Fig. 3.1
Contact dermatitis showing eroded vesicles on all three skin types
ACD usually presents with pruritus [3, 18–21]. Skin may be normal, erythematous, or edematous with vesicles and blisters [5]. Fine desquamation can be a sign of evolving allergic contact dermatitis [22]. In severe cases, ACD is erosive and disfiguring [23]. In its late stage, ACD may manifest as lichen simplex chronicus [24]. Of note, lichen simplex chronicus may be the end point of a variety of eczematous dermatitis or superimposed on other inflammatory processes (e.g., psoriasis, lichen sclerosus, lichen planus, etc.). Not infrequently, the process that started the itch-scratch cycle leading to lichen simplex chronicus changes may have resolved at the time of the biopsy. Of note, both ICD and ACD are not uncommonly present with minimal clinical findings or even as vulvodynia [25, 26].
Vulvar skin is a unique environment due to moisture, occlusion, and friction in which the effects of externally applied agents may be magnified and/or altered [27]. Numerous irritants and allergens have been implicated in vulvar dermatitis, most commonly constituents of cosmetics, preservatives, and medications (including topical steroids), as well as body fluids and overzealous hygiene practices (Table 3.1) [4, 5, 19, 20, 28, 29]. The genetics and pathophysiology of contact dermatitis are complex and multifactorial and remain poorly understood [30]. Patients may have some degree of predisposition to contact dermatitis, and an allergic/atopic history is frequently elucidated [1, 2]. Atopic dermatitis has been linked to filaggrin mutations; both may increase the risk of developing ICD [31].
Table 3.1
Important vulvar irritants/allergens
Body fluids | Latex | Neomycin (Neosporin) |
|---|---|---|
Soaps and detergents | Spermicides | Topical steroids |
Perfume | Chlorhexidine (KY) | Imiquimod |
Heat | Lanolin | Podophyllin |
Sanitary napkins and wipes | Benzocaine (Vagisil) | Trichloracetic/bichloracetic acid |
Central to patient management is identification and removal of the irritant/allergen. Patch testing may prove helpful in the workup [28]; however, due to the unique vulvar environment, results of traditional patch testing on non-vulvar skin may not be entirely applicable [32, 33]. With removal of the inciting agent, prognosis is excellent. Often, the inciting agent is not identified, and topical and systemic therapies may be needed to control the disease. In these situations, remissions are achievable but recurrences are common—these patients requiring long-term follow-up for management.
Histopathology
Biopsy findings of both ICD and ACD vary with the age of the lesion. Early lesions may show minimal spongiosis (Fig. 3.2) with progression to spongiotic vesicles, lymphoeosinophilic infiltrate, dermal edema and serum crust (Fig. 3.3). In subacute contact dermatitis, the epidermis becomes less spongiotic with development of early psoriasiform hyperplasia. (See Vignette 3 at the end of this chapter.) Chronic lesions will be acanthotic with hyperkeratosis and parakeratosis. With time, chronic irritation leads to the finding of lichen simplex chronicus [34] (Fig. 3.4).
Fig. 3.2
Early spongiosis in a case of allergic contact dermatitis. Rare eosinophils, focal parakeratosis, chronic inflammation, and pigment incontinence are present
Fig. 3.3
Acute contact dermatitis with spongiotic vesicles in epidermis and papillary dermal edema with lymphoeosinophilic infiltrate
Fig. 3.4
A case of contact dermatitis with early changes of lichen simplex chronicus with elongation of rete ridges and prominent vessels of papillary dermis
ICD and ACD show significant histopathological overlap and may be impossible to differentiate from each other [35]. Dyskeratosis and balloon cell change may suggest an irritant contact dermatitis [36, 37]. Neutrophilic infiltrate may be seen as a reaction to keratinocyte death. Eosinophils may be a helpful clue to an allergic nature [25] but are also a common finding in drug reactions. Prominent spongiotic vesiculation with eosinophils, Langerhans cell microabscesses, serum crust, and a relatively spared dermis are practically pathognomonic of ACD, but in the vulva, these changes may be less well developed as in nongenital skin, requiring the pathologist to maintain a high index of suspicion. Skin biopsy may be most useful to rule out other entities in the differential diagnosis. Tissue should be sent for direct immunofluorescence (DIF) studies when the differential includes bullous disorders.
Differential Diagnosis
The clinical differential diagnosis is broad and varies with the form and severity of dermatitis. Acute severe ICD and severe ACD may mimic blistering disorders (bullous pemphigoid, mucous membrane pemphigoid, pemphigus vulgaris, bullous, or erosive lichen planus), infection (severe candidiasis, herpes virus infection), erythema multiforme, fixed drug reaction, and Hailey-Hailey disease [4, 22, 23]. Blistering disorders will usually show intraepidermal or subepidermal vesiculation and can be further evaluated with DIF. Infection can be investigated with culture as well as search for viral cytopathic effect and use of special stains. While irritant contact dermatitis may show occasional necrotic keratinocytes, more extensive keratinocyte apoptoses along with variable vacuolar interface dermatitis are clues to fixed drug reaction and erythema multiforme. Extensive acantholysis is the hallmark of Hailey-Hailey disease and is not a feature of contact dermatitis.
