Paraneoplastic Pemphigus

Etiology

Lymphoproliferative neoplasms are the most commonly identified underlying diseases in paraneoplastic pemphigus development, accounting for up to 84% of cases.[5][9] Approximately two-thirds of PNP cases are due to non-Hodgkin lymphoma and chronic lymphocytic lymphoma.[10][11] However, other neoplasms are associated with PNP development, such as sarcomas, particularly follicular dendritic cell sarcomas,[12][13] thymomas,[14] squamous cell carcinomas of the skin, tongue, vagina, and carcinomas of the lung, stomach, and colon.[4][15][16]

In adults, non-Hodgkin lymphoma is the most frequent underlying neoplasm (38.6%), followed by chronic lymphocytic leukemia (18.4%), and Castleman disease (18.4%).[3] Non-hematological neoplasms account for 16% of cases. Paraneoplastic pemphigus in children and adolescents is often the presenting sign of Castleman disease.[17]

Recently, researchers have identified increased susceptibility to paraneoplastic pemphigus development in patients with HLA Class II Drb1*03 allele[18] and HLA-Cw*14.[19] These alleles are more common in Caucasian and Chinese populations, respectively. In contrast, HLA-DR4 and HLA-DR1-14 increase susceptibility to pemphigus vulgaris and pemphigus foliaceus, but have not shown an association with the development of PNP.[8]

Epidemiology

The exact incidence of paraneoplastic pemphigus (PNP) is unknown. It is much less common than pemphigus vulgaris or pemphigus foliaceus, comprising only 3 to 5% of all pemphigus cases.[5][2]

Paraneoplastic pemphigus typically develops in adults 45 to 70 years old.[5] The disease can occur in children and is usually associated with Castleman disease.[20][17] Men and women seem to share equal predilection.[3]

In a study of 496 patients with internal malignancy, 25 of these patients developed pemphigus (5%). The mean age of PNP patients was 64.7 years and PNP development correlated with increasing age.[21] Most cases of paraneoplastic pemphigus arise in patients with a known underlying neoplasm that may or may not have received previous treatment.[8] However, if no known neoplasm exists in a patient presenting with PNP signs and symptoms, an exhaustive workup for occult neoplasm is urgently indicated.[4]

Pathophysiology

The following proteins, among others, are targeted by autoantibodies in paraneoplastic pemphigus:[3][11][22][23]

• Desmoglein types 1 (160 kD) and 3 (130 kD) – Desmosome, extracellular (Dsg1, Dsg3)
• Desmoplakin 1 (250 kD) and 2 (210 kD) – Desmosome, intracellular
• Bullous pemphigoid antigen 1 (230 kD)– Hemidesmosome/lamina lucida (BP230)
• Envoplakin (210 kD) – Desmosome, intracellular
• Epiplakin (more than 700 kD) - Desmosome, intracellular
• Periplakin (190 kD) – Desmosome, intracellular
• Alpha-2-macroglobulin-like-1 antigen (170 kD) (A2ML1) - protease inhibitor[24][25][26]

Autoantibodies against plakin proteins are characteristic of PNP and not typically found in other forms of pemphigus.[23][27][28]

Histopathology

Histologic features of paraneoplastic pemphigus (PNP) include epidermal acantholysis and clefting, necrotic keratinocytes, vacuolization of the basal layer, and lymphocyte exocytosis.[29][3][30] Dyskeratosis with suprabasal acantholysis is a distinctive feature of PNP.[8] However, histopathologic characteristics will vary with the particular patient’s clinical lesion morphology, ranging from non-inflammatory bullous lesions to dense lichenoid inflammatory infiltrates.[30][29][31] Interface dermatitis secondary to a T-cell mediated autoimmune reaction and subsequent infiltration into the epidermis suggests a cell-mediated cytotoxicity component to PNP.[32]

Paraneoplastic pemphigus may mimic erythema multiforme both clinically and histologically, particularly if lesions are characterized by predominant interface dermatitis with necrotic keratinocytes. Therefore direct immunofluorescence and indirect immunofluorescence are imperative for correct diagnosis. Similarly, the characteristic suprabasal acantholysis and blister formation seen in paraneoplastic pemphigus are essentially identical to that observed in pemphigus vulgaris, although other vulgaris features are typically absent.[29] Lichen planus-like lesions in PNP may exhibit bands of lymphohistiocytic infiltrates in the papillary dermis accompanied by vacuolar interface change.[30][11]

