Vulvar mass- Cutaneous IgG4-RD misdiagnosed as vulvar cancer

Dear Editor,

Immunoglobulin G4-related disease (IgG4-RD), a fibrotic inflammatory disorder affecting multiple organs, including salivary, pancreatic, and lacrimal glands, rarely involves the skin, especially the vulva.¹ We report a case of a patient with a vulvar mass whose definitive diagnosis took seven years.

A 58-year-old woman had a 7-year history of an eroded vulvar growth. It started with an itchy ulcerated area from which a biopsy performed five years ago showed ulcerated epithelium and infiltrate of plasma cells confirmed on immunohistochemical analysis (mixed ĸ/λ, <40% IgG4+). Following surgical excision, she was diagnosed with locally advanced, highly differentiated vulvar squamous cell carcinoma (SCC). Over five years, she experienced two biopsy-confirmed recurrences, managed surgically, and complemented with paclitaxel-cisplatin chemotherapy and radiotherapy.

The lesion had recurred five months ago as a 2.5 cm- sized vulvar mass with erosions, ulcers, and purulent discharge [Figure 1]. Serum IgG4 was markedly elevated (5.84g/L normal: 0.03-2.01 g/L). Magnetic resonance imaging of the area showed T2 signal heterogeneity and enlarged inguinal lymph nodes. Histopathology revealed focal areas of full-thickness epidermal loss, squamous hyperplasia with dense subepithelial plasma cell infiltration (no fibrosis/obliterative phlebitis; Figure 2a-c]. Immunohistochemical analysis confirmed IgG4-RD: CD38+ plasma cells, IgG4 >200 cells/high-power field, IgG4/IgG ratio >40%, and polyclonal ĸ/λ [Figures 2d-2h]. Epstein-Barr virus was negative on tissue staining. There was no other significant medical history.

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Figure 1:

A firm mass, 2 cm centimetres in diameter, exhibiting erosion, ulcers, and pus, located on the bilateral labia minora and vaginal walls.

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Figure 2:

a-c: Histopathological examination revealed focal areas of full-thickness epidermal loss accompanied by hyperplasia of the squamous epithelium a) yellow arrow, elongation of epithelial rete pegs, and substantial infiltration of immune cells, predominantly plasma cells c) (red arrow), beneath the epithelium (Haematoxylin-eosin staining; a: 40x; b: 100x; c: 400x). d-h: Immunohistochemical analysis confirmed the expression of (d) CD38, (e) IgG, (f) IgG4, and (g) ĸ/ (h) λ (polyclonal plasma cell hyperplasia) in the infiltrating cells. (d-h: 100x magnification)

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The patient was prescribed 30 mg of prednisone daily, following which the lesion improved [Figure 3a]. The dose was reduced to 20 mg [Figure 3b] and then 15 mg. IgG4 levels decreased to 3.25 g/L. Ultrasonography showed a 0.7×0.6 cm sized left inguinal lymph node. However, after 20 days of improvement, she stopped the medication, and symptoms recurred [Figure 3c]. Therefore, the original dose was resumed with close monitoring of clinical response and tolerability.

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Figure 3a:

Improvement following one month’s administration of 30 mg of daily oral prednisone.

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Figure 3b:

Resolution observed after 20 mg of oral prednisone daily for two months.

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Figure 3c:

Recurrence of symptoms after self-discontinuation of treatment for 20 days.

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IgG4-RD mainly affects middle-aged men and is characterised by IgG4+ plasma cell infiltration and elevated serum IgG4. Cutaneous IgG4-RD is rare, especially primary cases.^1,2 Histopathologically, lesions typically demonstrate dermal lymphocyte and polyclonal plasma cell infiltration without epidermal involvement.² In this case, no significant fibrosis or obliterative phlebitis was observed, consistent with prior reports on histology of cutaneous IgG4-RD .³

Two diagnostic frameworks exist; the 2019 ACR/EULAR criteria and Umehara et al’s criteria.^4,5 The patient did not fulfil the ACR/ EULAR diagnostic criteria since it is based primarily on clinical manifestations and imaging characteristics of typically affected organ systems and cutaneous findings are not incorporated into this. However, she fulfilled the diagnostic criteria proposed by Umehara et al., which specifically address the limitations inherent in the ACR/EULAR classification system.⁵ Another cause of delayed diagnosis could be the IgG4 < 40% on immunohistochemistry early in the presentation. This highlights that this crucial indicator can change over time and with disease progression.

Vulvar cancer is a rare gynaecologic malignancy, accounting for 4% of all cancers in the female reproductive tract, with 90% being squamous cell carcinomas. Vulvar SCC may present as a palpable mass, visible lesions, or an elevated, flat ulcerated, or wart-like mass on the vulva.⁶ This patient was misdiagnosed with vulvar SCC, resulting in unnecessary treatments. Re-evaluation of initial pathology showed that SCC diagnosis relied on epidermal hyperplasia with elongated rete ridges, focal nests, and a reticulated pattern, stromal plasma cell infiltrates, scattered atypical squamous cells with mitotic figures and focal weak p16/p63 positivity on immunohistochemistry. However, pseudo-epitheliomatous hyperplasia may offer a more accurate interpretation of this pathology than SCC in situ.

Glucocorticoids remain the primary mode of treatment for IgG4-RD, effectively inducing and maintaining remission in most patients. However, the disease is prone to relapse, particularly when glucocorticoid doses are tapered or discontinued. Relapsed cases typically respond to reinitiation of glucocorticoids. For patients intolerant to glucocorticoids, exhibiting poor response, or experiencing significant adverse effects, alternative therapeutic options may include combinations of immunosuppressants and biologics. Traditional immunosuppressants include mycophenolate mofetil, azathioprine, etc.⁷ However, these immunosuppressants may exhibit a slower onset of action and are generally not advised during the acute, active phase of the disease. A common strategy involves controlling the acute phase with glucocorticoids, followed by the incorporation of steroid-sparing immunosuppressants for ongoing management.

In summary, we have documented an uncommon presentation of primary IgG4-RD affecting the vulva. Our aim is that this report not only offers valuable diagnostic insights but also raises awareness of this condition, ultimately assisting healthcare professionals in the effective management of similar cases in future.