Paraneoplastic pyoderma gangrenosum (PG) is a disease affecting the skin. It is not an infection or gangrenous despite its name; “pyoderma,” which means infectious, and “gangrenous,” which refers to causing gangrene (dead tissue often requiring amputation).¹ The quintessential feature distinguishing PG is the neutrophilic exudate from the ulcer.² If it manifests, it is usually an early sign of or accompanies an underlying disease, especially the paraneoplastic form.² Therefore, the diagnosis and identification of paraneoplastic PG is a crucial indicator for understanding the full picture of what is going on in the patient, especially when it occurs alongside cancer, requiring the collaboration of multidisciplinary teams.

What Is Paraneoplastic Pyoderma Gangrenosum?

PG is a rare skin condition which initially begins as a painful, fluid-filled pimple that gradually enlarges and deepens, often rapidly, into a blister and then an ulcer.¹ The diagnosis of PG is conducted by excluding other infectious or vascular skin conditions with similar symptoms, which impedes and delays direct diagnosis.^2,3

The pathogenesis of PB is poorly understood but assumed to be caused by cells producing more neutrophil chemotaxis factors; a substance that signals neutrophils (otherwise known as white blood cells) to travel towards it. The factors are a natural immune response to disease or infection, but this is exacerbated to a local area in PG.² Chemotaxis factors include IL-1β, IL-17, TNF-α, IL-8, IL-6, IL-1, and IL-23.² Matrix metalloproteinases (MMP’s) are thought to play a role - more specifically MMP9 and MMP10. MMPs are a family of enzymes whose primary role is to break down other proteins and are linked to many disease development processes through complicated pathways not yet fully understood.²

All manifestations of PG can appear anywhere on the body and begin as a small, painful, fluid-filled pimple, leading to a blister and into ulcers which may take on different forms.^1,2 The ulcers are not infections and any discharge contains neutrophils.¹ Ulcers are most often manifested on the shins or stomach area, where a previous stoma may have been.² These can be categorised into various kinds: the classic, bullous, vegetans or granulomatous, pustular, and peristomal:²

• Classic: Painful ulcer with irregular violet borders with undermined wound borders, and black or brown dead tissue lining the base of the ulcer
• Bullous: Large fluid-filled blisters are over 10mm in diameter with blue-grey borders, progressing into shallow erosions or ulcers. Typically found on the face and arms
• Vegetans or granulomatous: Red, protrudes from the skin surface, wart-like appearance, lesions typically appear on the head and neck
• Pustular: Painful pus-filled blisters on a red base, and can be accompanied by fever or joint pain

PG can occur at any age but usually in young to middle-aged adults between 20 and 50 and is slightly more frequent in women than men.³ Due to the rarity of PG, the incidence of PG is difficult to quantify, though the standardised European rate is estimated to be 0.63 for every 100,000 people years. Meaning that 0.63 PG cases are suspected if 100,000 people are observed for a year.³ PG can appear by itself, isolated from any other disease. However, in more than 75% of cases, it is associated with an underlying disease.⁴

The most common conditions associated with PG are inflammatory bowel disease, arthritis, rheumatic disorders or malignancies- cancers relating to the blood that do not result in tumour formation.⁶ Approximately 50% of PG cases are associated with the above disorders, with 4.5-9% of PG sufferers having tumours concomitantly.^6,7

Understanding Paraneoplastic Syndromes

Paraneoplastic describes syndromes strongly associated with the presence of tumours, either preceding, accompanying, or presenting later to the diagnosis of the tumour.² Paraneoplastic syndromes are linked to cancer, but are not distinctly caused by the tumour itself and are rather a consequence of cancer.⁵ The term paraneoplastic may describe PG when it is detected with a solid tumour present, therefore, PG conditionally may be classified as a paraneoplastic syndrome in such circumstances.

When PG Is a Sign of Cancer: The Paraneoplastic Form

The most common tumour-associated cancers with PG in descending order of prevalence are breast, rectal, gastric, renal, and lung cancer, with rare literature reports of neuroendocrine tumours and bladder cancer.^5,8 PG can develop months to years prior to tumour formation, alongside or recently after diagnosis of cancer, or even during cancer therapy where it may be a sign of worse disease course.⁶ Hence why prompt identification of PG is necessary with tumour detection as PG is the primary manifestation of occult cancer, which albeit rare, is cancer where the primary tumour is unidentified but a secondary tumour is instead found.⁶

Paraneoplastic pyoderma gangrenosum may be linked to solid tumours since cancer patients with advanced cancer stages exhibit elevated neutrophil levels, making them prone to skin disorders with excessive neutrophils like in PG.⁷ Furthermore, IL-1- another chemotaxis factor- is highly produced in many solid tumour types and is also found in high levels in PG ulcers, reinforcing the link between PG and its paraneoplastic form.⁷ As the cancer triggers PG, treating the cancer usually results in PG healing also, thus reiterating the need for early PG diagnosis for sooner cancer treatment and a better long-term outlook.