Histological findings of interface dermatitis, vacuolar changes, and dyskeratotic keratinocytes should raise suspicion for PNP, as these features are not present in classic pemphigus.[27]

History and Physical

Paraneoplastic pemphigus (PNP) almost always presents with early mucosal involvement, typically with vesicles or bullae that result in painful mucocutaneous erosions and severe stomatitis, similar in morphology to pemphigus vulgaris.[10][8][33][9] In fact, oral mucositis refractory to treatment may be the only presenting symptom of PNP.[4] Mucous membrane lesions of the oral cavity may progress to involve the vermilion borders, tongue, oropharynx, nasopharynx, and esophagus. The conjunctiva and anogenital region can also be affected.[34][3][35] Severe erosions, crusting, and ulceration on the tongue, lips, and palate may resemble Stevens-Johnson syndrome or erythema multiforme.[22]

Cutaneous involvement in paraneoplastic pemphigus is typically diffuse and can exhibit considerable variation in appearance and morphology.[8][7] Cutaneous manifestations often present after mucosal symptoms, ranging from pruritic red-purple papules, targetoid erythematous plaques, diffuse erythema, flaccid erosive blisters, and widespread exfoliative erythroderma.[10] For this reason, PNP can mimic other skin diseases such as lichen planus, erythema multiforme, bullous pemphigoid, pemphigus vulgaris, and graft-versus-host disease. The variety of clinical manifestations is likely secondary to the range of autoantibodies with which patients can potentially present.[8] Five major clinical subtypes of paraneoplastic pemphigus have been identified: pemphigus-like, bullous pemphigoid-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like.

Clinical Presentations of Paraneoplastic Pemphigus[3][5][7][8]

1. Pemphigus-like
   • Clinical: superficial vesicles, flaccid blisters, crusted erosions
   • Histopathology: intraepidermal and or suprabasal acantholysis with surrounding mononuclear cells
2. Pemphigoid-like
   • Clinical: scaling erythematous papules and tense blisters
   • Histopathology: dyskeratosis with subepidermal splitting, with or without basal cell vacuolization; sparse mononuclear infiltrate at the dermal-epidermal junction
3. Erythema Multiforme-like
   • Clinical: Scaling erythematous papules; severe, polymorphic cutaneous or mucosal lesions
   • Histopathology: Dyskeratosis with or without accompanying epidermal acantholysis; perivascular infiltrates
4. Graft-versus-Host Disease-like
   • Clinical: Diffuse red, scaly, sometimes dusky, papules
   • Histopathology: hyper-ortho/parakeratosis and variable dyskeratosis with or without vacuolar interface change
5. Lichen Planus- like
   • Clinical: small red to violaceous flat-topped scaly papules
   • Histopathology: hyperkeratosis with a lichenoid infiltrate at the dermal-epidermal junction

In a study of 104 patients, an erythema multiforme-like presentation was most common (56%), followed by PV-like (41%), lichen planus-like (13%), and bullous pemphigoid-like (3%).[24] However, others report an equal incidence of clinical subtypes amongst PNP patients.[7] Also, patients have presented with psoriasiform and pustular lesions.

An individual patient may have various forms of coexisting cutaneous lesions and have lesions that transform to a different morphology. Blisters and erythema multiforme-like lesions affecting the palms and soles can help differentiate PNP from pemphigus vulgaris, which typically does not involve these surfaces.

Extracutaneous Involvement

Paraneoplastic pemphigus can affect other types of epithelia. Thus internal organ involvement is common, particularly in the eyes, lungs, gastrointestinal tract, thyroid, kidney.[27] Incidence of pulmonary involvement ranges from 59.1% to 92.8% of PNP cases.[8][7] Eye involvement occurs in up to 70% of patients and may lead to irreversible blindness.[36][34] Ocular presentations of PNP include pseudomembranous conjunctivitis with progressive scarring, conjunctival or corneal erosions and ulcerations, eyelid thickening, and pterygium.[22][27] Cases reports exist of corneal melting.[36]

