Pyoderma Gangrenosum: An Uncommon Case Report and Review of the Literature

Background. Pyoderma gangrenosum (PG) is a rare ulcerative condition that is diagnostically and therapeutically challenging, as debridement leads to ulcer deterioration (pathergy phenomenon); immunosuppression is considered the gold standard therapy. Case Report. The authors present the case of a 42-year-old woman with PG and uncontrolled iatrogenic diabetes, secondary to a total pancreatectomy performed in another hospital in 1998 due to nesidioblastosis. In 2008, she was referred to the diabetic foot consultation at Centro Hospitalar Tondela-Viseu (Viseu, Portugal) due to an infected wound on the left leg thought to be related to a trauma from footwear, but the injury worsened despite treatment. Characteristics of the lesion led to the diagnosis of PG and treatment was adjusted. The patient was followed-up weekly at the diabetic foot consultation; at 2-months follow-up, the leg ulcer was closed but additional lesions emerged in multiple areas of her body. Therapy included local antiseptics, antibiotics, pain control, systemic corticosteroids, immunosuppressors, intravenous immunoglobulin, and surgical debridement. Due to her noncompliance, this proved to be a challenging case. Conclusion. Although PG is rare, clinicians should suspect it in the presence of purplish wound edges with a necrotic center. Surgical debridement, while necessary in other ulcers, can worsen the condition and should only be applied to self-detachable necrotic plaques.

In 1908, Louis Brocq, cofounder of the French Society of Dermatology, conducted a study on patients who had multiple ulcers with then-unknown characteristics.¹ He distinguished a regular elliptical boundary, a painful and erythematous wound edge, and a vertical inner facade that descended to the purulent deep wound bed. The term of this dermatosis, geometric phagedenism, emphasizes the geometric pattern and the rapid growth of those necrotic lesions (from the Greek phageton which means food consumption).^1,2 In these lessions, Brocq also found similar histopathological aspects such as the presence of a neutrophilic-predominant inflammatory and necrotic infiltrate which usually reached the hypodermis.^1,2 

In 1930, Burnsting et al termed this pathology echtyma gangrenosum, which later evolved to pyoderma gangrenosum (PG).^3,4 They considered PG as the dissemination of a distant focus of infection caused by streptococci and staphylococci. Today, more than 80 years later, the infectious hypothesis is completely abandoned.

Pyoderma gangrenosum is a rare, sterile, neutrophilic dermatosis with an estimated incidence of 2 to 10 cases per million inhabitants per year.^5-12 It is believed PG has an autoimmune origin, so the terminology pyoderma (pyo: pus; derma: skin) becomes equivocal. It is more common in women (1.14:1) and in adults aged 25 to 50 years; however, patients of all ages can be affected.^6,8,13 It is characterized by the presence of deep and necrotic skin lesions with violet edges and a necrotic migratory nature, affecting any region of the body. In very rare cases there could be extracutaneous involvement, most frequently in the lungs. There are also descriptions in the literature of cornea, liver, heart, central nervous system, gastrointestinal tract, pancreas, spleen, kidney, bone, and articular involvement (latter is known as pyogenic arthritis, pyoderma gangrenosum, and acne [PAPA] syndrome).^6,13-26

Although there are no pathognomonic histological findings, biopsy is essential for differential diagnosis; a neutrophilic inflammatory infiltrate is often found.^6,13 There are several proposed diagnostic criteria for PG based on typical morphology and histology, but none have been validated due to clinical variability and aspects that mimic other dermatoses.^14,27

Several variants/types of PG were described in the literature^{6,7,11,12,28,29}: 