Diagnosis

The diagnostic procedure for PG is complicated by the symptoms of PG, as the clinical manifestation of PG shares similarities to other skin conditions and has a non-specific histology i.e. the tissues are microscopically similar.² There is no general criterion for PG diagnosis aside from concluding that PG is the most likely disease by excluding the possibility of other diseases ⁵

Useful initial tests that would be conducted are full blood count, blood tests, liver and renal function tests, checking the speed of blood separation (erythrocyte sedimentation test) and chest X-rays. This may be followed by more advanced testing such as a skin biopsy of the ulcer centre and ulcer centre, gastrointestinal endoscopy and colonoscopy.^4,6 A positive skin biopsy for PG would confirm the presence of neutrophils and other white blood cells (i.e. perivascular lymphocytes) infiltrates in the area.⁵ Diagnosis of exclusion necessitates understanding the patient’s medical history to diagnose PG and to identify potential underlying diseases. Testing aims to confirm the incidence of PG followed by the potential type of cancer.

Treatment Approaches

General treatment of PG is centralised on local wound care consisting of cleaning, appropriate wound dressing with topical corticosteroid creams supplemented with oral corticosteroids, border care with zinc oxide or petrolatum and sufficient pain relief medication.^2,6 The corticosteroids suppress the immune response, which is overly activated in a specific area, leading to an oversaturation of neutrophils at the site of the PG ulcer. Commonly prescribed corticosteroids include prednisolone and ciclosporin.² Surgery to remove PG ulcers is not recommended, as 20-30% of PG cases experience a phenomenon where minor trauma leads to aggravation of the ulcer.¹

When PG is simultaneously present with cancer, treating only PG will usually not resolve PG as the core cancer is still present and will not respond to treatment or recur. Solid tumours should be suspected when PG is unresponsive to conventional therapies.⁹ Oftentimes, treatment of cancers results in PG resolution.

For persistent PG lesions, a treatment programme dubbed pulse therapy may be employed. Drugs are intermittently administered through the vein. For PG lesions, drugs used for pulse therapy include methylprednisolone, methotrexate, mycophenolate, colchicine, sulfasalazine, dapsone, minocycline, apremilast and thalidomide.² Alternatively, immunological treatments such as TNF-α inhibitors and infliximab elicited a good response but in turn suppress the immune response.⁶ Thus, for acute treatment of PG, systemic steroids are considered, whilst chronic treatment involves chronic immunosuppression.⁵  

Novel therapies can involve transfer of skin from a healthy site to the ulceration, bioengineered skin and intravenous immunoglobulin therapy, which rather than suppressing the immune system, weakens its response instead. By that method, it was seen that patients with paraneoplastic PG tended to respond better.^6,10 The number of PG lesions a patient has is a factor affecting therapy selection, with patients needing to be closely monitored as tumours are not immediately noticed.^6,10

What to Watch Out For & When to Seek Help

For people with a higher risk of cancer, if ulcers that are unresponsive to treatment and are persistently recurrent following affirmation of PG post-diagnosis of exclusion, examination for tumours should be considered with close monitoring by health professionals.⁴

As PG can appear before tumour formation as early as years earlier than the formation of a tumour, hence why upon the first sightings of PG formation into an ulcer, it is ideal to seek medical help. If left untreated, several ulcers, if in proximity, can combine and deepen to expose tendons, muscles and nerves.⁶ Even if the ulcer appears to heal, more ulcers may form if the underlying cancer is not treated. A detailed medical history can inform doctors of the most probable underlying conditions and will require multidisciplinary intervention from the dermatology, oncology, haematology and more departments depending on the type of cancer involved.

Summary

Though unusual symptoms may seem daunting, seeking medical assistance may save lives the sooner it is addressed. Specifically in paraneoplastic PG, earlier recognition will lead to better outcomes, especially when the time needed for accurate diagnosis is considered. The sooner the identification of paraneoplastic PG, the better the recovery and prognosis.