Respiratory involvement can present as dyspnea, dry cough, obstructive lung disease, or secondary pneumonia, with potential for rapid progression to bronchiolitis obliterans.[8][37] Paraneoplastic pemphigus with bronchiolitis obliterans is associated with high mortality rates.[38] The pathologic mechanism resulting in bronchiolitis obliterans development is not completely understood. The presumption is that autoantibodies play a role, causing loss of adhesion between respiratory epithelial cells and subsequent bronchiole obstruction.[27] Specifically, antibodies targeting epiplakin have been implicated.[23]

In a study of 58 PNP patients, 39% experienced significant muscle weakness. Myasthenia gravis was ultimately diagnosed in 35% of these patients as they exhibited high titers of anti-acetylcholine receptor or anti-acetylcholinesterase antibodies.[39] Interestingly, the levels of these antibodies significantly increased in patients with PNP with dyspnea. Patients with underlying thymomas showed an expected higher frequency of myasthenic symptoms than those with other underlying neoplasms.

Evaluation

No formally accepted diagnostic criteria exist for paraneoplastic pemphigus.[40] Diagnostic confirmation is typically by a combination of clinical presentation, histology, direct and indirect immunofluorescence microscopy, and immune serology. Immunoprecipitation and immunoblotting are both specific and sensitive for the detection of circulating autoantibodies.[31][41] Biopsy should ideally be taken from an early lesion so that an intact specimen can be examined (mature bullae typically rupture easily). Providers should avoid punch biopsy due to possible epidermal detachment from the dermis.

Anhalt’s et al. original PNP diagnostic criteria have as their basis on five immunological, histological, and clinical features:[6]

Clinical

Painful mucosal erosions with or without accompanying polymorphous cutaneous lesions in the setting of an underlying malignancy

Histopathology

Suprabasal (intraepidermal) acantholysis, interface dermatitis, and keratinocyte necrosis

DIF (Direct Immunofluorescence)

IgG and complement (C3) deposition within the intercellular spaces of the epidermis, often with linear, granular basement membrane zone deposition

IIF (Indirect Immunofluorescence)

Detection of autoantibodies targeting intercellular proteins found in transitional or stratified squamous epithelia

Immunoprecipitation

Precipitation of a characteristic proteins desmoplakin 1 (250 kD), bullous pemphigoid antigen (230 kD), desmoplakin 2 (210 kD), periplakin (190kD), alpha-2-macroglobulin-like-1 antigen (170 kD)

Joly et al. evaluated these diagnostic criteria and identified three features with both high specificity (84%-100%) and sensitivity (82-86%).[31] These were:

1. Presence of an underlying lymphoproliferative disorder
2. An IIF positive for autoantibodies on rat bladder
3. Detection of autoantibodies against periplakin and envoplakin on immunoblot

As more atypical presentations and disease manifestations of PNP get reported, researchers continue to propose variants to the classic diagnostic criteria. For instance, Camisa and Helm created diagnostic guidelines that classify criteria as either major or minor. PNP diagnosis requires three major criteria, or two major and two minor criteria.[42][8]

Major Criteria

• Polymorphic mucocutaneous eruptions
• Concomitant internal neoplasm
• Serum antibodies with a specific immunoprecipitation pattern

Minor Criteria

• Acantholysis observed histologically
• DIF displaying intercellular and basement membrane staining
•  IIF staining positive on rat bladder epithelium

Diagnosis of PNP

Histopathology: Dyskeratosis with suprabasal acantholysis with possible basilar vacuolization are classic histological features of PNP.[11][43] However, the histopathologic findings correlate and vary with an individual patient’s clinical lesions that may be a result of a primarily humoral or cellular immune response, or a mixture of both. Overlapping patterns between lesions are common. Additionally, acantholysis is not specific for paraneoplastic pemphigus or pemphigus diseases as a whole, as it may present in several other pathologies.[43]

Direct Immunofluorescence (DIF): Typically reveals intercellular IgG and C3 in the epidermis, often in a net-like pattern between cells. Granular or linear IgG and C3 deposits along the basement membrane zone at the dermal-epidermal junction may also be present - a characteristic unique to PNP compared to other forms of pemphigus.[22] However, DIF can be negative in up to 50% of cases.[31] As such, some researchers have proposed removing DIF as an essential criterion for the diagnosis of PNP.[17]