When the biopsy shows primarily spongiosis and inflammation, the pathological differential diagnosis includes fungal infection, insect bite reaction, drug reaction, and early lichen sclerosus [39, 40]. Special stains including periodic acid-Schiff (PAS) or Grocott’s methenamine silver (GMS) for fungal infection should be performed. Although the presence of numerous eosinophils suggests insect bite and drug reactions, this finding cannot be relied upon for diagnosis since it can be seen a variety of conditions. Features of early lichen sclerosus are subtle, and its definitive diagnosis would require clinicopathologic correlation. Eosinophilic spongiosis may also be seen in early phases of immunobullous disorders [41, 42]; however, marked dermal edema, dermal eosinophils, and blister formation are seen in the developed phase of these disorders. Immunofluorescence may be helpful if a blistering disorder is suspected. The chronic form of contact dermatitis resembles psoriasis or chronic fungal infection and may evolve to lichen simplex chronicus. Neutrophils are a central component to the diagnosis of psoriasis and are frequently seen in fungal infections but are relatively less common in contact dermatitis. Ultimately, clinical correlation is required for accurate diagnosis.
The differential diagnosis for chronic contact dermatitis includes lichen simplex chronicus, psoriasis, seborrheic dermatitis, tinea cruris, erythrasma, candidiasis, Paget disease, and squamous cell carcinoma in situ [4, 22]. Psoriasis shows a unique constellation of findings: dilated papillary dermal vessels, thinning of suprapapillary plates, confluent parakeratosis with diminution of the granular layer, and neutrophilic collections. Infection should be evaluated with the aid of special stains and microbiology culture. Paget disease will show proliferation of large epithelioid cells of glandular derivation throughout the epidermis with ascent toward the stratum corneum. Squamous cell carcinoma in situ is an intraepidermal proliferation of dysplastic squamous cells. It should also be noted that contact dermatitis is often superimposed on other vulvar pathology, thus altering the clinical picture and complicating diagnosis [20, 38].
Summary
Clinical Presentation
Acute irritant/allergic contact dermatitis
Well demarcated
Generally confined to site of contact; as a result skin folds are relatively spared (particularly in cases of irritant contact dermatitis)
Erythema, edema, erosions, and blistering
Chronic irritant/allergic contact dermatitis
Pruritus (more pronounced in allergic than irritant contact dermatitis)
Poorly demarcated
Variable skin changes may include lichenification and pigmentary alteration
Vulvodynia
Pseudoverrucous papules and nodules (a unique form of chronic irritant contact dermatitis)
Histologic Features
Early lesions
Epidermal spongiosis with variable vesicle formation
Dyskeratosis and balloon cell degeneration in irritant reactions
Dermal chronic inflammatory infiltrate accentuated in a perivascular pattern
Variable exocytosis
Dermal and epidermal eosinophils frequent in allergic reactions
Late lesions
Hyperkeratosis
Parakeratosis
Epidermal acanthosis and hypergranulosis
Dermal fibrosis and perivascular lymphocytic infiltrate
Differential Diagnosis
Fungal infection
Drug reaction
Arthropod assault
Bullous disorders
Early lichen sclerosus
Psoriasis
Lichen simplex chronicus (often super-imposed)
Paget disease
Takeaway Essentials
Clinically Relevant Pearls
Contact dermatitis is a common cause of vulvar symptoms and should be considered in any patient presenting with vulvar complaints, including those with minimal clinical changes and those not responding to therapy.
The presentation of contact dermatitis is highly variable and often superimposed on other pathology, which may confound diagnosis.
Vulvar eczema is common, but due to social stigma may often be underreported and self-medicated, which can also be a challenge to diagnosis.
Pathology Interpretation Pearls
Biopsy findings may be nonspecific but may be very helpful in ruling out other disease processes.
Special stains for fungal organisms or immunofluorescence studies may be useful adjuncts.
Acute and irritant contact dermatitis may be indistinguishable on pathology.
Amicrobial Pustulosis of the Folds
Clinical Features
Amicrobial pustulosis of the folds (APF) is a recently described entity [43], with approximately 40 cases reported in the literature to date. Patients tend to be females in the third or fourth decade of life with an underlying autoimmune disturbance, most commonly lupus erythematosus [44]. Other diseases associated with APF include: idiopathic thrombocytopenic purpura [45], myasthenia gravis [45], celiac disease [46], mixed connective tissue disease [47], lupus erythematosus-scleroderma overlap [48], discoid lupus erythematosus with Sjogren’s syndrome [49], IgA nephropathy with Sjogren’s syndrome [50, 51], Hashimoto’s thyroiditis [52, 53], Grave’s disease [53], and autoimmune hepatitis [54]. Patients with APF may also have autoantibodies or elevated immunoglobulins but fail to fulfill criteria for autoimmune disease [44, 49, 55].
