UPMC Dermatopathology “Case of the Month” Presentations
UPP - Department of Dermatology, Dermatopathology Unit
Authors: Sarah Harper MS-IV, and Drazen Jukic M.D., PhD.
June /July 2004 CASE OF THE MONTH
DISCUSSION & DIAGNOSIS
Diagnosis:
Final Diagnosis case 1: PEMPHIGUS VULGARIS
Final Diagnosis case 2: PARANEOPLASTIC PEMPHIGUS
Discussion:
The designation of pemphigus refers to a group of autoimmune blistering diseases of the skin and mucous membranes characterized histologically by intradermal blister and immunopathologically by the finding of in vivo bound and circulating immunoglobulin G (IgG) antibody directed against the cell surface of keratinocytes. The primary types of pemphigus include pemphigus vulgaris (PV), pemphigus foliaceus, pemphigus vegetans, and paraneoplastic pemphigus (PNP). Each type of pemphigus has distinct clinical and immunopathologic features; here, we discuss PV and PNP
PV accounts for approximately 70% of pemphigus cases. Patients with active disease have circulating and tissue-bound autoantibodies of both IgG1 and IgG4 subclasses. Pemphigus antibody binds to keratinocyte cell surface molecules desmoglein 1 and 3, resulting in acantholysis. Pemphigus antibody also fixes components of complement to the surface of epidermal cells.
1. Histopathology from the edge of a lesion demonstrates an intradermal blister. Suprabasal epidermal cells separate from the basal cells to form the blisters with acantholytic cells (Figure 13). The basal cells separate from one another but remain attached to the basement membrane resulting in the "tombstone" pattern characteristic of PV (figure 14). With histology, PV can be differentiated from pemphigus foliaceous, which demonstrates a more superficial epidermal cleavage.
2. Direct immunofluorescence (DIF) on normal-appearing perilesional skin usually shows in vivo deposits of IgG (1 and 4) deposited on the surface of the keratinocytes in and around lesions (see Figure 4). Complement components such as C3 (figure 5) and immunoglobulin M are present less frequently than IgG. DIF shows intercellular deposition throughout the epidermis. This pattern of immunoreactants is not specific for PV and is also seen in pemphigus vegetans, pemphigus foliaceus, and pemphigus erythematosus.
3. Indirect immunofluorescence (IDIF) should also be done using the patient's serum if DIF is positive. In the patient's serum, IDIF demonstrates the presence of circulating IgG autoantibodies that bind to epidermis. Circulating intercellular antibodies are detected using IDIF in 80-90% of patients with PV. The titer of circulating antibody often correlates with disease course.
Paraneoplastic pemphigus (PNP) is an autoimmune blistering and erosive mucocutaneous disease associated with neoplasia (and despite clinical similarities, most likely, has no direct etiopathologic relationship with PV) . Characteristically, it manifests with erosions and ulcerations of the oral mucosa extending to the surface of the lips. Conjunctival lesions are also present in over half of the patients. Skin lesions are of different histopathologic flavor: pemphigus-like, pemphigoid-like, erythema multiforme-like, graft versus host disease-like and lichen planus-like (Note: In our case, a combination of latter three could be seen - see figures 7 to 9 and figure 12). Most PNP cases are associated with a hematologic malignancy, but there have been cases of PNP with solid non-hematologic neoplasms including thymomas, poorly differentiated sarcoma, bronchogenic squamous cell carcinoma, and follicular dendritic cell sarcoma.
1. Histopathology of oral and cutaneous lesions reveals variable epidermal necrosis, suprabasal acantholysis, dyskeratotic keratinocytes, vacuolar interface dermatitis, and lymphocytic exocytosis. Suprabasal acantholysis can result in clefts and "tombstoning," which is the appearance of the basal cell layer below the cleft, and it can be indistinguishable from pemphigus vulgaris (this pattern is seen rarely - akin to PV pattern demonstrated in Figure 14). However, a distinctive feature of paraneoplastic pemphigus is dyskeratosis (Figure 9); the presence of dyskeratosis in a suprabasal acantholytic bullous disorder is indicative of paraneoplastic pemphigus rather than PV (see also figure 12).
