Acupuncture-exacerbated Pyoderma Gangrenosum Associated With IgG Multiple Myeloma

PG is an uncommon, noninfectious neutrophilic dermatosis first reported by Brunsting et al¹ in 1930. PG associated with hematologic malignancies represents only 8.9% of all cases with underlying systemic diseases.^2,3 The characteristics and potential relationship between PG and hematologic malignancies are still unclear. MGUS is a relatively commonly reported hematologic malignancy associated with PG. The transformation of MGUS to MM can be observed in the setting of PG, and IgA is the most common subtype in MGUS and MM patients with PG lesions.^4,5 MM is a malignant plasma cell proliferative disorder with lytic bone lesions, anemia, immune dysfunction, and sometimes specific or nonspecific cutaneous lesions. MM is heterogeneous in its clinical presentation and progression, and very few cases of bullous PG as the first manifestation of IgG myeloma have been reported.⁵ HE4, a precursor of human epididymis protein, may be a marker for bone metastasis, and there is evidence of significant overexpression of HE4 in several other human cancers.^6,7 Researchers have observed that the concentration of HE4 increased during the progression of bone metastases in a patient with malignant melanoma.⁷ Another study found that HE4 was increased in patients with lung cancer, especially those who identified bone metastases by whole-body bone scintigraphy and had probable bone metastases, when compared with a healthy person.⁸ The value of HE4 as a novel serum biomarker for monoclonal gammopathy-related PG with bone metastases has not yet been reported. The current study presents a case of acupuncture-exacerbated PG associated with MM and discusses the potential diagnostic value of HE4 when applied to malignancies presented with PG and bone destruction.

A 49-year-old female, who had painful patches and ulcers located on the lower extremities for the past 5 months, was admitted to the authors’ dermatology department in September 2020. The patient’s lesions were initially misdiagnosed as vasculitis, followed by ineffective treatments. One month before readmission, the dark red patch on the right thigh rapidly progressed to a deep painful ulcer, triggered by unregulated acupuncture treatment. The patient was then admitted to the outpatient department with nonhealing ulcers and a sudden abdominal skin patch. New bullae and necrosis were observed on the original abdominal lesion, and the patient was subsequently hospitalized for further examination and treatment.

Dermatologic examination revealed a large dark-red patch with necrosis on the  abdominal skin (Figure 1) and a conspicuous ulcer on the right thigh (Figure 2). Laboratory tests indicated severe anemia, IgG monoclonal hypergammaglobulinemia, a rising level of urinary and blood light chain κ values, and a strikingly increasing HE4 serum level. No growth was noted in the bacterial culture of the secretion samples taken from the ulcer. A histopathologic examination of the biopsy taken from the abdominal lesion region revealed inflammatory cell infiltration in the superficial dermis (Figure 3, Figure 4). Direct immunofluorescence showed linear complement C3 deposition along the basement membrane zone (Figure 5), and PET-computed tomography indicated multiple osteolytic changes. Bone marrow biopsy and cytomorphologic features revealed plasma cell myeloma with an increasing proportion of plasma cells, accounting for 9.5% of all cells. The patient was diagnosed with PG associated with IgG κ-type myeloma.

The patient was initially administered 1 mg/kg of IV methylprednisolone daily and topical periodic dressing change with recombinant human epidermal growth factor hydrogel. After the MM diagnosis was confirmed, the patient was transferred to the hematology department, and the systemic therapeutic option was switched to 1.2 mg/m² of IV bortezomib (on days 1, 4, 8, and 11) plus 20 mg of doxorubicin (on day 8) and oral prednisone acetate for one treatment cycle. The lesions started to heal and gradually showed scarring. Two months after discharge, the anemia had improved, and the patient underwent a third chemotherapy session with no new ulcers detected. The patient rejected a bone marrow transplant for MM owing to financial reasons and is on follow-up thus far.