Lesions are ill-defined collections of papules and pustules on an erythematous base that are both follicular and non-follicular in distribution. Papules and pustules coalesce to form plaques and areas of macerated erosion. Lesions involve major and minor skin folds and are also common on the scalp, around the external ear canal, and nostrils (Fig. 3.5). Secondary impetiginization with crusting is common. Scalp lesions may be associated with hair loss in the form of a non-scarring alopecia [47, 49, 56]. Diagnostic criteria have been proposed that include obligate and minor criteria (Table 3.2); diagnosis requires fulfillment of all obligate criteria plus one minor criteria [46]. Lesions are generally confined to the skin; however, in one case, extracutaneous oral and gastrointestinal manifestations were present [57].
Fig. 3.5
Amicrobial pustulosis of the folds showing scaling, crusted lesions in axilla; similar lesions were also seen in inguinal folds, labia majora, and mons pubis (Photo courtesy of Neil Prose, M.D.)
Table 3.2
Diagnostic criteria for amicrobial pustulosis of the folds
Obligate criteria | Minor criteria |
|---|---|
Pustulosis involving one or more major skin folds, one or more minor skin folds, and anogenital area | Association with one or more autoimmune disorder |
Histopathology showing intraepidermal spongiform pustules | Positive ANA (1:160 or higher) |
Negative microbiology culture results | One or more serum autoantibodies |
APF is a chronic, relapsing disease. Patients often have a protracted history of a “rash” present for months to years prior to diagnosis. The associated autoimmune disturbance is either well known [54] or uncovered at the time of workup of APF [53]. Patients who fall short of fully developed autoimmune disease may go on to develop one in the future, necessitating close follow-up [58]. For the most part, cutaneous involvement by APF is independent of the activity of underlying autoimmune disease. However, in some cases, skin findings have resolved with resolution of the underlying disease [49, 50, 54].
The etiology and pathogenesis of APF remain unclear. Most consider APF as belonging to the category of neutrophilic dermatoses/autoinflammatory syndromes [57–62], yet it also has strong links to autoimmune disease. This raises questions of interplay between the innate and adaptive immune systems in the pathogenesis of APF [63]. In the setting of autoimmune disease, autoantibodies may erroneously activate complement within the skin, generating chemotactic factors that induce neutrophil migration or otherwise activate the innate immune system [51, 59, 61]. The proinflammatory chemokine and cytokine profiles in APF tissue share similarities with those in other neutrophilic dermatoses and pustular disorders [59, 64].
Histologic Features
Intraepidermal and subcorneal spongiform pustules are the hallmark of APF (Fig. 3.6). The surrounding epidermis shows mild spongiosis with neutrophilic exocytosis. Epidermal acanthosis or psoriasiform hyperplasia is common. The stratum corneum may contain parakeratosis and neutrophilic debris. Neutrophils and lymphocytes populate the superficial to mid dermis. The dermal inflammatory infiltrate is accentuated around blood vessels, hair follicles, and sweats ducts and may be associated with nuclear dust between collagen fibers. Eosinophils and plasma cells are a less commonly reported component of the dermal inflammatory infiltrate. Papillary dermal edema and superficial dermal capillary dilation have been reported, which is important to remember when considering distinction of APF from psoriasis. The dermal mononuclear infiltrate consists primarily of CD3+ CD4+ lymphocytes, while CD15+ granulocytes are found in the spongiform pustules [48, 65]. Ki67 and Bcl-2 may be increased, accompanied by redistribution of involucrin expression to the lower portion of the stratum spinosum [65]. CD8 and p53 immunohistochemical staining may be useful in differentiating APF from psoriasis [65]; however, this remains to be substantiated with larger studies. The results of DIF/lupus band studies in the majority of cases are negative. Of note, not all APF patients have a clinical diagnosis of LE. Even among those who do, not all tested are positive in the lupus band test.
