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PEMPHIGUS (TIER 2)
The pemphigus disorders are characterized by a disruption of the cohesive structures that bind particular squamous epithelial cells to their neighbors. Pemphigus is
a disease of squamous epithelium; more specifically, the initial site of damage is at the level of desmosomes. Autoantibodies PVA and PFA react with transmembrane structural glycoproteins of the E-cadherin class.
There is variation in the structure of glycoproteins at levels in the epidermis. Those of the superficial layers are characterized as desmoglein 1 and those of the deeper layers of the epidermis as desmoglein 3.
Damage to these glycoproteins, in response to the effects of autoantibodies, are cited as the basis for the variation in patterns, when lesions of pemphigus vulgaris are compared with lesions of pemphigus foliaceus.
In pemphigus vulgaris (basal-level acantholysis of desmoglein 3 type), basal keratinocytes lose their connection to their neighbors, but remain attached to the
basement membrane. Inter-cellular spaces among individual basal keratinocytes are widened; inter-cellular bridges do not bridge the spaces. In addition, the loss of inter-cellular bridges among basal keratinocytes
(the basal row of cells at the interface with the basement membrane) results in a separation of the suprabasilar epithelium (epithelial cells above the level of the most basal row of cells) from the basal layer; the
formation of a bulla is the result (S6C7P1-1-3). The bulla is an acantholytic defect; it may be almost uniformly suprabasilar, or
there may be a few layers of loosely attached keratinocytes along the floor (S6C7P1-3). In some examples, the defect is relatively
free of inflammatory cells. In other examples, particularly in lesions showing not only acantholysis, but also acanthosis, dermal infiltrates of inflammatory cells may be prominent. In some examples, eosinophils are
a feature; they may be found in the intra-epidermal defects (S6C11P5-1). The keratin layer may be unaltered. The defect often will
dissect along hair follicles (S6C8P2-6 & 7). In some lesions, the defect along the surface of the skin will be suprabasilar and the
defect along the luminal surface of follicles will be more superficial (S6C11P5-2).
In some example of pemphigus vulgaris, the epidermis is thin. In other examples, the roof of the defect shows some degree of acanthosis; in such examples, the intact
epidermis bordering the defect (S6C8P2-1-2) may also be acanthotic. In still other examples, acanthosis is a more prominent feature; the
patterns will merge with those of pemphigus vegetans (S6C9P3-3 & 4).
In some examples, the defect seems to form at the interface between the superficial and the basal units of the epidermis. This pattern might suggest that the lesion
is old, and that regeneration has begun along the floor of the bulla. On the other hand, it may be that, in some lesions, the defect forms initially between the two functioning (i.e., the superficial and the basal)
units of the epidermis. Perhaps the state of the epidermis at the time of the autoimmune insult determines the location of the defect (S6C9P3-5).
Perhaps, an intermediate form of pemphigus should be given recognition. Some examples of IgA pemphigus are characterized by changes at this intermediate level.
Pemphigus vegetans is characterized by epidermal hyperplasia with elongated, coarsened rete ridges. The papillary dermis is widened. Eosinophils are prominent in the
dermal infiltrates. In some of the elongated columns of keratinocytes, defects are found. These defects contain acute and chronic inflammatory cells with a component of eosinophils. In addition, the defects contain
individual, rounded, acantholytic cells, as well as clusters of less affected keratinocytes (S6C10P4-1-3)
In some examples, elongated dermal papillae are edematous (S6C8P2-5, & S6C9P3-1)).
In the process of acantholysis, individual keratinocytes may be released into the intraepidermal defect; the unattached cells are rounded; they have a symmetrically
rounded nucleus, often with a prominent nucleolus. A perinuclear halo often is a feature. The cytoplasm of the acantholytic cells condenses and becomes brightly acidophilic (S6C8P2-3 & 4, S6C9P3-2, & S6C9P3-6); these alterations qualify as dyskeratosis. In some examples, the acantholytic cells are plentiful in the defect and the patterns
may be difficult to distinguish from those of Hailey-Hailey disease (S6C12P6-5).
Pemphigus foliaceus (superficial acantholysis of desmoglein 1 type) often presents in a psoriasiform pattern with regular elongation of the rete ridges. If the
keratin layer has separated from the underlying epidermis, it often shows normal “basket-weave” patterns, but there may be areas showing focal parakeratosis. Often, the keratin layer will have been lost, either
prior, during, or after a biosy. In any case, the acantholytic changes occur in the granular layer, or at the interface between the keratin layer and the granular layer. Hypergranulosis is often a feature. Along the
floor of the defect, loosely attached acantholytic cells may retain their polygonal, or angular, outlines; they often contain keratohyaline granules in the cytoplasm (S6C11P5-2 & 3, S6C12P6-3 & 4). Along the floor of
the defect, some of the acantholytic cells, which have not completely separated from their neighbors are rounded in outline (S6C11P5-4 & 5);
they bulge into the defect. The acantholytic process usually dissects along the epithelium of follicles at the same level as seen along the surface of the skin, but there are exceptions.
Many lesions of pemphigus will be characterized by defects at the interface between the basal and the superficial units of the epidermis. For some examples, the
defects resemble old spongiotic vesicles; such examples may be lesions undergoing repair along the floor of what was originally a suprabasilar defect (S6C11P5-6). In other examples, the defects, even in a single lesion, are variable in location with areas that are suprabasilar, areas
that are intermediate, and areas that are superficial (S6C11P5-1 & 2)
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Joly P, et al: Sensitivity and specificity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus.
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Firooz A, Mazhar A, Ahmed R: Prevalence of autoimmune disease in the family members of patients with pemphigus vulgaris. J Am Acad Dermatol 1994;31: 434-7.
Carmisa C, et al: Para neoplastic pemphigus: a report of three cases including one long-term survivor. J Am Acad Dermatol 1992;27: 547-53.
Bowen GM, et al: Lichenoid dermatitis in paraneoplastic pemphigus: a pathogenic trigger of epitope spreading? Arch Dermatol 2000;136: 652-6.
Chan LS: Epitope spreading in paraneoplastic pemphigus: autoimmune induction in antibody-mediated blistering skin diseases. Arch Dermatol 2000;136: 663-4.
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HAILEY-HAILEY DISEASE
Benign familial “pemphigus” (Hailey-Hailey disease) is a genetic, acantholytic disorder affecting the basal unit of a hyperplastic epidermis; hair follicles in such
a lesion are likely to be spared. The process results in a supra-basilar cleft in which the cells of the basal unit are loosely arranged, or form loose clusters (S6C12P6-5). The acantholytic cells are rounded in outlines; they show cytoplasmic acidophilia, and concentrically arranged cytoplasmic
fibrils (dyskeratosis) (S6C12bP6b-1-4). The superficial unit often is hyperplastic and intact above the defect. The keratin
layer may show focal areas of parakeratosis; some examples are ichthyotic; they show compact hyperkeratosis (S6C12aP6a-1).
In some examples, the level of the defect varies; over the tips of the dermal papillae, the defect is supra-basilar; over the elongated rete ridges, the defect is at
the interface between the basal unit and the superficial unit (it is intermediate) (S6C12aP6a-1-4 & S6C13P7-2-3).
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