1. Classic or ulcerative (most common): It begins with a pustule or nodule that undergoes necrosis, leading to a central ulceration in 24 to 48 hours and a purulent and hemorrhagic exudate. It may be single or multiple and it has a purplish edge surrounded by a hardened erythematous area up to 2 cm. Ulcers may be confined to the dermis, but more often extend into the fat and even down to the fascia. It is usually located in the pretibial region, reflecting its tendency to occur in trauma regions, but can also occur in other areas (breast, dorsum of the hands, thorax, head, or neck). These are very painful and usually require aggressive systemic immunosuppressive therapy for control. The clinical course could be explosive (with rapid spread of hemorrhagic, suppurative, and extensive necrotic lesions) or indolent (with gradually spreading ulcers and spontaneous regression). Histologically, a neutrophilic dermolysis is apparent.^6,7,11,12
2. Pustular: They start with 1 or more aggregated pustules, which later converge and develop to a persistent and painful ulcer with a surrounding erythematous halo that arises mainly on the torso and extensor areas of extremities. It is a very rare form of PG and is always connected to inflammatory bowel disease (IBD). Histopathologic features include subdermal edema with a dermal neutrophilic infiltrate and subcorneal neutrophil accumulation.²⁹
3. Bullous or phemphigoid: Lesion appears as a large vesicle that evolves into a more superficial ulcer than in the classical form. It has a central necrosis, erosion, and a surrounding halo of erythema. The necrolytic tissue produces the characteristic blistering of this PG type. It affects mainly the face and upper extremities. Systemic immunosuppressive therapy is required and has a poor prognosis when associated with hematological malignancy.³⁰
4. Vegetative: This type is characterized by the presence of a single inflammatory plate with several superficial ulcers with a nonpurulent base and no undermined borders and verrucous lesions. It is the least aggressive type (though Perry et al³¹ described this variant as malignant PG). It has a slow progression and often responds to topical, intralesional, or less aggressive systemic therapy. Lesions are nonpainful, and this type is not related to systemic diseases. Tissue eosinophilia, granuloma formation, and prominence of histiocytes within the neutrophilic infiltration are among the histopathological features.^6,11,13,28
5. Periostomal: Lesions are similar to the classical type but surround abdominal stomas (colostomies, ileostomies, and ureterostomies) with possible bridges of healthy skin. It is associated with patients with IBD, cancer, or diverticulitis who have stomas. Pathergy evolving from the surgical procedure is the suggested mechanism.^32-34 
6. Genital: Classical type lesions surrounding the vulva, penis, or scrotum.⁶
7. Infantile: A rare form where classical type lesions appear in children, most frequently in perianal and genital areas.⁶
8. Extracutaneous: Lesions in the lungs, heart, central nervous system, or other internal organs in the absence of cutaneous lesions.⁶

In 50% to 70% of cases, PG is associated with systemic diseases (IBD, rheumatoid arthritis, ankylosing spondylitis, psoriasis, monoclonal gammopathy, leukemia, myelodysplasia, lymphoma, Behçet’s disease, Sweet’s syndrome, hepatitis, human immunodeficiency virus infection, systemic lupus erythematosus, Takayasu arteritis, thyroid diseases, and diabetes are among the most common), and previous trauma or surgical procedures; the clinician must suspect of PG in a patient exhibiting consistent lesions and having any of these records.^{6,7,11-15,28,35} Incidence of idiopathic PG is 25% to 50%. The Table summarizes the characteristics of each type of PG and diseases that are most often associated. 

It is well known that PG requires more than local ointments; often a long-term immunosuppressive systemic therapy is needed for remission.¹⁰ But, unlike most skin ulcers, PG lesions worsen or new lesions develop following surgical gestures (pathergy, also named isomorphic response or Koebner phenomenon). Trivial trauma may create these ulcers, which suggests uncontrolled inflammatory responses to nonspecific stimuli.⁶ Sweet’s syndrome, Wegener’s granulomatosis, polyarteritis nodosa, Behçet’s disease, primary T-cell lymphomas, pustular vasculitis, acute cellulitis, cutaneous neoplasms, and antiphospholipid syndrome are within the differential diagnoses.^6,11,28,36 This case report focuses on the difficult diagnosis and the challenging treatment of a potentially mutilating PG in a noncompliant patient.

A 42-year-old woman with diabetes as a result of a total pancreatectomy in 1998 due to nesidioblastosis and with extensive PG ulcerative lesions presented to the diabetic foot consultation at Centro Hospitalar Tondela-Viseu (Viseu, Portugal) in January 2008. Data were collected from the patient’s medical record in the Centro Hospitalar Tondela-Viseu. Photos were taken with the patient’s consent. 

The patient presented with an infected wound on the left leg with a necrotic center, which was thought to be related to a footwear-related trauma. Patient records included chronic smoking habits and difficult-to-control iatrogenic diabetes. Despite treatment (hydrofiber dressings, antibiotics, and debridement on demand), the injury worsened, increasing its area and depth, and led the authors to diagnose it as PG.

Five weeks later, 2 new necrotic, exuberant, extensive, deep, and painful lesions with purplish edges emerged: 1 on the left thigh (Figure 1), and the other on the right leg; both worsened and grew (Figure 2). The biopsy of 1 lesion showed chronic inflammatory infiltrate. The culture from ulcerated lesions showed no infection, and serum analyses were normal. The nonspecific biopsy, the absence of an infection, the presence of an underlying disease (diabetes), the pathergy phenomenon, and the characteristic lesions were compatible with PG. The rapid and aggressive evolution seen after and the features of the lesions (deep, exudating, and painful with rapid spread and initially at pretibial localization) lead the authors to consider the classic/ulcerative variant with explosive course.