Fig. 3.6
Amicrobial pustulosis of the folds microscopically exhibits neutrophilic pustules, variable spongiosis, and mild acute and chronic inflammation in the dermis. High power {inset photo} shows a large neutrophilic pustule beneath the cornified layer and involving the upper dermis
Differential Diagnosis
The differential diagnosis includes other pustular disorders such as pustular psoriasis, subcorneal pustular dermatosis (Sneddon-Wilkinson disease), and acute generalized exanthematous pustulosis (AGEP). Personal/family history and triggering events can usually be elucidated in cases of psoriasis. Subcorneal pustular dermatosis affects an older patient population, spares the face, is less erythematous, and is often associated with IgA gammopathy, inflammatory bowel disease, or pyoderma gangrenosum. AGEP is characterized by sudden onset of a widespread, non-follicular-based rash in patients who are acutely ill, with subsequent spontaneous resolution. On pathology, the above pustular disorders can have significant overlap with APF. Confluent parakeratosis with hypogranulosis may be a clue to psoriasis. The observation of follicle-centered pustulation, if present, can be helpful as this feature should not be a component of pustular psoriasis, subcorneal pustular dermatosis, or AGEP. Ultimately, the presence of spongiosis in addition to pustules, in combination with clinical data, will point to a diagnosis of APF. Infection and drug reaction must be ruled out. Cultures should be included in the workup. APF-like eruptions may be a form of anti-TNF alpha drug reactions [66]. Blistering disorders such as IgA pemphigus and pemphigus foliaceus may also be considered. The presence of acantholysis as well as positive immunofluorescence studies will be helpful in making the distinction from APF.
In summary, APF is a diagnosis of exclusion that requires a high level of suspicion and ultimately depends upon synthesis of clinical and histopathological data.
Summary
Clinical Presentation
Folliculocentric and non-folliculocentric lesions
Papules/pustules on erythematous base
Coalesce into plaques (+/− crusting/erosion) with intact papules/pustules at borders
Involvement of major and minor skin folds and anogenital area
Microbiology cultures negative
Associated with autoimmune disease or presence of autoantibodies
Histologic Features
Intraepidermal and subcorneal spongiform pustules
Epidermal spongiosis and neutrophil exocytosis
Dermal inflammatory infiltrate of lymphocytes and neutrophils may be accentuated in a perifollicular and perivascular distribution
Special stains for infectious organisms are negative
Differential Diagnosis
Pustular psoriasis
Subcorneal pustular dermatosis
Acute generalized exanthematous pustulosis
Infection
Drug reaction
IgA pemphigus
Takeaway Essentials
Clinically Relevant Pearls
Amicrobial pustulosis of the folds is a unique clinicopathological condition but requires a high index of suspicion and ultimately is a diagnosis of exclusion.
There is a strong correlation between amicrobial pustulosis of the folds and autoimmune disorders, so thorough screening and follow-up are recommended.
Cutaneous lesions do not appear to wax and wane with the underlying autoimmune disease.
Pathology Interpretation Pearls
Unlike most pustular disorders, amicrobial pustulosis of the folds has a spongiotic component.
Immunofluorescence is helpful to rule out blistering disorders.
Cytotoxic/Vacuolar Interface Pattern
Fixed Drug Eruption
Clinical Features
Fixed drug eruptions are rare, and recurrent type IV hypersensitivity reactions triggered by a wide range of medications. More than 100 drugs have been implicated in this reaction, but major offenders include analgesics, antibiotics, and sedatives (Table 3.3). Several factors may complicate the identification of the culprit, such as: drug as a component of other medications (e.g., phenolphthalein in laxatives), patients with multiple medications, and the cross reactivity among various drugs. Occasionally, the offending medication cannot be identified; these cases have been called “fixed drug-like eruptions” [67]. Patients may complain of a burning or itchy sensation, but systemic symptoms are rare. The clinical appearance may differ depending on the affected anatomic location. On keratinized vulvar skin, fixed drug eruption presents as one or few well-demarcated erythematous round plaques that can evolve to blisters and erosions. This symmetric vulvitis with erosive changes may extend from labia majora to inguinal folds and the perineum. On the other hand, mucosal and modified vulvar mucous membranes commonly blister leading to erosions with irregular borders. Lesions have the tendency to occur in the same anatomic location after exposure to the medication; however, new lesions may appear in each episode. Sites of predilection besides the genitalia include face and lips. The time lapse between first exposure and the clinical lesion is 1–2 weeks and is often reduced to less than 24 h in subsequent exposures but may be as short as “minutes.” Although nongenital fixed drug eruption leads to postinflammatory hyperpigmentation, vulvar lesions have the tendency to be of the nonpigmenting type [68]. The pathogenesis of fixed drug eruption has not been completely elucidated; it appears that the offending drug acts as a hapten and binds to proteins present in cells. In the nonpigmenting variant, the target antigen is believed to be dermal rather than epidermal [69]. A cellular cytotoxic response against the altered cells is elicited with cellular destruction executed by CD8+ lymphocytes mediated by Fas ligand triggering a caspase cascade [70]. The increased incidence of HLA-B22 supports a genetic susceptibility. The diagnosis of fixed drug eruption is reached after recognizing the relationship between the abrupt onset of an erythematous well-demarcated, erythematous, and symmetrical vulvitis with the ingestion of a medication known to produce this type of skin eruption.
