What is Paraneoplastic Pemphigus?

Paraneoplastic pemphigus (PNP) is an uncommon disease affecting both the skin and mucous membranes which is nearly always linked to an underlying cancer. PNP is in a category of diseases known as pemphigus, where the immune system forms specific molecules known as IgG autoantibodies. These molecules cause disruption in intercellular connections, or desmosomes, between skin cells known as keratinocytes. The result is often painful sores and blisters on the skin. There are three main types of pemphigus identified by scientists: pemphigus foliaceus, pemphigus vulgaris, which is the most common, and paraneoplastic pemphigus.

Paraneoplastic pemphigus typically manifests itself as painful sores and dark patches on the skin that later peel off. Various types of skin lesions, ranging from weak blisters to widespread lichen-like eruptions, have been observed in people with paraneoplastic pemphigus. However, all patients have extensive and often serious lesions on the mucous membranes, which can be one of the earliest signs of the disease. Widespread loss of the top layer of the skin can lead to severe dehydration, protein loss, and an increased chance of infection. Because of this, patients often need intensive care and should be treated as if they have burns. Most commonly, adults between 45 to 70 years old are affected by PNP, although it can also occur in children. The disease was first recognised in 1990 by a researcher named Anhalt who also proposed the initial diagnostic criteria.

Since then, the term “paraneoplastic autoimmune multiorgan syndrome” (PAMS) has been introduced to describe different non-bullous skin manifestations and additional systemic findings, such as a condition known as bronchiolitis obliterans. Tragically, the mortality rate for PNP is very high, approaching 90%.

What Causes Paraneoplastic Pemphigus?

Lymphoproliferative neoplasms, or abnormally high production of lymph cells, are the most common diseases that lead to the creation of a rare skin disorder called paraneoplastic pemphigus, accounting for up to 84% of instances. These lymphoproliferative diseases are various forms of lymphoma, particularly non-Hodgkin lymphoma and chronic lymphocytic leukemia, which together cause approximately two-thirds of cases.

However, paraneoplastic pemphigus can also be associated with other types of tumors such as sarcomas (cancer that arises from transformed cells of mesenchymal origin), especially a type of sarcoma called follicular dendritic cell sarcoma, thymomas (a tumor originating from the epithelial cells of the thymus), squamous cell carcinomas (a type of skin cancer), and carcinomas (a type of cancer that starts in cells that make up the skin or the tissue lining organs) of different body parts like the skin, tongue, vagina, lung, stomach and colon.

In adults, non-Hodgkin lymphoma is the most frequent tumor related disease (38.6%), followed by chronic lymphocytic leukemia (18.4%), and a rare disease of lymph nodes named Castleman disease (18.4%). There are also cases of paraneoplastic pemphigus that are caused by non-blood related cancers, which make up around 16% of cases.

In children and teenagers, paraneoplastic pemphigus is often the first sign of Castleman disease.

Recent scientific studies have found that certain genetic traits make people more likely to develop paraneoplastic pemphigus. Specifically, people with the HLA Class II Drb1*03 allele and HLA-Cw*14 have a higher risk of developing this condition. HLA Class II Drb1*03 is more common in people of Caucasian heritage, while HLA-Cw*14 is more common in the Chinese population. Conversely, HLA-DR4 and HLA-DR1-14 are genetic traits that increase susceptibility to other skin diseases, namely pemphigus vulgaris and pemphigus foliaceus, but they do not appear to be linked with the development of paraneoplastic pemphigus.

Risk Factors and Frequency for Paraneoplastic Pemphigus

Paraneoplastic pemphigus (PNP), a skin condition, is quite rare and the exact number of cases is not known. It only makes up 3 to 5% of all cases in the broader pemphigus family, which includes conditions like pemphigus vulgaris and pemphigus foliaceus. It’s usually seen in adults between the ages of 45 and 70, but children can also get it, sometimes in connection with a condition called Castleman disease. Both men and women have an equal chance of developing PNP.

