the medial malleolus.  As well as having mild spongiosis the major thing you are going to see is proliferation of superficial dermal blood vessels.  In cases where there is persistent and significant venous hypertension you will get capillaritis with extravasation of red blood cells and this gives rise to the brown hemosiderin pigmentation particularly seen in these areas.  There is often also a degree of fibrosis.  Rarely if this condition persists you may get underlying panniculitis as well and features described as lipodermasclerosis.

View this Virtual Slide of Stasis Dermatitis

Spongiotic drug reactions are characterised by varying degrees of spongiosis, sometimes with intraepidermal vesicles occurring.  Usually the cells that infiltrate are eosinophils but plasma cells can also be seen in some cases.  The reaction most likely to give intraepidermal vesicles is in fact an allergic contact dermatitis, but as I have already said drugs such as thiazide diuretics and calcium channel blockers can also cause spongiotic drug reactions.  The eosinophils may infiltrate into the epidermis or they may be mainly perivascular in the dermis.

View this virtual slide of Spongiotic Drug Reaction

 The Gianotti-Crosti syndrome is usually diagnosed on the basis of papules or papulo vesicular lesions on the outer aspects of the arms, legs and the cheeks in a child who is otherwise well.  If these are ever biopsied then the lesions may show mixed pathologies with focal areas of spongiosis, some oedema in the dermal papillae and quite marked perivascular lymphocytes.  There is a degree of overlying parakeratosis but many times these lesions don't seem scaly.

View this Virtual Slide of Gianotti Crosti Syndrome

Grover's disease is another condition that can cause spongiosis but then Grover's can cause a variety of histologies.  Often it is recommended that you take several biopsies to show this variability in histological reaction patterns.  Spongiosis is perhaps the commonest pattern but acantholysis is the one that is usually needed to make a definitive diagnosis. The combinations of focal acantholysis and spongiosis are highly suggestive of Grover's disease.  Many cases of Grover's have an associated dermatitis in the surrounding skin.

View this Virtual Slide of Grover's Disease

The PUPPPS syndrome or pruritic urticarial papules and plaques of pregnancy again is a diagnosis that is usually made clinically.  It is usually red and in most cases it is not scaly.  The lesions occur in the stretch marks.  Histologically there is a degree of spongiosis but it is often relatively mild.  There is more likely to be oedema of the papillary dermis with a superficial perivascular lymphocytic infiltrate.  Again often the clinical history is needed to give the histological diagnosis.

View this Virtual Slide of PUPPPS

Pityriasis alba is one of the mild variants of atopic dermatitis so you would expect any degree of spongiosis is going to be quite mild.  There may be a reduction of melanin in the basal layer as well that accounts for the white spots that are seen in this condition. 

View this Virtual Slide of Pityriasis Alba

Other unusual conditions that can occur in children with spongiosis include lichen striatus but as the name suggests there is usually a mixture of both lichenoid histology and spongiotic reaction patterns.  The fact that there is significant lichenoid infiltrate means that there is usually basal layer damage and melanocytic damage so there are often melanophages in the dermis. Because of the lichenoid nature of the T-cell infiltrate there are usually some dyskeratotic cells where there has been a degree of satellite cell necrosis.  The lymphocytic infiltrate in the skin also extends around eccrine glands and this can be a useful feature in making the diagnosis.

View this Virtual Slide of Lichen Striatus

We have spoken already about lymphocytic infiltrates in mycosis fungoides and that the lymphocytes are usually atypical and may congregate in Pautrier microabscesses.  In very early cases it can be difficult to make this diagnosis and the lesions may be reported as chronic superficial dermatitis so you have this mild spongiosis with associated atypical lymphocytes infiltrating the epidermis.  

View this Virtual Slide of Chronic Superficial Dermatitis

Acantholysis

Acantholysis

Acantholysis is a feature seen in the epidermis as an isolated feature in some skin cancers including solar ks, SCCs and even in melanoma.


It is a major finding in Hailey Hailey disease,  Darier's disease and in Pemphigus but is also seen to a lesser extent in Grover's disease. Rarely acantholysis is seen in Pityriasis rubra pilaris.