Table 3.3
Frequent drug offenders in vulvar fixed drug eruption
Ibuprofen | NSAIDs |
|---|---|
Cyclooxygenase-2 inhibitors | Barbituric acid |
3-hydroxy-3-methyl-glutaryl-coenzyme reductase inhibitors | Tetracyclines |
Pseudoephedrine | Metronidazole |
Fluconazole | Griseofulvin |
Trimethoprim-sulfamethoxazole | Carbamazepine |
Histopathology
In its classic form, fixed drug eruption displays an interface inflammatory pattern with a superficial and deep mixed inflammatory infiltrate. Its healing phase is characterized by marked postinflammatory melanin incontinence; however, vulvar fixed drug reaction may not demonstrate classic histologic features [68]. In the vulva, fixed drug reactions commonly show epidermal spongiosis associated with a mild perivascular and interstitial lymphocytic infiltrate admixed with eosinophils and neutrophils. This predominantly dermal-based reaction lacks the classic postinflammatory pigmentary incontinence, leading to the designation as “nonpigmentary fixed drug eruption.”
Differential Diagnosis
The presence of a recurrent, cutaneous, erythematous plaque in the same anatomic location in conjunction with the recent ingestion of a medication known to produce fixed drug eruption is pathognomonic. Genital lesions with focal blister formation and erosions raise the differential diagnosis of contact dermatitis, herpes simplex, pemphigus vulgaris, Behçet syndrome, and erythema multiforme/toxic epidermal necrolysis. Epidermal spongiosis can be seen in both contact dermatitis and fixed drug eruption; however, identification of Langerhans cells granulomas favors contact dermatitis. The superficial and deep perivascular inflammatory infiltrate with the presence of neutrophils favors fixed drug eruption over erythema multiforme and toxic epidermal necrolysis. The simultaneous presence of oral ulcers, documentation of pathergy, and involvement of internal organs supports the diagnosis of Behçet syndrome. Viral cytopathic changes can differentiate herpes virus infection from fixed drug eruption. If a blistering disorder is strongly suspected, a DIF test on properly fixed tissue (such as in Michel’s medium) may clarify the diagnosis.
Summary
Clinical Presentation
Hair-bearing skin: recurrent, circumscribed erythematous recurrent plaque
Modified mucosa: recurrent, erythematous plaque with irregular erosions
A nonpigmenting variant of fixed drug eruption is commonly seen on the vulva.
The hallmark is the reappearance of the lesion in the same anatomic location with rechallenge by the offending drug.
Histologic Features
Vacuolar interface dermatitis (classic)
Superimposed spongiotic change (a common variation, especially in early lesions)
Perivascular lymphocytic infiltrate with few neutrophils and eosinophils
Differential Diagnosis
Contact dermatitis
Erythema multiforme
Toxic epidermal necrolysis
Takeaway Essentials
Clinically Relevant Pearls
Careful history taking is essential to reach diagnosis.
A fixed drug reaction is diagnosed when lesions subsides after cessation of the drug intake and or recur after rechallenge.
Since hypersensitivity to the drug is lifelong, the cure is to avoid the drug.
The dissimilarity to the classic clinical presentation of fixed drug reaction, high frequency of nonpigmentary type, makes it unlikely to be clinically suspected.
Fixed drug reaction should be considered in any acute or recurrent vulvitis with nonspecific biopsy, negative microbiology, and unresponsiveness to treatment.
Pathology Interpretation Pearls
The presence of a deep infiltrate is a clue to differentiate fixed drug eruption from erythema multiforme and toxic epidermal necrolysis.
In recurrent flare-ups, histologic features of acute and chronic inflammation coexist.
Erythema Multiforme
Clinical Features
Erythema multiforme (EM) is a cutaneous hypersensitivity phenomenon characterized by acute onset of self-limited, pleomorphic lesions. The clinical episode of EM lasts from 1 week to 10 days. Commonly, it affects extremities in a symmetrical distribution. Rarely the vulva is the only affected anatomic location, and in a review of 65 patients with recurrent EM, 25 % exhibited genital involvement [71]. Infection (e.g., herpes virus, Streptococcus, and Mycoplasma) is often the underlying cause; other stimuli include drugs and pregnancy. Medications triggering this reaction encompass antibiotics (particularly sulfonamides and their derivatives like the cyclooxygenase-2 inhibitor celecoxib), oral contraceptives, selective serotonin reuptake inhibitors, 5-fluorouracil sestamibi, and many others. The disease can affect patients with a wide range of age, but it is uncommon in childhood. Clinically, painful areas of erythema are quickly followed by the development of vulvar blisters that end in painful enlarging ulcers. The hallmark clinical presentation is the targetoid or “bull’s eye” lesion (central zone of necrosis, blister, or erosion surrounded by edema and erythema) (Figs. 3.7 and 3.8). A variation of the classical targetoid lesion, known as the “atypical targetoid lesion,” can also occur in the form of a round raised lesion with only two zones: central edema and an erythematous border. Two forms of EM have been delineated on the basis of frequency and time course of an episode(s): recurrent and persistent types. The persistent form is associated with malignancies and Epstein-Barr virus infection, while the recurrent type is seen in patients suffering from recurrent infections like herpes simplex virus (HSV). Recurrent attacks of EM-like eruptions secondary to herpes viral infection can be halted with use of treatment during HSV prodromal or contiguous suppressive therapy.
