Successful Mastectomy and Chemotherapy in a Patient with Breast Cancer and Active Generalized Pyoderma Gangrenosum

Introduction. Pyoderma gangrenosum (PG) is a rare, ulcerating neutrophilic dermatosis often associated with inflammatory bowel disease, rheumatoid arthritis, and myeloproliferative disorders. The classic description of PG includes irregularly shaped ulcers with undermined edges with a gun-metal gray or violaceous hue. The etiology remains unclear but appears to be related to genetically predisposed dysregulation of the innate immune system. Diagnosis of PG can be difficult as it can present with symptoms similar to cutaneous infections including erythema, edema, ulceration, fever and leukocytosis. Surgical procedures are generally contraindicated in patients with PG due to the risk of pathergy, excessive cutaneous injury, or ulceration in response to trauma. Case Report. The authors report the development of PG with the initiation of chemotherapy in a 46-year-old woman with breast cancer. The patient had a complicated clinical course after multiple surgical debridements due to an initial misdiagnosis of necrotizing fasciitis. The patient’s rapid onset of post-procedural ulceration was consistent with the pathergy of PG. The diagnosis of PG was confirmed by skin biopsy, which revealed a diffuse neutrophilic infiltrate, and with the patient’s negative cultures and response to steroids. The patient was treated with perioperative prednisone and intravenous immunoglobulin prior to a mastectomy for her breast cancer. The surgery was not complicated by pathergy. Conclusions. This unique case highlights the challenging aspects in the medical and perioperative management of active PG in a patient with breast cancer.

Pyoderma gangrenosum (PG) is an ulcerative skin condition that poses a diagnostic challenge, especially when associated with systemic symptoms and/or when present in conjunction with other non-inflammatory entities, such as neoplasms.¹ About one-third of patients may report a history of pathergy.² Treatment also may be even more challenging when patients with active PG ulcers need surgical interventions. 

The authors describe the case of a woman with a recent diagnosis of stage II, grade 3 breast cancer who developed PG to highlight several challenging aspects in the diagnosis and management of PG. 

A 46-year-old woman with stage II, grade 3 infiltrating ductal carcinoma of the left breast, diagnosed 30 days prior, presented to the emergency department with erythema and pain in her right upper extremity (RUE) near the site where a subclavian implantable venous catheter (PORT-A-CATH; Smiths Medical) was placed 16 days earlier. In addition to the diagnosis of breast cancer, the patient was estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor 2-positive (HER2+). The patient had no history of autoimmune disorders or previous cutaneous wounds; she also had no previous history of pathergy or wound dehiscence after surgical procedures. 

Five days after receiving a round of neoadjuvant chemotherapy, consisting of trastuzumab, pertuzumab, carboplatin, and docetaxel, the patient presented with a 2 cm x 1 cm area of erythema and swelling in her RUE, which rapidly progressed over the next 24 hours to form pustules and blisters (Figure 1). She was admitted with the diagnosis of possible shock (fever, hypotension, and a leukocytosis of 52 000 mm³ neutrophils/µL). A computerized tomography scan of the RUE showed extensive skin thickening and subcutaneous soft tissue stranding, suggestive of possible necrotizing fasciitis (NF). 

The patient was started on empiric antibiotic therapy, which consisted of vancomycin 15 mg/kg every 12 hours, cefepime 1gm intravenous (IV) every 6 hours, and metronidazole 500 mg IV every 8 hours as well as surgical debridement of the RUE and right chest wall (Figure 2A, B). the initial debridement, the wound continued to ulcerate and enlarge, which prompted 2 additional wide debridements of the right chest wall and RUE (Figure 2C). At this point the RUE wound measured 19.3 cm x 15.5 cm and the right upper chest measured 16.5 cm x 12.2 cm. Alarmingly, the patient then began to develop pain and swelling around the catheter line site on her contralateral (Figure 2D) left upper extremity (Figure 2E). This catheter line had been placed upon initial admission. The swelling and pain progressed to overt ulceration and the area was surgically debrided (Figure 2E). 

At this point, dermatology was consulted and the antibiotic course was switched to amoxicillin 500 mg every 12 hours. Histopathology of tissue samples showed focal necrosis with a diffuse neutrophilic infiltrate within the dermis and subcutaneous tissue. Blood and tissue microbiological cultures taken every other day for the first 12 days of her 29-day hospitalization, and the results were consistently negative. The skin biopsy confirmed the suspected clinical diagnosis of PG, given the patient’s progressively worsening condition with repeat debridements, and negative cultures. She was subsequently started on high-dose prednisone (80 mg/day), which resulted in rapid improvement after 2 days and continued to improve after 1 week (Figure 2F). 