In a study of 496 patients with internal tumors, 25 of them (or 5%) developed PNP. The average age of these PNP patients was around 65, and the chances of developing PNP increased with age. Most people who get PNP already have a known tumor, whether or not they’ve received treatment.

However, if a patient shows signs of PNP but does not have a known tumor, it’s very important to do a thorough search for a hidden tumor right away.

Signs and Symptoms of Paraneoplastic Pemphigus

Paraneoplastic pemphigus (PNP) is a medical condition that typically starts with painful mouth sores and skin erosion, similar to a condition called pemphigus vulgaris. One of the early signs could be a hard to treat oral inflammation. The mouth sores can spread to other parts of the mouth like the lips, tongue, back of the mouth and throat, and even to the eating tube. The eyes and area around the genitals and anus can also get affected. Severe sores or ulcers in the mouth can resemble conditions like Stevens-Johnson syndrome or erythema multiforme.

The skin symptoms of PNP are usually widespread and can look different in different people. Skin symptoms often appear after the mouth symptoms and can include itching red-purple spots, crimson round skin patches, widespread redness, weak blisters, and widespread skin redness and peeling. Because of these varied skin symptoms, PNP can look like other skin conditions like lichen planus, erythema multiforme, bullous pemphigoid, pemphigus vulgaris, and graft-versus-host disease.

There are five main subtypes of paraneoplastic pemphigus:

Pemphigus-like
Pemphigoid-like
Erythema Multiforme-like
Graft-versus-Host Disease-like
Lichen Planus-like

In a study of patients with PNP, the most common type was the Erythema Multiforme-like subtype (56%), followed by Pemphigus-like (41%), Lichen Planus-like (13%), and Bullous Pemphigoid-like (3%). However, other studies report equal numbers of each subtype in patients with PNP. Patients have also shown up with symptoms looking like psoriasis and skin lesions with pus.

PNP can sometimes affect other organs in the body, especially the eyes, lungs, digestive tract, thyroid gland, and kidneys. Involvement of the lungs can range from 59.1% to 92.8% of PNP cases. Up to 70% of patients can have eye issues, which can unfortunately lead to permanent blindness. This can include issues like inflammatory film covering the inner layer of the eyelids, erosions or ulcers on the clear, front part of the eye or eyelids, eyelid thickening, and abnormal tissue growth on the eye. There have also been cases reported of corneal melting.

Lung involvement can show up as shortness of breath, dry cough, lung disease blocking air flow, or secondary pneumonia, and can rapidly develop into a condition called bronchiolitis obliterans. PNP with bronchiolitis obliterans is associated with high death rates. It’s not fully understood how bronchiolitis obliterans develops, but it’s generally suspected that antibodies attacking one’s own body play a part, causing a loss of connection between lung cells and leading to blockage of the air tubes in the lungs. Certain antibodies like the ones targeting epiplakin have been implicated.

In a study of 58 patients with PNP, 39% experienced significant muscle weakness. Resultantly, 35% of these patients were diagnosed with a condition called myasthenia gravis as they had high levels of antibodies that affect nerve-muscle communication or break down a chemical that stimulates muscle contraction. High levels of these antibodies were found significantly more often in PNP patients with shortness of breath. Patients with growths in the thymus gland were more likely to have symptoms of myasthenia gravis than those with other underlying tumors.

Testing for Paraneoplastic Pemphigus

Paraneoplastic pemphigus (PNP) is a complex condition that does not have any widely-accepted criteria for diagnosis. To confirm if a person has PNP, doctors usually combine several methods which include evaluating the symptoms, conducting a tissue study under a microscope (histology), analyzing small samples of tissue using fluorescence microscopy (direct and indirect immunofluorescence microscopy), and testing the immune system responses (immune serology).