Fig. 3.7
Eroded area on labia majora from erythema multiforme
Fig. 3.8
Targetoid lesions in axilla in patient with erythema multiforme. Most patients with vulvar erythema multiforme will have lesions on other cutaneous surfaces
EM can present with mucosal involvement, fever, and systemic symptoms. Medications and infections with Mycoplasma pneumoniae are usually associated with these severe cases. The latter form of EM needs to be separated from Stevens-Johnson syndrome (SJS). A critical difference between these two diseases is internal organ involvement in SJS. EM has typical or raised atypical targetoid lesions on the extremities or face in a patient with less fever and milder mucosal lesions but frequent recurrences, while SJS exhibits flat atypical targetoid lesions or purpuric macules that are widespread or limited to the trunk. When bullae are present, to diagnose EM, the epidermal detachment must be less than 10 % of body surface [72].
Patients with widespread lesions are toxic and exhibit an increased risk of secondary infection and temperature instability comparable to burn patients. The mortality in these cases is around 40 % [73].
Histopathology
The histology of a lesion of EM varies depending on the clinical stage of the disease. Early lesions may show changes mainly in the dermis in the form of edema, chronic inflammation, and red cell extravasation associated with focal interface changes—a constellation of findings that correlate with the clinical appearance of purpura. The classic picture of an acute fully developed lesion includes normal stratum corneum overlying squamous epithelium with marked destruction of the basal layer by vacuolar alteration of keratinocytes and presence of dyskeratotic cells (Figs. 3.9 and 3.10). Ballooning and reticular degeneration of keratinocytes is associated with individual cell necrosis and associated fluid accumulation. Individual cell death may progress to confluent epidermal necrosis. The inflammatory cell infiltrate is comprised of lymphocytes with histiocytes located in the upper dermis. Eosinophils may be identified. Leukocytoclasis is not seen. Eventually, the epidermis detaches forming a subepidermal blister leading to an ulcer and reepithelialization. Histologic changes cannot point to a particular trigger; however, the presence of keratinocyte necrosis in the acrosyringium associated with eosinophils is most frequently seen in drug-mediated EM [74]. Histologic changes when seen in the vulvar-modified mucosa or mucosa are similar to hair-bearing skin; however, intercellular edema is more prominent and blisters more quickly evolve to erosions/ulcers. DIF shows intraepidermal Civatte bodies, staining usually with IgM and occasionally with C3. Commonly there is granular staining for C3 along the dermoepidermal junction.
Fig. 3.9
Low power view of erythema multiforme with normal cornified layer and minimal dermal change
Fig. 3.10
Higher power of erythema multiforme where necrotic keratinocytes and sparse dermal inflammatory infiltrate of lymphocytes and eosinophils are seen
Differential Diagnosis
EM shares similar histologic features with SJS; however, EM shows a more inflammatory reaction, while SJS exhibits more keratinocytic necrosis. Ultimately, it is the extensive mucosal and internal organ involvement seen in SJS that separates these two disorders. EM-like changes can be seen in paraneoplastic pemphigus and in the hypersensitivity reaction to phenytoin and carbamazepine; a DIF test and the clinical presentation is essential to differentiate EM from these diseases. EM may be sometimes confused with connective tissue disease (e.g., systemic and subacute lupus erythematosus and dermatomyositis) and graft-versus-host disease (GVHD). Dermal mucin and presence of hyperkeratosis with parakeratosis, evidence of chronic disease, are associated with connective tissue disease. Satellitosis can be seen in EM and GVHD; hyperkeratosis, hypergranulosis, and hyperpigmentation of the basal layer would favor GVHD. The presence of deep dermal infiltrate can separate fixed drug reaction from EM. Importantly, none of the abovementioned findings are absolutely pathognomonic of any of the diseases, and only a clinicopathologic correlation will ensure their distinction.
Summary
Clinical Presentation
Vulvar involvement is often accompanied by lesions on nongenital sites
Painful erythema leading to blister and ulcer (<10 % body surface detachment)
Targetoid lesions
Atypical targetoid lesions
Painful vulvar areas of erythema followed by blisters and ulcers (ulcers often worse on modified mucosa and mucosa)
Histologic Features
Marked vacuolar basal layer degeneration and presence of necrotic keratinocytes at all levels of epidermis
Isolated and scattered keratinocytic necrosis may become confluent.
Subepidermal blister due to damage of basal layer can be seen.
Prominent dermal infiltrate of lymphocytes and histiocytes
Eosinophils can also be seen in the infiltrate.
Differential Diagnosis
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Fixed drug reaction
Connective tissue disease
Graft-versus-host disease
Takeaway Essentials
Clinically Relevant Pearls
The diagnosis is made by the conjunction of abrupt onset and clinical appearance of the lesions in a patient recently exposed to medications or suffering from infection.
