Vesiculobullous and desquamating skin disorders: Pathology review

Definitions & Key takeaways

Vesiculobullous and desquamating skin disorders are a group of conditions that affect the skin and cause blisters, sores, and scaling. These disorders can be caused by a variety of factors, including autoimmune disorders, infections, and allergic reactions.

Vesiculobullous disorders are characterized by the formation of fluid-filled blisters, which can vary in size and severity. Examples of vesiculobullous disorders include pemphigus vulgaris, bullous pemphigoid, and herpes simplex virus infections. Desquamating skin disorders, on the other hand, are characterized by the shedding or peeling of skin, often in the form of scales or flakes. These conditions can be caused by a variety of factors, including infections, allergies, and underlying skin disorders. Examples of desquamating skin disorders include psoriasis, atopic dermatitis, and seborrheic dermatitis.

Treatment options may include topical or systemic medications, such as corticosteroids or immunosuppressive drugs, as well as lifestyle modifications, such as avoiding triggers or irritants that can worsen the condition.

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Case Study0:00–1:01

At the dermatology clinic, 58 year old Alan presents complaining of painful lesions on his skin and mouth for the past two months.
On examination, there are flaccid bullae with erosions all over his trunk and extremities, as well as erosions on the oral and gingival mucosa.
When lateral pressure is applied to a lesion, the outermost layer seems to slough off. On the same day, 17 year old Gabriella comes in with an intensely itchy rash that appeared a couple of weeks ago.
She has also experienced frequent nausea and diarrhea after meals. Physical examination shows multiple papules, vesicles, and bullae on both of her knees, forearms, and elbows, as well as her back and buttocks.
Lab tests reveal elevated levels of anti-gliadin IgA and IgM. Based on the initial presentation, Alan and Gabriella seem to have some form of vesiculobullous or desquamating skin disorder.

Physiology1:01–2:14

Okay, first, let’s talk about physiology real quick. Normally, the skin is divided into three main layers, the epidermis, dermis, and hypodermis.
The hypodermis is made of fat and connective tissue that anchors the skin to the underlying muscle. Above the hypodermis is the dermis, containing hair follicles, nerve endings, glands, blood and lymph vessels.
And above the dermis is the epidermis, which contains 5 layers of developing keratinocytes. Keratinocytes start their life at the lowest layer of the epidermis, so the stratum basale or basal layer.
As keratinocytes in the stratum basale mature, they migrate into the next layers of the epidermis, called the stratum spinosum, stratum granulosum, stratum lucidum, and finally, the stratum corneum, which is the uppermost and thickest epidermal layer.
Before we dive into the various inflammatory skin disorders, there are several high yield terms to describe skin lesions.

Terminology2:14–2:34

The most important here are the vesicles, which are up to 1 centimeter in diameter and look like clear blisters filled with fluid, and bullae, which are fluid-filled blisters larger than 1 centimeter.All right then, onto vesiculobullous and desquamating skin disorders!

Pemphigus Vulgaris2:34–5:28

Let’s start with autoimmune blistering diseases, which are a group of autoimmune disorders that affect the skin and mucous membrane like those found in the mouth.
They are caused by a type II hypersensitivity reaction. That’s when the immune system B cells produce antibodies that bind to the body's own proteins.
A disorder belonging to this group is pemphigus vulgaris, which is mainly seen in adults between the age of 40 and 60. Now normally, the epidermal cells, particularly those in stratum spinosum, are bound together by proteins called desmosomes, while other proteins called hemidesmosomes anchor basal cells to the basement membrane.
In pemphigus vulgaris, there are IgG autoantibodies that can bind to the desmosome proteins, desmoglein 1 and 3.As a result, the epidermal cells become separated from each other; this phenomenon is called acantholysis.
Now, in pemphigus vulgaris, the hemidesmosomes are not affected, so cells remain attached to the basement membrane. Upon histology, this kind of looks like a row of tombstones, and is called tombstoning.
Now, the result is the formation of intraepidermal blisters or bullae characteristic of pemphigus vulgaris. These blisters or bullae are flaccid, meaning that they may easily slough off and give rise to very painful erosions.
Erosions are frequently seen in the oral mucosa, which can make it hard for these individuals to eat. Now for diagnosis, a classic sign of pemphigus vulgaris is the Nikolsky sign.
This is when lateral pressure is applied to the lesion, and it causes a split to form between the upper and lower layers of the epidermis.
In addition, a skin biopsy can be performed to look for signs of acantholysis and tombstoning. Direct immunofluorescence can also be useful; that’s where antibodies marked with fluorescent molecules are used to tag the autoreactive IgG antibodies, which are attaching to the intercellular desmosomes.
This appears with a reticular or ‘fish net’ staining pattern. Treatment for pemphigus vulgaris can include both topical and systemic corticosteroids, immunosuppressants like azathioprine or mycophenolate, and rituximab, a monoclonal antibody that binds to B cells and inhibits the production of anti-desmosomal IgG antibodies.
If not treated, pemphigus vulgaris can be fatal, usually due to the lesions becoming infected. Bullous pemphigoid is another autoimmune blistering disease typically affecting those over 60 years of age but is more common than pemphigus vulgaris.