2. Direct immunofluorescence for skin biopsies of PNP shows IgG deposition to the keratinocyte cell surfaces ("fish-net" pattern) in the entire epidermis and C3 deposition to the cell surfaces in the lower epidermis (usually in a band-like fashion).
3. Indirect immunofluorescence using normal human skin sections also shows IgG anti-cell surface antibodies in the PNP sera. However, unlike PV, circulating and tissue-bound antibodies in patients with this disease are directed against a group of molecules in the plakin family which are found in desmosomes and hemidesmosomes and are important in intermediate filament attachment. The most reliable substrate is rodent bladder.
Comparison between PV and PNP
|
|
PV |
PNP |
|
Epidemiology |
Rare, M=F, onset between 40-60, more common in Jewish and Mediterranean |
Very rare, F:M=2:1, onset at 60 years and older, associated with malignancy, most often lymphoid |
|
Clinical |
Flaccid blisters or crushed erosions, located on head, upper trunk, intertriginous areas, and mucosa; often begins on oral mucosa, may lead to hoarseness; skin is usually painful and Nikolsky's sign positive |
Extensive painful mucocutaneous erosions, resembling pemphigus vulgaris, in the presence of neoplasm; targetoid erythematous papules with dusky centers resembling erythema multiforme may also be present |
|
Dx |
Light: suprabasilar blister with acantholysis |
Light: suprabasilar blister with acantholysis (similar to
PV), with basal cell vacuolation, exocytosis, and dyskeratotic keratinocytes
(similar to erythema multiforme) |
|
Tx |
Corticosteroids taper to maintenance; may add azathioprine; methotrexate, Cytoxan, CellCept; plasmapheresis |
treatment of the neoplasm, symptomatic treatment with corticosteroids/immunosuppressive |
|
Target Antigen |
Desmoglein 3, desmoglein 1 |
Periplakin/envoplakin, desmoplakins I&II, BP230, desmoglein 1, desmoglein 3, HDI/plektin |
|
Other |
May be fatal if untreated, risk of infection |
Usually rapidly fatal |
SUMMARY:
The goal of PV treatment is to reduce the synthesis of these autoantibodies. Combination of systemic therapy with corticosteroids and immunosuppressive agents is usually required. In fulminant cases, plasmapheresis has been used to remove autoantibodies from the circulation. Paraneoplastic pemphigus is also usually treated with combination therapy to help alleviate symptoms, but treatment of the malignant neoplasm does not appear to alter the progression of the condition. Patient 1 was tried first on steroids and Imuran. After several days without a slow down in the progression of her disease, she received 3 plasmapheresis treatments. After the third treatment she was started on Cytoxan and her symptoms improved considerably. Her lesions began to heal and she did not obtain any new lesions. She was also placed on TPN until she was able to eat. She was placed on a PCA pump for pain control and was switched to p.o. pain medication prior to discharge. Patient 2 was lost to follow-up. .
References:
1. Anhalt GJ, Kim SC, Stanley JR, et al., Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N. Engl. J. Med. 323 25 (1990), pp. 1729-1735.
2. Kimyai-Asadi A and Jih MH , Paraneoplastic pemphigus. Int. J. Dermatol. 40 6 (2001), pp. 367-372.
3. Nikolskaia OV, Nousari CH, Anhalt GJ, Paraneoplastic pemphigus in association with Castleman's disease. Br J Dermatol. 149 6 (2003):1143-51
4. Nousari HC and Anhalt GJ, Pemphigus and bullous pemphigoid. Lancet 354 (1999), pp. 667-672.
5. Thivolet J and Jablonska S, Bullous disorders: from histology to molecular biology. Clin. Dermatol. 19 (2001), pp. 538-543.