In bullous erythema multiforme, a biopsy for direct immunofluorescence is recommended to rule out autoimmune disease as treatments drastically differ.
The rapid onset of erythema multiforme can separate this entity from bullous disorders, while the number and anatomic distribution of lesions can help differentiate erythema multiforme from fixed drug eruptions.
Pathology Interpretation Pearls
The presence of necrotic keratinocytes at the opening of the sweat gland and eosinophils in the dermal infiltrate are frequently associated with a drug etiology.
Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome
Clinical Features
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are cutaneous eruptions that display diffuse, tender erythema rapidly evolving to blistering, and extensive shedding of skin. Fortunately, these life-threatening conditions have low incidence with 1.2–6 cases and 0.4–1.2 cases per million for SJS and TEN, respectively. When blisters remain discrete and are associated with mucous membrane involvement, the condition is classified as SJS; when blisters rupture and coalesce in areas of denuded erythema, the disease is diagnosed as TEN. A consensus paper by Bastuji-Garin and colleagues in 1993, established the clinical criteria such that detachment of more than 30 % of the body surface qualifies for the diagnosis of TEN [75]. Vulvar lesions are commonly part of the diffuse mucous-cutaneous involvement.
Clinical lesions range from blisters and erosions to atypical targetoid lesions (round lesions with central edema surrounded by erythema). In vulvar mucosal or modified mucosal involvement, the blisters have a short life span—turning rapidly into erosions (Fig. 3.11). Severe cases of SJS may lead to complications like vaginal stenosis [76] and visual impairment secondary to keratitis with conjunctival scarring. The risk of death, reportedly around 35 %, can be predicted using a quantitative “severity of illness” score (SCORTEN) [77].
Fig. 3.11
Erythematous and eroded area at introitus in a patient with toxic epidermal necrolysis
Factors associated with poor prognosis are advanced age, large areas of denuded skin, deteriorating renal function, and extensive involvement of the bronchial epithelium. In the majority of cases of TEN, a drug is the culprit with less than 15 % of cases associated with other stimuli like immunizations or infections. Only half of the cases of SJS are associated with a therapeutic drug. A constantly growing list of medications has been seen reported as offenders in SJS and TEN; the most common group of drugs include antibiotics, nonsteroidal antiinflammatory drugs, and anticonvulsants (Table 3.4). The epidermal destruction is mediated by factors like CD8+ lymphocytes with cytokine effectors, such as tumor necrosis factor (TNF) alpha, perforin, and granzyme B. Apoptosis of keratinocytes may also occur through activation of CD40/CD40L and Fas and Fas-ligand pathways on epidermal cells. Cytokines may explain the disparity between degree of lymphocytic infiltrate and degree of epidermal destruction [78].
Table 3.4
Most frequent drugs associated with increased risk for toxic epidermal necrolysis and Stevens-Johnson syndrome
Sulfonamides | Phenytoin | Doxycycline |
|---|---|---|
Trimethoprim-sulfamethoxazole | Nonsteroidal antiinflammatory | Nucleoside reverse-transcriptase inhibitor |
Phenobarbital | Oxicam | Cyclooxygenase inhibitors |
Carbamazepine | Allopurinol | Corticosteroids |
Nitroglycerin patch | Griseofulvin | Sustained-release bupropion |
Histopathology
The spectrum of histologic finding in SJS and TEN are similar to EM. All three entities display sparsely inflamed interface dermatitis with basal layer vacuolization and keratinocyte necrosis that may become confluent (Fig. 3.12). Eventually a blister is formed with necrotic epidermis as the roof. In patients in which skin is denuded, it may be “rolled” and embedded on end to examine the epidermis without performing a biopsy. The full-thickness necrosis can be readily seen (Fig. 3.13). Histologic exam may have prognostic importance, as the degree of inflammation may predict survival; in one study, inflammation and survival correlated inversely [79]. In the healing phase, milia can be seen on the hair-bearing surface of the vulva, and adenosis may be detected in the mucosa or modified mucosa of the vulva and vagina [80].
Fig. 3.12
Toxic epidermal necrolysis with vacuolar degeneration and full-thickness necrosis of epidermis with normal orthokeratin layer, signifying acute nature of process
Fig. 3.13
Denuded skin from patient with toxic epidermal necrolysis, arranged in a “roll” showing changes of necrosis ranging from basal layer to full-thickness epidermis. The keratin layer shows little change, signifying the acute nature of the process
Differential Diagnosis
Staphylococcal scalded skin syndrome is an important clinical differential diagnosis (see Chap. 4). This entity is characterized by subcorneal detachment with collection of neutrophils and absence of full-thickness necrosis. On histologic grounds, EM can overlap with SJS and TEN. The presence of a marked inflammatory reaction, restriction of the necrosis to the lower portion of the epidermis, and erythrocyte extravasation favor EM.