Although the patient did not show signs or symptoms of other diseases, several additional exams were performed: an esophagus, stomach, and large bowel endoscopy; imaging study with computed tomography and positron emission tomography; serum anti-Saccharomyces cerevisiae antibodies, perinuclear antineutrophil cytoplasmic antibodies, and rheumatoid factor; and serum and urinary proteins electrophoresis. No changes were found that would lead to suspicion of concomitant diseases.

The basis of therapy was immunosuppression and infection and pain control. Locally, lesions were washed with Dakin’s solution for 15 minutes to promote chemical debridement. Surgical debridement took place only when necrotic plaques were detached easily, avoiding trauma and, therefore, the pathergy phenomenon. Corticosteroid ointment (1 mg/g betamethasone) was applied to the aseptic ulcer. In the absence of infection, the diabetic foot consulting team, in an outpatient regime, dressed the wounds. Systemic corticosteroids and immunosuppressors (3–6 mg/kg/day of cyclosporine or 0.5–2 mg/kg/day of prednisolone) were the basis of systemic therapy.

If an infected wound was detected (presence of evident fetid, purulent exudate and/or Celsius signals or positive tissue culture), Dakin’s solution was also a main treatment to potentially save the viable tissue without surgical debridement. Thereafter, the wound was washed with Dakin’s solution and a dressing soaked with the same liquid was applied; when bone and tendon were exposed, a collagen and gentamicin dressing (Septocoll E; Biomet Deutschland GmbH, Berlin, Germany) (Figure 3), a charcoal dressing (Actisorb; Acelity, San Antonio, TX), or other suitable material was used. In critical situations, an intravenous antibiotic was administered in the hospital ward; otherwise, oral antibiotic intake at home was enough. 

Although improvement and healing of lesions were made, the disease remained active in 2009 due to noncompliance of the prescribed oral corticosteroids and immunosuppressors. Emerging osteomyelitis-associated necrotic ulcers (Figure 4) on toes lead to a transmetatarsal amputation of the left foot and of all right toes (Figure 5).

In 2009 and 2010, the patient developed other lesions located in the anterior chest wall and right breast (Figure 6), left hand, left elbow, left thigh (Figure 7), left shoulder, and abdomen (Figure 8), with muscle, tendon, and bone involvement. The injury on the right breast reached the ribcage in September 2009, causing osteomyelitis of 2 underlying ribs that conduced to a partial excision and use of Dakin’s solution-soaked dressings for sepsis control. The left breast was affected on April 2010 (Figure 9), with total destruction of the glandular tissue. 

After infection control, gentamicin and collagen dressings were applied, particularly on the regions with bone and tendon exposure, to promote healing and prevent reinfection. Intravenous immunoglobulin cycles were used in more active periods of the disease or in the absence of response to usual therapeutic regimen. Opioids were needed for pain relief. In 2011 and 2012, most of the described lesions healed.

However, in 2013 (5 years after diagnosis), the patient still had 2 active lesions on her left thigh (Figure 7). In addition, a chronic kidney disease was detected after 15 years of diabetes, and because of the patient’s noncompliance, neither diabetes nor renal disease were controlled and her general status worsened. Later that same year, the patient had a minor trauma in the lower right leg, leading to acute pain and functional incapacity. Right tibia and fibula fractures were identified (Figure 10), probably related to osteomalacia from renal failure.  A plaster of Paris was applied and oral analgesics prescribed. At that time, the aforementioned lesions healed (Figure 11).

Despite instructions and explanations provided for chronic therapy, the patient still did not follow the proposed medication properly. In January 2014, the patient died due to renal failure.

A diagnosis of PG is difficult but can be deduced by a patient’s clinical history, appearance of lesions, histopathology, and presence of a concomitant disease. Initial lesions (ie, papules or nodules) should always be distinguished from cellulitis or folliculitis, Sweet’s syndrome, Behçet’s syndrome, nodal polyarteritis, and other similar diseases. In ulcerated or vegetative lesions, neoplasms must be excluded (cutaneous lymphoma or squamous-cell or basal-cell carcinoma) as well as venous and arterial ulcers, infections, and vasculitis. When there is joint or bone involvement, primary osteomyelitis, septic arthritis, and PAPA syndrome should be excluded; PG is an exclusion diagnosis.