Other specific tests might be conducted to spot the presence of certain antibodies in our blood, which are proteins produced by our immune system to combat harmful substances. These tests are immunoprecipitation and immunoblotting.

For tissue samples, ideal specimens are from early-stage tissue damage, as mature damage (bullae) tends to burst easily. A ‘punch biopsy’, a procedure that involves taking samples using a circular blade, isn’t advisable as it might cause the top layer of the skin (epidermis) to separate from the deeper layer (dermis).

Anhalt’s et al. suggested a list of criteria to help diagnose PNP which includes:

1. Painful erosions (sores) on the mucous membranes with or without accompanying abnormal skin lesions in the context of an underlying cancer.
2. Tissue study (Histopathology) showing abnormal separation of skin cells (acantholysis), inflammation at the junction between the skin and underlying tissue (interface dermatitis), and the death of skin cells (keratinocyte necrosis).
3. The presence of IgG (a type of antibody) and complement (a group of proteins that enhance the body’s immune responses) in the gaps between skin cells, often seen together with linear/granular deposits along the skin’s basement membrane zone.

Using the original criteria as a foundation, researchers continue adjusting and proposing new criteria for diagnosing PNP better, considering more atypical presentations and disease manifestations. For example, Camisa and Helm suggested dividing the criteria into ‘major’ and ‘minor’. To diagnose PNP, a patient must fulfill at least three major criteria or combine two major and two minor criteria.

Concerning the confirmation of the PNP diagnosis, a biopsy or tissue study (Histopathology) is normally conducted. Another widely used technique is Direct Immunofluorescence (DIF), which shows the distribution of IgG, an antibody, and complement (C3), a protein, between skin cells, and along the basement membrane zone in the PNP condition. Additionally, the Indirect Immunofluorescence (IIF) technique can help doctors detect any circulating antibodies targeting specific cellular proteins. A subsequent serological test can further confirm the presence of PNP and assist the diagnosis.

Besides these tests, once PNP is confirmed, it’s mandatory to test for any underlying cancer. Various tests such as Complete Blood Count (CBC), lactate dehydrogenase (LDH – an enzyme often present an abundance in cancer cells), flow cytometry (a technique used to measure the properties of cells), and imaging scans of the chest, abdomen, and pelvis may be recommended.

Treatment Options for Paraneoplastic Pemphigus

The best approach to treat paraneoplastic pemphigus, a rare autoimmune blistering disorder, is still uncertain. However, the first step is always to promptly identify and treat any underlying cancer. For solid tumors, surgery is important, involving an attempt to cut off the tumor’s blood supply while minimizing any disruptions that could spread disease-causing antibodies elsewhere in the body. Intravenous immunoglobulins might be given before and after surgery, which could help decrease the risk of complications like bronchiolitis obliterans, a lung condition commonly linked with this disorder.

Medical treatment usually involves reducing inflammation, suppressing the immune response, and ensuring proper care for any wounds. High-dose corticosteroids, anti-inflammatory medications, are usually the first line of treatment. If the disease doesn’t improve or gets worse despite steroid treatment, other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil, might be necessary. Other therapies that target the body’s own immune proteins or immune cells have also shown some promise in treating this condition—including rituximab (which eliminates a specific type of immune cell) and alemtuzumab (which acts against different immune cells). These therapies have shown some success in patients who have immune system disorders associated with cancer.

Despite treatments, skin lesions may improve within three months, but mucosal involvement (affecting the linings of body cavities) can resist treatment. The progression of paraneoplastic pemphigus doesn’t always mirror the treatment of the underlying cancer, meaning skin problems may worsen even if the underlying cancer is being successfully managed.

It’s crucial to identify and treat any complications or infections related to the skin condition quickly. Skin integrity loss leaves patients vulnerable to infection, dehydration, and electrolyte imbalance. Optimal care for these patients might be best at a certified burn center. The patient’s treatment plan often calls for an interdisciplinary approach, involving experts in cancer, eye disorders, urinary disorders, infectious diseases, gastrointestinal issues, and more.