Summary
Clinical Presentation
Painful erythema, blisters, and ulcers on the vulva may be part of in diffuse disease
Stevens-Johnson syndrome
Flat atypical targetoid lesions and erythematous macules
Blisters and erosions of one or more mucous membranes
Less than 10 % body surface detachment
Toxic epidermal necrolysis
Flat atypical targetoid lesions and/or erythematous macules
More than 30 % body surface detachment
Overlap Stevens-Johnson syndrome/toxic epidermal necrolysis
Flat atypical targetoid lesions and/or erythematous macules
10–30 % body surface detachment
Histologic Features
Pauci-inflammatory interface dermatitis
Keratinocytic necrosis leading to full-thickness necrosis
Mild superficial dermal infiltrate of lymphocytes and histiocytes
Eosinophils may be present
Differential Diagnosis
Erythema multiforme
Staphylococcal scalded skin syndrome
Takeaway Essentials
Clinically Relevant Pearls
Mucosal and conjunctival involvement is noted.
Pathology Interpretation Pearls
When a blister is sampled, the edge of the lesion is essential to identify the primary interface process.
Presence of dead keratinocytes in the acrosyringium and eosinophils in the dermal infiltrate favor a drug-related etiology.
Graft-Versus-Host Disease
Clinical Features
Graft-versus-host disease (GVHD) is a major multisystem complication in transplant patients—targeting the skin, gastrointestinal tract, lung, and liver. GVHD classically occurs in bone marrow transplant patients but also can follow solid organ transplantation, transfusion of nonirradiated blood or blood products in severely immunosuppressed patients, and as a complication of transplacental transfer of maternal lymphocytes in an immunodeficient fetus. The pathogenesis is extremely complex, but it essentially occurs when transplanted immunocompetent donor T-cell lymphocytes are activated and react to foreign host major histocompatibility complex (MHC)-antigens in an immunosuppressed recipient patient. Cytokines including IL-1, TNF alpha, and granulocyte-monocyte colony-stimulating factor (GM-CSF) also play a role in the pathogenesis of this disease. Besides human leukocyte antigen (HLA) disparity, development of acute GVHD may be secondary to sex mismatch, increased patient age, and the development of infection. Twenty-four percent to 36 % of patients suffering from GVHD develop genital involvement [81]. Vulvar manifestations may be GVHD’s first or only presentation [81]. These patients are at increased risk of infection which is a concerning cause of morbidity and mortality.
In 2005, the National Institute of Health proposed to divide GVHD into the following: classic acute, persistent, classic chronic, and overlap syndromes [82] (Table 3.5). Acute GVHD may resolve or in 35 % of cases evolve to chronic GVHD. The risk of chronic GVHD is eleven times greater if the patient has experienced acute GVHD. Chronic GVHD develops in 10 % of all patients with allogeneic bone marrow transplant with involvement of organs such as the skin, eyes, mouth, esophagus, liver, genitalia, muscle, and central and peripheral nervous system.
Table 3.5
National Institutes of Health consensus development project on criteria for chronic graft-versus-host disease
Classic acute GVHD: acute GVHD presenting within 100 days after HCT or donor leukocyte infusion |
Persistent, recurrent, or late-onset acute GVHD: acute GVHD occurring more than 100 days after transplantation without chronic GVHD symptoms |
Classic chronic GVHD: chronic GVHD without features of acute GHVD regardless of timing from transplantation |
Overlap syndromes: both acute and chronic GVHD features present regardless of timing from transplantation |
Vulvovaginal GVHD can be seen at any stage of the disease coexisting with manifestations of GVHD in other organs. 75 % of patients with vulvar involvement by GVHD have manifestations of chronic disease in nongenital skin [83]. The severity of genital GVHD is independent of the severity of GVHD found in other organs. Most gynecologic manifestations develop an average of 1 year after transplantation, although reported late-onset cases highlight the need of a long-term gynecologic follow-up in these patients. Symptoms include vulvar or vaginal dryness, irritation, dyspareunia, and postcoital bleeding. Examination shows excoriated and ulcerated erythematous patches, fissures, thickened mucosa, vestibular tenderness, and a narrowed introitus (Fig. 3.14). Scarring of the vulva and vagina presents in the form of labial fusion and vaginal closure, respectively. Early diagnosis of genital GVHD prevents progression to fibrotic stages and decreases morbidity in these patients. The clinical presentation is classified in three tiers based on the degree and extension of the gynecologic findings in the vulva and vagina (Table 3.6). Its most extreme presentation includes a TEN-like eruption. This classification better portrays the dynamic character of the diseases. The majority of the patients exhibit a mild form of genital GVHD; only 6–12 % present with severe forms. These patients are at high risk of fungal, bacterial, and viral infection. The higher risk of genital infection by HPV in these patients is underscored by the increased incidence of cervical cancer in long-term stem cell transplantation survivors compared to general population [84].