The pathogenesis of PG lesions with MM is still unknown and may involve several immune mechanisms. Skin damage, an important PG inducer, can be caused by surgery and accidental trauma. Acupuncture therapy and other invasive medical procedures should be avoided as much as possible in patients with PG. The pathergy phenomenon compounds preexisting lesions related to abnormal neutrophil function, stimulation of various inflammatory factors, and genetic susceptibility. Increased levels of IL-1β, IL-8, IL-17, and TNF-α contribute to disease development, and they have provided potential therapeutic targets for biologic agents.⁹

Exclusive PG diagnosis relies predominantly on clinical presentation, including sudden onset of sterile papules, pustules, and bullae, followed by rapidly developing painful ulcers. Gradually, the overlap between new ulcers and old scabs contributes to chronic underlying ulcers and cribriform scars. The histopathologic characteristics of the skin biopsy are usually non-specific but can be used to exclude infection or vasculitis. Clinical laboratory tests may aid in diagnosing an underlying systemic disease and evaluating the treatment response. HE4 is a member of the “four-disulfide core” family and is a novel immune biomarker for ovarian and respiratory malignancies. It has immunomodulatory properties that show cell proliferation inhibition, the biologic mechanisms of which may be related to the EGFR-MAPK signaling pathway.¹⁰ Researchers have demonstrated the potential value of HE4 for bone destruction findings in lung cancer and malignant melanoma patients with bone metastases.^7,8 In the current case, increasing HE4 levels were detected accidentally, and the only plausible explanation was the obvious bone destruction. Compared with established biomarkers for early diagnosis, such as serum free light chains, HE4 may be a promising indicator for bone destruction progression in patients with PG lesions and hematologic malignancies. Further research is needed in this regard.

Once the diagnosis of the underlying systemic disease is confirmed, patients with PG should simultaneously receive aggressive treatment for the primary disease as well. Early intervention in monoclonal gammopathy-related PG with bortezomib-dexamethasone regimens has been shown to be effective.¹¹ For the current patient in this report, further chemotherapy or other hematologic therapies are required to halt the progression of MM and prolong survival. Usually, 4 to 6 weeks of treatment with systemic GCs is the recommended first-line therapy for PG.¹² Immunosuppressive drugs, in combination with GCs, are applicable in patients whose disease is in severe stages or who cannot tolerate large systemic GC doses. Biologic agents should be used with caution, as Shareef et al¹³ reported on a patient who developed myeloma after treatment with infliximab for PG.

In this case, the diagnosis was delayed due to PG underrecognition. Severe anemia is a symptom of end-organ damage, which resulted in an increased focus from dermatologists on determining potential underlying malignant hematologic diseases. IgG monoclonal hypergammaglobulinemia, which may be involved in ulcer pathogenesis, developed gradually before myeloma occurred but can remain unnoticed for years. The most crucial diagnosis that affected the prognosis, in the current case, is that of MM and not PG. Although the ulcers healed with scars during systemic treatment, the long-term prognosis for this patient is poor because the MM was advanced at the time of presentation and is challenging to treat. In addition, this case study consists of only one case reported with no medical history, medication, or comorbidities included. Serum concentrations of IL-1β, IL-8, IL-17, and TNF-α cannot be measured routinely in the authors’ clinical laboratory.

Early PG detection will result in faster intervention and improve outcomes, especially in patients with malignancies. More emphasis should be put on HE4 regarding the progression of monoclonal gammopathy-related PG with bone destruction to provide new ideas for dermatologists and hematologists to understand the pathogenesis of this disease.

Authors: Jiajie Lyu, MD; Sun Wang, MD; Hanshuo Zhang, MD; and Shengxiu Liu, PhD, MD

Affiliation: Department of Dermatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

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

Correspondence: Shengxiu Liu, PhD, MD; Department of Dermatology, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Shushan District, Hefei, Anhui, China 230032; liushengxiu@ahmu.edu.cn