Bandages that retain moisture in the wound should be used to support healing while preventing further loss of fluid and electrolytes. Skin and mucosal lesions should be cleaned gently, kept moist, and bandaged with low-adhesive wound dressings. Silver dressings can be particularly beneficial since they lower the risk of infection and don’t need changing as frequently. Pain can be managed with topical pain relievers and opioids as needed. Certain lesions might benefit from additional topical treatments like corticosteroids or calcineurin inhibitors. Oral lesions can be helped with corticosteroid gels and pain-relieving mouthwash. Severe cases might necessitate the use of bioengineered dressings intended for severe burns. If the patient can’t eat because of lesions in the mouth or throat, a nasogastric tube may be necessary. Protein supplementation can aid in wound healing. In bedridden patients, it’s important to change their position often to avoid bedsores.

Caution is necessary to recognize and promptly treat severe secondary infections with appropriate medications. Any patient displaying symptoms of infection like fever, low blood pressure, rapid heartbeat, or alterations to their mental status should quickly receive tests to rule out sepsis, a possibly life-threatening infection complication. Also, efforts ought to be made to prevent the undesirable side effects of long-term use of corticosteroids and other immune-suppressing medications.

When trying to diagnose a condition called paraneoplastic pemphigus (PNP), doctors need to consider other conditions that can cause similar symptoms. These can include:

Stevens-Johnson syndrome or erythema multiforme
Toxic epidermal necrolysis
Lichen planus
Graft-versus-host disease
Herpes simplex virus
Drug-induced pemphigus
Pemphigus vulgaris
Mucous membrane pemphigoid
Sores from cancer treatment, also called major aphthous or chemotherapy-induced stomatitis
A condition caused by staph bacteria, called staphylococcal scalded skin syndrome
Bullous pemphigoid

A correct diagnosis would involve looking at the pattern of symptoms, examining tissue under a microscope, and using targeted tests to pinpoint the cause.

What to expect with Paraneoplastic Pemphigus

Even when treated, a condition called paraneoplastic pemphigus (PNP) often leads to unfavorable outcomes, with up to 90% of people succumbing to the condition. Common causes of death include infections from skin loss, complications from the treatment that suppresses the immune system, the progression of the related cancer, and bronchiolitis obliterans, a serious lung condition.

But the outcomes can vary. People with less dangerous or removable cancers generally have a better chance of survival.

People with PNP have a worse outlook when they have dead skin cells and skin conditions resembling erythema multiforme, especially if there are widespread lesions or sores on the skin and mucous membranes at the time they are diagnosed.

In a study of 144 patients with PNP and underlying blood cancer, the presence of envoplakin autoantibodies, proteins that attack the body’s own tissues, and the development of bronchiolitis obliterans, pose an increased risk of death. People who displayed symptoms similar to toxic epidermal necrolysis or a condition called bullous pemphigoid had a reduced survival rate.

The levels of serum IgG autoantibodies, another type of protein that reacts against the body’s own cells, against two proteins called Dsg1 and Dsg3 can reflect the severity of symptoms in PNP. This means that a test for these antibodies (the Dsg-ELISA test), can be used as a marker of disease activity in pemphigus, the group of diseases PNP belongs to.

Possible Complications When Diagnosed with Paraneoplastic Pemphigus

Paraneoplastic pemphigus, a type of autoimmune blistering disease, often affects the eyes. Therefore, close monitoring is essential to prevent vision loss and blindness. Early referral to an eye doctor can help manage these issues. Treatments may involve the application of steroid eye drops, artificial tears, a medicinal compound called 10% N-acetylcysteine, and in severe instances, surgery may be needed.