Basal vacuolization

The Interface  vacuolar reaction pattern can give rise to epidermal changes but it is mainly through the process of keratinocyte destruction. Usually this is caused by lymphocytes invading the epidermis and directly destroying keratinocytes or where keratinocytes are collateral damage where the primary antigen is a drug attached to the keratinocyte. Usually there is associated vacuolar changes to the basal keratinocytes and so the interface pattern is divided into lichenoid and vacuolar pattern subtypes.





The main conditions showing vacuolar changes that significantly affect the epidermis are the following.

In erythema multiforme the typical lesions are the target lesions, where there is a surrounding area of erythema and a central area that is much darker.  Sometimes this central area can be bullous, again a reflection of the degree of damage that is occurring to the epidermis at certain points.  

Fixed drug reaction can also give rise to a bullous lesion usually with very little in the way of surrounding erythema but there is often post-inflammatory hyperpigmentation and this may be the feature with melanin melanophages which is most apparent histologically depending on the stage at which you are viewing the specimen.

This idea of lesions having lives was one put forward by Bernard Ackerman and basically it means that the pathological process varies depending on the stage of the illness and the stage of development of the lesion that is being examined. 

Prominent interface damage at the dermal/epidermal junction with prominent vacuolar change to the basal keratinocytes and pink Civatte bodies or dyskeratotic cells throughout all levels of the epidermis indicate a more severe immunological challenge to the epidermis and this picture is typically seen in erythema multiforme and in fixed drug eruptions.  In erythema multiforme the epidermal cell death can occur at all levels and there is often a marked infiltrate of the lymphocytes into the epidermis itself so that it is difficult to see the dermal/epidermal junction.  Remember that in these circumstances with erythema multiforme, either secondary to a viral infection such as herpes simplex or a drug reaction, that the target cells are the keratinocytes themselves.

A fixed drug reaction has a very similar picture, again for the same immunological reasons, but here the drug is probably attached to a keratinocytic protein and is acting as a hapten and it is a Type 2 immune reaction that can give very extensive damage to the epidermis. If it is extensive enough you will actually get blisters.  Otherwise you can almost get complete necrosis of the epidermis and the latter is a feature of the condition toxic epidermal necrolysis where not just localised areas as in fixed drug but generalised areas of the skin can be subject to this immunological attack.  In a fixed drug, depending on the stage at which it is biopsied, you may see a lot less of this vacuolar change at the dermal/epidermal junction and more melanin continence with melanin in melanophages.  The prominence of eosinophils in this area of infiltrate is much more in favour of a fixed drug eruption.

Graft versus host disease is also a lichenoid infiltrate but it is often much more sparse than in lichen planus and again, though there can be significant vacuolar damage at the dermal/epidermal junction,  it is seldom full thickness.  It is similar to a mild form of erythema multiforme and it may show the phenomenon of what is called satellite cell necrosis where you have a lymphocyte next to a dead keratinocyte.

Lupus erythematosis can give both a lichenoid and an interface vacuolar pattern and the degree of one or the other determines to some extent the clinical appearance.  The three major clinical variants of lupus are discoid lupus, subacute lupus and systemic lupus.  In discoid lupus a lot of the damage is centred round hair follicles, also at the dermal/epidermal junction and with a superficial and deep perivascular infiltrate in the dermis.  There is often thickening of the basement membrane and a few scattered Civatte bodies or dyskeratotic cells.  A degree of hyperkeratosis and follicular plugging is also seen. 

 In subacute lupus you have much more damage at the dermal/epidermal junction with basal vacuolar change and you may in fact get epidermal atrophy.  There can be a bit of mucin also in the dermis in conjunction with thickening of the dermal/epidermal junction.  In a condition called tumid lupus there is even more mucin in the dermis but there is not as much epidermal involvement and there is still a superficial and deep perivascular  infiltrate. 

 In systemic lupus you have much more basal vacuolar damage but  the infiltrate of lymphocytes can be a lot less than you might expect.  The damage is more centred on the keratinocytes in the epidermis itself and you may also see sub papillary oedema and  extensive mucin in the dermis.  There are usually much fewer dyskeratotic cells in the epidermis, so there is less epidermal reactivity and hence less epidermal scaling and the like. Typically systemic lupus shows mainly skin erythema. There is also sometimes vascular damage with fibrin in the blood vessels. 

In lupus panniculitis the main area of damage is  in the fat layer and here you have a lobular panniculitis with lymphocytes invading and destroying the fat lobules.  There may be some overlying epidermal changes of discoid lupus as well. 