The patient was discharged on 80 mg of oral prednisone daily for 30 days. Despite significant concern for the risk of pathergy with subsequent surgical procedures, the patient required surgical treatment of her breast cancer. In addition to her current taper of systemic corticosteroids (60 mg/day), perioperative administration of high-dose IV immunoglobulin (IVIG; 2 g/kg) was administered 9 days preoperatively. 

After 1 month of initiating prednisone treatment, the patient underwent a left simple mastectomy without complications. Fortunately, over the next month, the surgical incision site healed fully, and no new ulceration was observed. After the procedure, the patient was placed on oral prednisone 60 mg daily and instructed to taper by 10 mg weekly for 6 weeks. After completing the prednisone taper, the wound measured 11.6 cm x 7.9 cm in the RUE and 9.5 cm x 5.5 cm in the right upper chest. After finishing the steroid taper, she began weekly adjuvant chemotherapy (paclitaxel, trastuzumab), which also included dexamethasone 8 mg with every cycle for 12 weeks. Additional infusions of IVIG every 4 weeks for up to 6 doses were recommended, but the patient never received postoperative IVIG treatment due to insurance issues.

A few days after the completion of the 12^th week of paclitaxel and trastuzumab infusions, absorbent dressings (calcium alginate) were applied to the wound. At this point, 7 months after the initial debridement, the wounds were noted to measure 10.4 cm x 7.1 cm in RUE and 7.5cm x 4.4 cm in the right upper chest.  Reduced drainage, tenderness, erythema, and diameter of the wound were observed. Wound care was optimized with the use of timolol 0.5% gel-forming solution once weekly for 4 weeks (Figure 2G, H). Imaging, performed 8 months after the initial debridement, revealed remission of the breast cancer. 

Currently, the patient is taking tamoxifen for the treatment of her breast cancer. After 23 months, the wounds have continued to heal with no recurrence and measure approximately 5.5 cm x 3.2 cm in RUE and 4.1 cm x 3.3 cm in the right upper chest (Figure 3). 

The case report described the rapid progression of PG in association with systemic symptoms after the initiation of chemotherapy in a woman with newly diagnosed breast cancer. Initially, the patient was thought to have NF as the painful and rapidly expanding ulceration appeared consistent with a skin infection. 

Yet, the worsening ulceration in response to debridement combined with consistently negative cultures suggested an alternative diagnosis. While PG is a diagnosis of exclusion and has no specific test to confirm the diagnosis, the patient’s clinical picture was consistent with PG. According to the Delphi criteria,¹ the patient met the major criterion of neutrophilic infiltrate in the histopathology of the ulcer, as well as 5 out of the 8 minor criteria: (1) exclusion of infection; (2) pathergy; (3) history of a papule or pustule ulceration within 4 days of appearing; (4) peripheral erythema, undermining border, and tenderness at ulceration site; and (5) decreasing ulcer size within 1 month of initiating immunosuppressive medication, for the diagnosis of PG.

Albeit uncommon, the authors believe chemotherapy and breast cancer might have been contributory triggers, as both have been reported in association with PG.^3,11 Various medications, including the small-molecule tyrosine kinase inhibitors — gefitinib, imatinib, sunitinib, and pazopanib — and the colony-stimulating factor, filgrastim, have been associated with induction of PG.³ The current patient received trastuzumab and pertuzumab, HER2 inhibitors. Human epidermal growth factor receptor 2 is overexpressed in about 20% of breast cancers⁶ and belongs to the epidermal growth factor receptor (EGFR) family.⁶ Blockade of the EGFR pathway results in the cessation of keratinocyte growth, induction of keratinocyte apoptosis, and subsequent epidermal breakdown.⁴ Disruption of the epidermal barrier amplifies immune stimulation and increases pro-inflammatory cytokine secretion, leading to cutaneous inflammation.⁵ 