Also, as many as 30% to 90% of patients with this condition may develop a lung disease called bronchiolitis obliterans, which shows up as a persistent dry cough, difficulty breathing, and low oxygen levels in the blood. This lung disease is considered a leading cause of mortality amongst these patients. Lung tissue examination might show fibrosis (scarring), immune cell infiltration, and deposition of autoantibodies (self-attacking antibodies) inside the lung’s small airways. This possibly stems from the harmful action of these autoantibodies, infections, or adverse effects from drugs. Tumor removal followed by intravenous immunoglobulin (a blood product) infusion may help reduce the risk of this lung condition.

A study involving Japanese patients with paraneoplastic pemphigus found a link between the development of bronchiolitis obliterans and epiplakin autoantibodies. Moreover, repeat infections can make bronchiolitis obliterans even worse.

Moreover, patients can suffer from skin erosion and blistering leading to fluid, protein, and electrolyte loss, which can cause dehydration and imbalances in the body’s electrolyte levels. Open skin can also facilitate infections and sepsis, particularly due to weakened immunity from treatments for this condition and possible associated cancers. Mouth sores are often hard to treat, persisting even after intensive care, potentially leading to dehydration and malnutrition. For such cases, a nasogastric tube (a feeding tube) might be necessary to ensure proper nutrition.

Preventing Paraneoplastic Pemphigus

If someone has widespread blisters, it could cause stiffening and tightening of their body parts. In such cases, physical therapy and rehabilitation could help them regain normal movement and function. If there are sores on the skin and mucus membranes, it would be useful to gently clean these areas with warm, sterile water twice a day. To keep these areas moist and promote healing, they can be covered with a soft, oily cream and a wound dressing that doesn’t stick to the skin too much, like a bandage soaked in petroleum jelly.

Using bandages that contain silver could be beneficial since they help to reduce the chance of infection. Another benefit of using silver bandages is that they don’t need to be changed as frequently as other types of bandages.

Frequently asked questions

The prognosis for Paraneoplastic Pemphigus (PNP) is generally poor, with a high mortality rate approaching 90%. Common causes of death include infections from skin loss, complications from immune system-suppressing treatment, progression of the related cancer, and bronchiolitis obliterans. However, outcomes can vary depending on factors such as the type and stage of the underlying cancer, with people who have less dangerous or removable cancers generally having a better chance of survival.

Paraneoplastic pemphigus can be associated with various types of tumors, including lymphoproliferative neoplasms (such as non-Hodgkin lymphoma and chronic lymphocytic leukemia), sarcomas, thymomas, squamous cell carcinomas, and carcinomas of different body parts. It can also be the first sign of Castleman disease in children and teenagers. Recent scientific studies have found that certain genetic traits, such as HLA Class II Drb1*03 allele and HLA-Cw*14, can increase the risk of developing paraneoplastic pemphigus.

Signs and symptoms of Paraneoplastic Pemphigus include: - Painful mouth sores and skin erosion, similar to pemphigus vulgaris - Hard to treat oral inflammation - Spread of mouth sores to other parts of the mouth, lips, tongue, back of the mouth, throat, and even the eating tube - Involvement of the eyes, genitals, and anus - Skin symptoms such as itching red-purple spots, crimson round skin patches, widespread redness, weak blisters, and widespread skin redness and peeling - Resemblance to other skin conditions like lichen planus, erythema multiforme, bullous pemphigoid, pemphigus vulgaris, and graft-versus-host disease - Five main subtypes: Pemphigus-like, Pemphigoid-like, Erythema Multiforme-like, Graft-versus-Host Disease-like, and Lichen Planus-like - Possible resemblance to psoriasis and skin lesions with pus - Involvement of other organs such as the eyes, lungs, digestive tract, thyroid gland, and kidneys - Lung involvement can lead to shortness of breath, dry cough, lung disease, secondary pneumonia, and bronchiolitis obliterans - Eye issues including inflammatory film, erosions or ulcers, eyelid thickening, abnormal tissue growth, and corneal melting - Muscle weakness, which can be associated with myasthenia gravis in some cases