Bullous lupus will have a subepidermal blister and surprisingly there are often neutrophils in the dermal papillae with lymphocytes in the perivascular area, but this is a rare condition.

The other collagen diseases such as dermatomyositis are similar to lupus, more perhaps to the subacute lupus variant than any of the others. The perivascular infiltrate is usually superficial rather than superficial and deep and the degree of basal vacuolar damage is not as great, neither is the amount of mucin that is deposited in the dermis.  However there may be a little bit more epidermal atrophy than you will see in some cases of lupus.

The only other lichenoid interface condition that perhaps we should mention is lichen sclerosus et atrophicus.  Again it depends on the stage of the illness that  is biopsied.  In the late stage there will be quite marked collagen deposition in the upper dermis and this band of collagen is quite a prominent feature.  It is usually relatively acellular and there is usually atrophy of the overlying epidermis.  Of course if you see this at an earlier stage there may be a more superficial dermal infiltrate of lymphocytes with perivascular prominence and damage to the basal layer. The sclerotic changes only occur as a later feature.  There also may be follicular plugging in this condition, again because of the early epidermal involvement. Sometimes bleeding is also seen.

Sub epidermal blister or separation

PATHOLOGY OF VESICLES

When you consider the mnemonic for the clinical diagnosis of vesicles you remember it is ICI, I for infective both viral, bacterial and fungal, C for contact dermatitis and the second I for immunological and inflammatory.  Histologically a vesicle will look like a space in the epidermis.  The epidermal covering to the vesicle may be thin or may be thick depending on the level at which the vesicle is formed in the epidermis and the area of the body in which it has formed because the thickness of the epidermis and stratum corneum varies across body sites 

Vesicles can form because of keratinocyte necrosis particularly secondary to a herpesvirus infection, but they can also form because of an accumulation of fluid between the keratinocytes as in a spongiotic dermatitis, particularly pompholyx eczema where you have the thick overlying wall of the stratum corneum and epidermis on the fingers, the palms and the soles.  

Vesicles may subsequently become pustules if the clear fluid is infiltrated by neutrophils.  In acute dermatitic vesicles the intraepidermal vesicle is surrounded by some spongiosis in the adjacent epidermis.  There may also be exocytosis of lymphocytes.  Spongiotic vesicles can also be seen in pityriasis rosea, in miliaria crystallina and in some dermatophyte infections and candida and rarely as part of an erythema annulare centrifugum, but again this is just secondary to a large degree of spongiosis. Vesicles and blisters can also occur because of Acantholysis either due to congenital deficiency of adherent molecules such as desmogliens in Hailey Hailey and Darier's disease, or acquired in Pemphigus or Grovers syndrome

If a vesicle has a lot of eosinophils in it then consider Incontinentiapigmenti.  Excess of eosinophils in the epidermis can also be seen in an allergic contact dermatitis, arthropod bite reactions and rarely in both pemphigoid and pemphigus vulgaris and foliaceous.

Vesicles caused by herpes virus are due to damage and lysis of virally invaded keratinocytes.  This results in large multi-nucleated keratinocytes and is seen not only in herpes simplex but also in herpes zoster and also in some common warts or varicella

Occasionally intraepidermal vesicles may occur in erythema multiforme but usually in this condition the damage is at the dermoepidermal junction and any blisters that form are sub-epidermal blisters.

If we now go back and look at a mnemonic of ICI then the infective causes of vesicles are mainly the herpes viruses but also Orf and even Hand, Foot and Mouth disease.  There is also the fungal vesicle variant due to dermatophytes or candida.  Bacteria themselves usually cause blisters rather than vesicles and the split is subcorneal.  It is rare for a bacterial infection to cause an intraepidermal vesicle.

The C is for contact dermatitis. These vesicles may join to form large blisters which are commonly seen in plant contact dermatitis, but it is a mild intraepidermal form that is seen first.

Clinically sometimes subepidermal fluid accumulation can look as if it is causing vesicle formation.  This phenomenon is particularly seen in a severe type of erythema multiforme with vacuolisation of the basal layer and subepidermal bulla formation.  A similar picture can be seen in Sweet's syndrome, again with the severe papillary oedema seen in this condition.  Really it can also be a feature of a polymorphous light eruption.

Dermatitis herpetiformis may also give apparent vesicles, but again the oedema is found in the sub basement membrane layer of the papillary dermis.