Indirect Immunofluorescence (IIF): The presence of circulating antibodies targeting the intercellular proteins of cells within stratified squamous or transitional epithelia are characteristic of PNP.[2][22] IIF testing of patient serum on plakin-rich rat bladder is especially helpful in discriminating paraneoplastic pemphigus from pemphigus vulgaris or pemphigus foliaceous and may be useful as a specific screening test for diagnosis.[31][30]

Immunoprecipitation and Immunoblot: Serologic detection of autoantibodies against the 210-kD band of envoplakin and the 190-kD band of periplakin is both sensitive and specific for the diagnosis of PNP.[31] Additionally, PNP serum may react with desmoglein 3, desmoglein 1, desmoplakin I (250 kD), desmoplakin II (210kD), bullous pemphigoid antigen I (230kD), and the recently identified 170-kD antigen, alpha-2-macroglobulin-like-1, among others. One report identified alpha-2-macroglobulin-like-1 autoantibodies present in 50% of PNP patients but found none in patients with other forms of pemphigus.[44] Immunoblot is considered the gold standard for PNP diagnosis.[31] Enzyme-linked immunosorbent assays (ELISAs) targeting envoplakin and periplakin have undergone development for paraneoplastic pemphigus diagnosis.[41][45][46]

Additional Work-Up

Upon diagnosis of PNP, evaluation for an underlying malignancy is mandatory. Suggested studies and labs include CBC, LDH, flow cytometry, and imaging of the chest, abdomen, and pelvis.

Treatment / Management

Overall, the treatment of paraneoplastic pemphigus remains controversial and undefined.[8][47] Early diagnosis and treatment of the underlying malignancy are of utmost importance. Solid tumors should undergo surgical resection with all attempts to block tumor blood supply and minimize manipulation to prevent the hematogenous spread of associated autoantibodies. Infusion of high dose IV-immunoglobulin before and after surgery may reduce the risk of bronchiolitis obliterans, a common complication of PNP, by blocking the action of any released autoantibodies.[8][30](B2)

Medical treatment should aim at reducing inflammation, suppressing the immune response, and providing proper wound care. High-dose corticosteroids are considered first-line therapy. Additional systemic immunosuppressants (such as azathioprine or mycophenolate mofetil) may be required if the disease continues to progress or is refractory to treatment with steroids alone.[11][27][35] Therapeutics targeting IgG autoantibodies or B-cells have also found use in PNP treatment. Rituximab (anti-CD20 B-cell depleting monoclonal antibody) and more recently alemtuzumab (monoclonal antibody targeting CD52 expressed on T and B-cells) have shown some efficacy in PNP with underlying lymphoproliferative malignancies.[48][49][50] Other therapies discussed in the literature include cyclosporine, cyclophosphamide, plasmapheresis, intravenous immunoglobulin, and the use of biosynthetic dressings.[3](B3)

While cutaneous lesions may improve within 12 weeks, mucosal involvement can be poorly responsive to treatment.[16][48] Though PNP treatment depends on addressing the underlying malignancy, there is not always a parallel evolution between PNP severity and the malignancy’s treatment.[2][8] Lesions may continue to progress even if the underlying malignancy is removed or controlled.(B3)

It is essential to recognize and address extracutaneous manifestations and secondary infections promptly. Loss of epidermal integrity places patients at significant risk of infection, dehydration, and electrolyte imbalances. Ideally, PNP patients should receive treatment at a certified burn center for optimal wound care.[16] Extracutaneous involvement and secondary complications guide specialist consultation. In addition to oncology, therapy for paraneoplastic pemphigus often requires the interprofessional participation of ophthalmology, urology, infectious disease, gastroenterology, and urology/gynecology.(B3)

Occlusive, hydrating dressings should be used to prevent further fluid and electrolyte loss while promoting healing.[51] Ulcerated skin and mucosal lesions should be cleaned with sterile warm water compresses twice daily, and kept moist with emollients and low adhesive wound dressings, such as petroleum jelly-impregnated gauze. The use of silver dressings is advantageous as they reduce the incidence of infection and also require less frequent dressing changes.[52] Manage pain with topical analgesics and opioids as needed.[53] For selected lesions, a potent corticosteroid or calcineurin inhibitor can be topically applied. Orally applied topical corticosteroids (such as triamcinolone acetonide gel) and analgesic mouthwashes can be useful for oral lesions.[53] Bioengineered dressings used for burn patients may be necessary in severe cases. Nasogastric tubes are required if a patient is unable to eat due to painful oropharyngeal lesions. Inadequate protein intake hampers wound healing; thus, nutritional protein supplementation may show benefits.[52] Bedridden patients should receive frequent position changes to prevent pressure ulcer formation.

