Paraneoplastic Pemphigus

The exact cause of PNP remains unknown, however, it's notably common in individuals with underlying  neoplasms, suggesting a triggering autoimmune response. Autoantibodies are generated predominantly against the plakin family of proteins, which are found in desmosomes and hemidesmosomes. These structures are responsible for the connections between cells and are important for the maintenance of tissue architecture. 

Lymphoproliferative malignancies, such as non-Hodgkin lymphoma and CLL, constitute the most frequently identified underlying conditions in the development of paraneoplastic pemphigus. A variety of other malignancies have been connected to PNP, especially those of the gastrointestinal tract and lymphoid tissue. For example, Castleman disease, a rare condition characterized by the overgrowth of lymphatic tissue within lymph nodes, has also been associated with this condition, especially among children and adolescents. Overall, paraneoplastic pemphigus typically emerges in adults between the ages of 45 and 70, and both sexes appear to be equally susceptible to PNP. 

PNP most commonly affects the mucous membranes and skin, presenting with diverse clinical appearances, categorized into five subtypes: pemphigus-like, pemphigoid-like, erythema multiforme-like, graft-versus-host disease-like, and lichen planus-like. The pemphigus-like subtype manifests as superficial vesicles, flaccid blisters, and crusted erosions. In the pemphigoid-like presentation, individuals experience scaling, erythematous papules (i.e., raised lesions on the skin that is less than one centimeter wide) and firm blisters. Erythema multiforme-like cases are characterized by scaling erythematous papules, often leading to severe polymorphic cutaneous or mucosal lesions. The graft-versus-host disease-like presentation presents with diffuse red, scaly papules that can sometimes appear dark. Lastly, the lichen planus-like subtype involves small, red-to-violet flat-topped, scaly papules.  

PNP is most typically characterized by vesicles (i.e., a small thin-walled sac filled with a clear fluid, ) or bullae (i.e., larger blisters, more than five millimeters, filled with clear fluid) that may rupture, resulting in painful erosions and severe inflammation in the mucocutaneous areas (e.g., oral mucosa, conjunctiva, trunk, anogenital area, and extremities). Initially, resistant oral mucositis (i.e., inflammation of the oral mucosa) might be the only initial symptom of PNP. The lesions on mucous membranes, commonly starting in the oral cavity, can progress to affect other regions like the lips, tongue, oropharynx, nasopharynx, and esophagus. The conjunctiva and anogenital area can also be impacted.  

In PNP, diffuse areas of skin may be involved and can exhibit a wide range of appearances. The cutaneous signs often arise after mucosal symptoms and can include pruritic, red-purple papules; diffuse erythema  with targetoid lesions; and soft erosive blisters. Extensive loss of the outer skin layer as a result of lesion sloughing can result in severe dehydration, protein loss, and heightened infection risk. PNP can resemble other skin conditions like lichen planus, erythema multiforme, bullous pemphigoid, and pemphigus vulgaris.  

Extracutaneous Involvement 

Paraneoplastic pemphigus can also affect internal organs in addition to the mucous membranes and skin. Particularly, the eyes, lungs, gastrointestinal tract, thyroid, and kidneys are commonly affected. Pulmonary involvement is observed in a substantial proportion of PNP cases, manifesting as dyspnea, dry cough, obstructive lung disease, or secondary pneumonia, and can rapidly progress to bronchiolitis obliterans (i.e., an irreversible condition causing inflammation and scarring of the lung tissue). PNP associated with bronchiolitis obliterans carries high mortality rates. The exact mechanism leading to bronchiolitis obliterans isn't fully understood, but it's hypothesized that autoantibodies may disrupt adhesion between respiratory epithelial cells, resulting in bronchiole obstruction. Eye involvement is also commonly detected, with potential irreversible blindness. Other ocular manifestations include conjunctivitis with progressive scarring; conjunctival or corneal erosions and ulcerations; eyelid thickening; and pterygium (i.e., a triangular-shaped overgrowth of the conjunctiva). Muscle weakness is also notable among individuals affected by PNP.  Interestingly, those with underlying thymomas displayed a higher prevalence of myasthenic symptoms, such as weakness, compared to individuals with other underlying neoplasms. 

Diagnosis of PNP is typically made by clinical presentation; biopsy and histology; direct and indirect immunofluorescence microscopy; and immune serology. Biopsy should ideally be taken from an early lesion so that an intact specimen can be examined, as mature bullae typically rupture easily. Providers should avoid punch biopsy due to possible epidermal detachment from the dermis. The original diagnostic criteria for PNP include clinical, histopathological, and immunological features. The criteria involve painful mucosal erosions, specific skin changes, suprabasal acantholysis, immune deposition patterns, autoantibody detection, and protein precipitations. Variants of the criteria have been proposed due to atypical presentations.  