The types of tests needed for Paraneoplastic Pemphigus include: 1. Evaluation of symptoms 2. Tissue study under a microscope (histology) 3. Analysis of tissue samples using fluorescence microscopy (direct and indirect immunofluorescence microscopy) 4. Testing immune system responses (immune serology) 5. Immunoprecipitation and immunoblotting to detect specific antibodies in the blood 6. Biopsy or tissue study (histopathology) to confirm the diagnosis 7. Direct Immunofluorescence (DIF) to show the distribution of antibodies and proteins in the skin cells 8. Indirect Immunofluorescence (IIF) to detect circulating antibodies targeting specific cellular proteins 9. Additional tests to identify any underlying cancer, such as Complete Blood Count (CBC), lactate dehydrogenase (LDH), flow cytometry, and imaging scans of the chest, abdomen, and pelvis.

The doctor needs to rule out the following conditions when diagnosing Paraneoplastic Pemphigus: 1. Stevens-Johnson syndrome or erythema multiforme 2. Toxic epidermal necrolysis 3. Lichen planus 4. Graft-versus-host disease 5. Herpes simplex virus 6. Drug-induced pemphigus 7. Pemphigus vulgaris 8. Mucous membrane pemphigoid 9. Sores from cancer treatment, also called major aphthous or chemotherapy-induced stomatitis 10. A condition caused by staph bacteria, called staphylococcal scalded skin syndrome 11. Bullous pemphigoid

When treating Paraneoplastic Pemphigus, there can be several side effects. These include: - Skin lesions may improve within three months, but mucosal involvement can resist treatment. - Skin problems may worsen even if the underlying cancer is being successfully managed. - Skin integrity loss leaves patients vulnerable to infection, dehydration, and electrolyte imbalance. - Long-term use of corticosteroids and other immune-suppressing medications can have undesirable side effects. - As many as 30% to 90% of patients may develop bronchiolitis obliterans, a lung disease that can cause a persistent dry cough, difficulty breathing, and low oxygen levels in the blood. - Patients can suffer from skin erosion and blistering leading to fluid, protein, and electrolyte loss, which can cause dehydration and imbalances in the body's electrolyte levels. - Open skin can facilitate infections and sepsis, particularly due to weakened immunity from treatments and possible associated cancers. - Mouth sores can be hard to treat, potentially leading to dehydration and malnutrition.

Dermatologist

Paraneoplastic pemphigus is quite rare and makes up 3 to 5% of all cases in the broader pemphigus family.

Paraneoplastic pemphigus is treated by promptly identifying and treating any underlying cancer. Surgery is important for solid tumors, with the goal of cutting off the tumor's blood supply while minimizing disruptions that could spread disease-causing antibodies. Intravenous immunoglobulins may be given before and after surgery to decrease the risk of complications. Medical treatment involves reducing inflammation, suppressing the immune response, and ensuring proper wound care. High-dose corticosteroids are usually the first line of treatment, but if the disease doesn't improve or worsens, other immunosuppressive drugs may be necessary. Other therapies that target the body's immune proteins or cells, such as rituximab and alemtuzumab, have shown promise. Complications and infections related to the skin condition should be identified and treated quickly, and optimal care may be provided at a certified burn center. Bandages that retain moisture, gentle cleaning and dressing of lesions, and pain management are important. Severe cases may require bioengineered dressings or a nasogastric tube for nutrition. Caution should be taken to recognize and treat severe secondary infections promptly, and efforts should be made to prevent the side effects of long-term use of corticosteroids and immune-suppressing medications.

Paraneoplastic pemphigus (PNP) is an uncommon disease that affects both the skin and mucous membranes and is almost always associated with an underlying cancer. It is a type of pemphigus, where the immune system produces specific molecules called IgG autoantibodies that disrupt the connections between skin cells, leading to painful sores and blisters on the skin.