Pyoderma gangrenosum lesional skin has been shown to express upregulated levels of innate immune components, particularly pattern recognition receptors, thus it is theorized that increased exposure of antigens to innate immune pathways plays a role in the etiology of PG.⁵ Interestingly, the selective EGFR inhibitor, gefitinib, has been reported to be associated with PG.⁶ In light of the role of HER2/EFGR signaling in keratinocyte homeostasis and the rapid onset of erythema and ulceration of the port site following chemotherapy administration, it is possible trastuzumab and pertuzumab may have resulted in the induction of PG in the present patient. Moreover, pertuzumab inhibits heterodimerization of HER2 with other EGFR members.^7-9 The ability of pertuzumab to inhibit HER2/human epidermal growth factor receptor 1 (HER1) heterodimerization and thus possibly alter HER1/EGFR signaling could account for the increased cutaneous side effects that accompany the addition of pertuzumab to trastuzumab-based chemotherapy.¹⁰ Moreover, the neutrophilic and IL-1 driven nature of PG correlates to the pro-inflammatory phenotype of many solid tumors such as breast cancer.¹¹

Diagnostic criteria of PG has been proposed, but diagnosis still remains a challenge because some PG lesions can morphologically mimic NF with rapid skin necrosis.¹² Misdiagnosis of PG can lead to unnecessary surgical procedures, such as debridement and amputation.¹² A recent case series of 54 patients¹³ with necrotizing neutrophilic dermatoses (PG and Sweet’s syndrome) mimicking NF revealed various overlapping characteristics, including erythema, ulceration, tenderness, violaceous margins, fever, sepsis, shock, leukocytosis, and an elevated C-reactive protein. A significant proportion (76%) of these cases mimicking NF had an initial pathergy insult, such as surgery.¹³ Moreover, in patients who were initially diagnosed with NF and did not improve after more than 2 surgical debridements of the affected areas, necrotizing neutrophilic dermatoses should be taken into consideration in the differential diagnosis.¹³ This is distinct from postoperative PG (PSPG), another disease that mimics NF, which is frequently associated with operations involving the breast, chest, or abdomen and commonly appears 7 to 11 days postop.² The overlapping features of NF and PG very likely contributed to the delay in this patient’s diagnosis.

After establishing the diagnosis of PG, the patient required further surgical treatment for her cancer. A consensus perioperative management regimen for active PG when surgery is indicated has not been well defined, but first-line treatment traditionally has been systemic corticosteroids.^1,14 

Surgical procedures are generally contraindicated in patients with PG due to the risk of pathergy.^2,14 A recent review¹⁴ reported a postoperative recurrence or exacerbation risk of 15% in patients with an established history of PG. Increased risk was noted with more invasive procedures (ie, open surgical procedures, Mohs micrographic surgery, debridement).¹⁴ Despite the finding of low risk, physicians must take this management seriously due to the potentially devastating consequences of pathergy accompanying postoperative PG. 

As in the current patient, IVIG has demonstrated efficacy in preventing further ulceration when patients with active and quiescent PG undergo surgery, and IVIG maintains a relatively safe profile in avoiding further immunosuppression.¹⁵ Investigation of IVIG in the perioperative setting for patients with PG with a risk for pathergy is warranted because administration of IVIG over 2 to 3 consecutive days preoperatively has been the general recommendation based on previous cases,¹⁵ including the authors’ experience. Further, wound care regimens for PG are variable; however, once inflammation is under control, the addition of timolol 0.5% appears effective, as it has been used in the treatment of chronic ulcers of any etiology due to its effects on keratinocyte migration.¹⁶

Diagnosis of PG can be challenging, as the clinical picture can be difficult to distinguish from other cutaneous infections when having a shock-like presentation. Interestingly, PG can be associated with comorbidities other than inflammatory bowel disease and rheumatoid arthritis, including solid malignancies, and certain chemotherapeutic drugs may predispose patients to developing PG. While there are a lack of guidelines for the perioperative management of PG, the authors have highlighted the pathergy dampening effect of IVIG in the perioperative management of patients with active PG to perform surgical procedures not related to PG itself. 

Authors: Daniel C. Morse, MD¹; Payal M. Patel, MD²; Carter Haag, MD³; and Alex G. Ortega-Loayza, MD³

Affiliations: ¹Department of Dermatology, McGovern School of Medicine at the University of Texas Health Sciences Center at Houston, Houston TX; ²Department of Dermatology, St. Louis University School of Medicine, St. Louis, MO; and ³Department of Dermatology and Wound care and Hyperbaric Medicine, Oregon Health and Science University, Portland, OR

Correspondence: Alex G. Ortega-Loayza, MD, Associate Professor, Department of Dermatology, Oregon Health & Sciences University, 3303 SW Bond Avenue, CHD 16D, Portland, OR 97239; ortegalo@ohsu.edu

Disclosure: The authors disclose no financial or other conflicts of interest.