PNP can present with distinct features on histopathology which may aid in diagnosis. Pemphigus-like lesions show acantholysis (i.e., loss of coherence between epidermal cells due to the breakdown of intercellular bridges) within or just above the basal layer, accompanied by adjacent mononuclear cells on histopathology. Pemphigoid-like lesions reveal dyskeratosis (i.e., faulty construction of keratin within individual cells) coupled with separation of the epidermis from the underlying dermis. Vacuoles (i.e., small cavities in the tissues containing air or fluid) in the basal cell basement, and sparse mononuclear cells at the dermal-epidermal junction may also be present. In erythema multiforme-like cases, dyskeratosis is observed, sometimes accompanied by epidermal acantholysis. Additionally, perivascular infiltrates might be evident. Graft-versus-host disease-like biopsies typically show nucleated keratinocytes, variable dyskeratosis, and vacuolar interface changes. Lastly, the lichen planus-like subtype exhibits hyperkeratosis and a lichenoid, band-like, infiltrate of inflammatory cells in the superficial dermis. 

Direct Immunofluorescence (DIF) of PNP lesions usually displays intercellular IgG and C3 in the epidermis, often forming a net-like pattern. IgG and C3 deposits may occur along the basement membrane zone at the dermal-epidermal junction, which is unique to PNP. However, DIF could be negative in up to 50% of cases, leading to suggestions for reconsidering its essential diagnostic criterion. 

Indirect Immunofluorescence (IIF) characteristic of PNP is the presence of circulating antibodies targeting intercellular proteins in squamous or transitional epithelium. Testing patient serum on plakin-rich rat bladder through IIF is particularly valuable in distinguishing PNP from other pemphigus types, serving as a specific test for diagnosis. 

Immunoprecipitation (i.e., a laboratory technique used to isolate and concentrate a specific protein from a complex mixture of proteins) and immunoblot (i.e., also known as Western blot, is a technique used to detect and analyze proteins) includes detecting autoantibodies against the 210-kD band of envoplakin and the 190-kD band of periplakin. Both techniques are sensitive and specific for PNP diagnosis.

Immunoblot is considered the gold standard for PNP diagnosis. Enzyme-linked immunosorbent assays (ELISAs) targeting envoplakin and periplakin have also been developed for diagnosis. 

Upon diagnosing PNP, it is imperative to investigate potential underlying malignancies. Recommended studies and tests include complete blood count (CBC), lacate dehydrogenase (LDH), and imaging of the chest, abdomen, and pelvis. 

The management of paraneoplastic pemphigus lacks well-defined guidelines and typically involves management of the underlying malignancy and supportive care. Prompt identification and treatment of the underlying malignancy is of utmost importance. Surgical excision is recommended for solid tumors, emphasizing techniques that minimize the release and spread of associated autoantibodies. Administering high-dose intravenous immunoglobulin (IVIG) before and after surgery may reduce the risk of bronchiolitis obliterans. 

Medical intervention aims to control inflammation, suppress the immune response, and ensure proper wound care. Primary treatment involves high-dose corticosteroids. If disease progression persists or doesn't respond to steroids alone, additional systemic immunosuppressants, like azathioprine or mycophenolate mofetil, may be necessary. Targeting IgG autoantibodies or B-cells has shown efficacy. Rituximab and alemtuzumab have been shown to be effective in cases with lymphoproliferative malignancies. Other treatments include cyclosporine, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin. 

While skin lesions may improve within three months, mucosal involvement can be persistent. Continuous lesion progression is possible despite controlling the underlying malignancy. Addressing extracutaneous symptoms and secondary infections promptly is crucial. Epidermal breakdown heightens the risk of infection and fluid imbalances. Management often requires intensive care similar to burn patients, as PNP's mortality rates can reach 90%.  

To maintain hydration and promote healing, individuals are advised to use moisturizing dressings, clean ulcerated areas with sterile warm water compresses, and keep them moist with soothing and low-adhesive dressings. Silver dressings can reduce infections. Pain can be addressed with topical analgesics, corticosteroids, and opioids if needed. Nasogastric tubes may be necessary if oropharyngeal lesions interfere with eating. Lastly, adequate protein intake could be preferred to support wound healing.