Anti-septic baths and topical antimicrobials are preferable to systemic medications.[52] However, severe secondary infections must be identified early and treated with appropriate systemic antimicrobials to prevent sepsis. Patients with bronchiolitis obliterans are especially susceptible to secondary pneumonia requiring systemic antibiotics. Any patient with a new fever, hypotension, tachycardia, or changes in mental status should receive a full infectious workup for suspected sepsis.

Also, prophylaxis for side effects of prolonged corticosteroid and other immunosuppressive therapies merits provider focus.

Differential Diagnosis

Differential diagnoses for paraneoplastic pemphigus (PNP) include:

• Stevens-Johnson syndrome/erythema multiforme
• Toxic epidermal necrolysis
• Lichen planus
• Graft-versus-host disease
• Herpes simplex virus
• Drug-induced pemphigus
• Pemphigus vulgaris
• Mucous membrane pemphigoid
• Major aphthous or chemotherapy-induced stomatitis
• Staphylococcal scalded skin syndrome
• Bullous pemphigoid

Correct diagnosis relies on a combination of clinical presentation, histopathology, DIF/IIF, and immunoblot or immunoprecipitation studies.

Prognosis

Even with treatment, paraneoplastic pemphigus (PNP) outcomes are often poor, with mortality rates up to 90%.[2][8][54][10] Infection from widespread skin loss and immunosuppressive therapy, the progression of the associated malignancy, and bronchiolitis obliterans development are common causes of death. Less aggressive or resectable neoplasms are typically associated with improved prognoses.[3][55]

The presence of keratinocyte necrosis and cutaneous lesions resembling erythema multiforme, especially when accompanied by extensive mucosal and cutaneous lesions at presentation, are two factors associated with a worse prognosis.[47] In a study of 144 patients with PNP and underlying hematologic malignancy, the presence of envoplakin autoantibodies and bronchiolitis obliterans development correlated with an increased risk of death. Toxic epidermal necrolysis-like or bullous pemphigoid-like clinical presentations were associated with decreased survival.[38]

Concentrations of serum IgG autoantibodies against Dsg1 and Dsg3 may parallel the clinical symptoms. Thus Dsg-ELISA can be a serological marker of disease activity in pemphigus.[11]

Complications

Ocular involvement in paraneoplastic pemphigus is common and thus should be closely monitored. Early ophthalmology referral is key to prevent vision loss and blindness. Ocular therapy may include the use of topical corticosteroid drops, artificial tears, and 10% N-acetylcysteine, and sometimes requires surgical intervention in cases of extensive scarring.[36]

Bronchiolitis obliterans, presenting with a dry cough, dyspnea, and hypoxemia, affects an estimated 30% to 90% of PNP patients.[54][56] Respiratory failure due to bronchiolitis obliterans development was identified as the most common cause of death in a study of PNP patients with Castleman disease. Biopsy of the lungs may reveal bronchiole fibrosis, dense lymphohistiocytic infiltrate, and autoantibody deposition in bronchial epithelia.[54][30] Possible causes of bronchiolitis obliterans include autoantibody-mediated injury, infection, or drug toxic side effects.[54] For resectable tumors, infusion of high dose IV-immunoglobulin before and after surgery may reduce the risk of bronchiolitis obliterans development by blocking circulating autoantibodies released from the tumor. Results from a study of Japanese PNP patients suggests bronchiolitis obliterans development is associated with epiplakin autoantibodies, as epiplakin-negative PNP patients did not develop bronchiolitis obliterans.[23] Repeated infections can further complicate bronchiolitis obliterans.

Epidermal erosions and blister rupture may cause significant fluid, protein, and electrolyte losses resulting in dehydration and electrolyte imbalances. Breaching and subsequent loss of the skin barrier also predispose patients to infection and sepsis, compounded by the effect of immunosuppressive therapies used to treat PNP and the underlying malignancy. Mucosal lesions are often resistant and persistent even after intensive treatment.

Dehydration and malnutrition secondary to painful oropharyngeal erosions may occur. Thus a nasogastric tube may be required in some patients.