This case report shows the challenging path to diagnosis: the lesion mimicked an infected trauma ulcer, leading to inappropriate treatment and wound worsening. Patient’s records and suggestive wound characteristics were essential for the diagnosis. The biopsy helped mainly in excluding other diseases, because there are no pathognomonic histological findings.

The rarity of the disease has not yet allowed for trials that could support a gold standard therapy, although there is a consensus on the use of systemic and topical corticosteroids. Therapy should always be patient-oriented, and it must weigh the patient’s background, the presence of a concomitant disease, and the wound depth, diameter, and septic status.^6,10

First-line treatment recommended in the literature is systemic prednisolone, validating the treatment used on the patient presented herein.^{6,10,11,28,37} Cyclosporine could be used in order to enable the reduction of corticosteroid doses, it is not recommended for chronic use. Other drugs, including thalidomide, tacrolimus, mofetil mycophenolate, chlorambucil, colchicine, cyclophosphamide, dapsone, minocycline, sulfapyridine, methotrexate, azathioprine, infliximab, adalimumab, etanercept, and intravenous immunoglobulin are considered good alternatives with similar degrees of recommendation in the literature.^6,7,10,14,38

Topically, treatment should include local immunosuppressors for inflammation control, infection control and prevention, pain reduction, and exudate absorption. In the presence of infection, antiseptic and antibiotic solutions are useful, such as Dakin’s solution-soaked gauze; in milder forms, the use of topical corticosteroids is indicated.^11,13,28 Hyperbaric oxygen is also an alternative.^6,39,40

Surgical aggression should be avoided in order to prevent the wound’s progression due to pathergy. However, surgical debridement could be performed to remove any necrotic detachable plates, for infection control at extreme conditions (abscess drainage or infected bone), or when ligaments, tendons, cartilage, or bone are exposed in order to obviate serious infection.^6,14 There are reports about the use of autologous skin grafts, particularly for the breast, although there is always risk of injury to the donor area.²⁸ Processed allogeneic skin grafts, which avoid surgical aggression in the patient, are still under investigation.^14,28

In the literature, there are many cases of bone destruction in patients with PG secondary to lymphoproliferative disorders, steroid usage, and PAPA syndrome, but its incidence is unknown. There are also rare reports of bone fracture and joint destruction related to primary PG.^12,13,41 In the case of the patient herein, a previous minor trauma caused the fractures, possibly adjuvanted by osteomalacia due to her renal disease.

For most patients, the prognosis is good as it resolves after treatment, but it may reappear in the future.¹⁴ Other patients have chronic injuries, requiring long-lasting combination therapy, whereby toxicity and efficacy should be monitored. In rare cases, the prognosis is bad, such as in this case report. This patient had an unstoppable explosive course of the disease that did not reverse despite medical care provided, potentially due to the patient’s low compliance.

Treating a skin ulcer should always be adapted to its etiology.  Although PG is rare, in the presence of a pustule that develops to a purplish-edged wound with a necrotic center, clinicians should suspect this disease. In 50% of cases, PG is related to other systemic diseases that should be screened.^{6,7,11-15,28,35} Even though debridement is necessary for most wounds, it leads to worsening of the ulcers in PG (pathergy phenomenon) and should only be performed to self-detachable necrotic plaques. The therapeutic is based on systemic and topical immunosuppression as well as in the treatment of the concomitant disease.

Regardless of therapeutic panoply and many success series in the literature, this case report shows that this disease can be an overwhelming challenge. Clinicians must understand the pathophysiology and wisely choose treatments available so PG treatments can be adapted in the future. 

The authors would like to acknowledge the support of Assistant Professor, Catarina Lídia Lemos, PhD, in Biomedical Sciences, of UFP Energy, Environment and Health Research Unit, Biomedical Research Centre, from the Universidade Fernando Pessoa for translation and revision of the manuscript.

Affiliation: Serviço de Cirurgia 1, Centro Hospitalar Tondela-Viseu, Viseu, Portugal

Correspondence:
António Carlos Lemos, MD
Resident of General Surgery
Centro Hospitalar Tondela-Viseu
Av. Rei D. Duarte, 
3509-504 Viseu, Portugal
aclemos@live.com.pt

Disclosure: The authors disclose no financial or other conflicts of interest. The statements expressed herein belong only to the authors and are not an official position of the Centro Hospitalar Tondela-Viseu.