Bullous Pemphigoid5:28–6:40

Another difference between the two diseases is that in bullous pemphigoid, the autoantibodies bind to hemidesmosomes. This causes the basal cells to separate from the basement membrane, and a split forms between the dermis and epidermis, resulting in subepidermal bullae.
A trick to remember this is to think of the word ‘below’ when thinking of ‘bullous’ pemphigoid, since the bullae are ‘below’ the epidermis and basement membrane.
These bullae are tense, so they don’t break off easily. Now, bear in mind that bullous pemphigoid is milder than pemphigus vulgaris, and the oral mucosa is spared.
Now, for diagnosis, it’s high yield to know that Nikolsky sign is negative. In addition, a skin biopsy and immunofluorescence can be done, which will show a linear IgG deposition on the dermal-epidermal junction.
In terms of treatment, bullous pemphigoid responds well to corticosteroids.Next, there is dermatitis herpetiformis, which is strongly associated with celiac disease.

Dermatitis Herpetiformis6:40–7:36

Dermatitis herpetiformis is characterized by the formation of IgA antibodies against tissue transglutaminases. These antibodies deposit in the tips of dermal papilla, and can then cross-react with epidermal transglutaminases.
The IgA-transglutaminase complexes trigger the formation of intensely pruritic papules, vesicles, and bullae that appear bilaterally and symmetrically on the scalp, the extensor aspect of the extremities, and buttocks.
Diagnosis is clinical, and the most effective treatment is a gluten free diet. Additionally, some cases can benefit from treatment with the medication dapsone to help alleviate the itching.
Now, apart from autoimmune blistering diseases, there are also other blistering skin conditions. One of them is erythema multiforme, which is a type IV hypersensitivity reaction.

Erythema Multiforme7:36–8:44

As the name suggests, erythema multiforme can cause lesions in a variety of shapes and sizes. There can be macules, papules, vesicles, or bullae.
Now, what is very high yield is that the most characteristic lesions are target lesions that have central necrosis of the epidermis, surrounded by concentric rings of erythema, making them look like a bull’s eye or target.Now, the most important thing to remember here is that erythema multiforme commonly occurs along with infections, particularly herpes simplex virus or Mycoplasma, as well as with the use of specific medications like sulfa-containing medications, beta lactams, and phenytoin.
Diagnosis is clinical, and since it’s frequently self-limiting, it requires no treatment, though antihistamines can sometimes be used.Finally, Stevens-Johnson syndrome or SJS and Toxic Epidermal Necrolysis or TEN are severe type IV hypersensitivity reactions that most often result from an adverse drug reaction to certain medications, such as penicillin, sulfonamides, allopurinol, or anti-epileptic medications, especially lamotrigine.

Stevens-Johnson Syndrome8:44–10:55

Another cause can be an infection like mycoplasma pneumonia, especially in children and adolescents. Now, typically there’s a brief prodromal period of fever and flu-like symptoms, followed by development of painful macules, involving the skin and sometimes also the mucous membranes.
These macules then progress to vesicles, bullae, and ultimately, there’s skin sloughing due to epidermal-dermal separation and full thickness epidermal necrosis.
This is called the Nikolsky sign.Now, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis form a spectrum of disease.
So if less than 10% of the total body surface area is affected, it’s considered Stevens-Johnson syndrome; and if more than 30% is affected, it’s Toxic Epidermal Necrolysis.
Finally, between 10 and 30%, it’s an overlap Stevens-Johnson syndrome - Toxic Epidermal Necrolysis. The main issue is that, with such an extent of skin and mucosa compromised, individuals may die from a combination of dehydration, malnutrition, and infection from external pathogens leading to sepsis and organ failure.
That’s why they’re both life-threatening dermatological emergencies. Diagnosis is clinical, supported with a history of exposure to a trigger, clinical presentation, and positive Nikolsky sign.
Treatment includes immediately removing the trigger, followed by supportive care with IV fluids and parenteral nutrition.All right, as a quick recap… Vesiculobullous and desquamating skin disorders can be autoimmune, including pemphigus vulgaris, which is caused by antibodies against desmosomes and presents with flaccid intraepidermal bullae, a positive Nikolsky sign and a reticular pattern on immunofluorescence.

Review10:55–12:12

Bullous pemphigoid is also autoimmune, but it’s caused by antibodies against hemidesmosomes, and is less severe, presenting with tense, subepidermal bullae, a negative Nikolsky sign, and a linear pattern on immunofluorescence.Other non-autoimmune vesiculobullous and desquamating disorders are dermatitis herpetiformis, which is associated with celiac disease; erythema multiforme, which is associated with HSV or Mycoplasma infection and medication and classically causes target lesions; and Stevens-Johnson syndrome and toxic epidermal necrolysis, which are typically triggered by medications and cause fever, sloughing of skin at dermal-epidermal junction, a positive Nikolsky sign, and can be life-threatening.Okay, back to our cases.

Summary12:12–13:03

Alan is an older individual who presented with painful flaccid bullae, as well as erosions on the skin and mucosae, and a positive Nikolsky sign.
These clinical findings should make you suspect pemphigus vulgaris, which was then confirmed with immunofluorescence showing a reticular pattern around the epidermal cells.
Finally, Gabriella is a young female with an intensely pruritic rash that appeared bilaterally and symmetrically on the extensor aspect of her extremities, her back, and buttocks.
Additionally, her persistent gastrointestinal symptoms and elevated anti-gliadin antibodies point to celiac disease. Putting this together, the most likely diagnosis for Gabriella is
Vesiculobullous and desquamating skin disorders | Osmosis