A rare case of mastitis involving granulomatosis with polyangiitis after immune checkpoint inhibitor therapy

Abstract

Immune-related adverse events (irAE) are a concern during immune checkpoint inhibitor therapy (ICI), and vasculitis is a rheumatic irAE. Granulomatosis with polyangiitis (GPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by necrotizing granulomatosis. GPA in the mammary glands is rare and causes granulomatous mastitis. We describe an older woman with metastatic hepatocellular carcinoma who was receiving ICI therapy. She developed a rapidly growing painful mass in her right breast. Biopsy of the breast revealed necrotizing granulomatous mastitis, which implied an association with autoimmune disease. We detected c-ANCA (proteinase 3)-positivity and a nodule forming a cavity in her right lung; lung biopsy revealed granulomatosis. We diagnosed GPA, possibly arising as an irAE. Prompt initiation of prednisolone therapy led to complete resolution of clinical symptoms within 2 weeks. This case represents the first known report of rare autoimmune mastitis with GPA flared after ICI therapy.

Introduction

Granulomatous mastitis (GM) is a rare inflammation of the breast that usually affects women of childbearing age [1]. The symptoms and imaging findings of GM mimic inflammatory breast cancer [1]. Although the exact cause of GM is unknown, most GM are associated with various infectious agents, such as Corynebacterium species, Mycobacterium tuberculosis, and fungi, and require antibiotics therapy [2]. Recent reports have indicated that some cases of GM are related to autoimmune diseases with various systemic symptoms and require specific management [1, 3].

Granulomatosis with polyangiitis (GPA; formerly Wegener’s disease) is one of these autoimmune GMs [1, 3]. GPA is an anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). GPA is characterized by necrotizing granulomatous inflammation with vasculitis affecting small- to medium-sized vessels and usually involves the upper respiratory tract, lungs, and kidneys [1, 3]. Although the detection of ANCA, especially positivity for proteinase 3 (c-ANCA), strengthens the diagnosis, histological examination of the affected organ is essential for definitive diagnosis [1, 3]. Breast involvement in GPA is very rare and sometimes precedes symptoms in other affected organs [1, 3, 4]. Though recognition of this autoimmune disease is essential to initiate effective steroid treatment, the diagnosis is difficult, especially for breast surgeons who are unfamiliar with autoimmune diseases.

Immune-related adverse events (irAEs) are gaining increasing attention as immune checkpoint inhibitor (ICI) therapy is extended to a wide range of cancers. irAEs occur in almost every organ system, and commonly affect the skin, intestines, endocrine organs, lung, and the musculoskeletal system [5]. The number of studies on rheumatic irAEs is increasing rapidly; however, rheumatic irAEs are not as common as other irAEs, with a reported incidence of approximately 0.7–7.7% [5]. Rheumatic irAEs comprise inflammatory arthritis, vasculitis, polymyalgia rheumatica, sarcoidosis, scleroderma, and Sicca syndrome [5]. Rheumatic irAEs introduced by T-cell activation by ICIs can occur both during and after therapy [5]. Although most irAEs are mild to moderate, clinicians must recognize potentially fatal complications and consider appropriate interventions using interdisciplinary collaboration. In this article, we report a difficult case of GM with GPA that occurred after ICI therapy.

Case report

A 75-year-old woman with Stage IV hepatocellular carcinoma (HCC) presented with a painful mass in her right breast that appeared suddenly 2 weeks earlier. She had an 11-year history of multimodal therapies for anti-hepatitis C virus-positive HCC. She underwent multiple local therapies for recurrent intrahepatic relapses after the first hepatectomy, such as transcatheter arterial chemoembolization and radiotherapy. She started combined ICI therapy for the repeated intrahepatic relapses with durvalumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, and tremelimumab, an anti-cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4) antibody. Computed tomography (CT) 4 months after ICI administration revealed stable intrahepatic metastases but several new nodules in the upper lobe of her right lung, suggesting pulmonary metastases. She underwent second-line systemic therapy with atezolizumab, an anti-PD-L1 antibody, and bevacizumab, an anti-vascular endothelial growth factor antibody. Two weeks after the initiation of this therapy, she noticed a new breast mass.

We palpated a reddish induration in the DE area in her breast. Mammography showed a serrated mass with distortion (category 4), and ultrasonography showed a hypoechoic tumor measuring 19 mm (Figs. 1 and 2). Although these imaging findings supported the diagnosis of a malignant tumor, fine needle aspiration obtained thick pus from the mass. Definitive core needle biopsy detected severe active inflammation and necrosis without malignancy. The initial therapy led to a chronic course, despite surgical drainage, the discontinuation of bevacizumab and the administration of cefalexin for the mammary abscess. Neither bacteria nor acid-fast bacilli were cultured from the abscess. Thus, we planned an excisional biopsy with debridement and changed the antibiotic to azithromycin. The pathological findings showed granulomatous mastitis with necrosis and inflammatory cells severely infiltrated mammary tissue (Fig. 3). We could not find pathological findings of vasculitis in breast tissue. No fungi and no acid-fast bacteria were detected with Gram staining, Grocott staining, and Ziehl–Neelsen staining. We confirmed that the T-SPOT result was negative. We considered a differential diagnosis of granulomatosis with autoimmune diseases, possibly induced by ICI therapy. Three weeks after the appearance of the breast mass, the patient developed a cough and blood-stained sputum, and blood testing revealed high levels of anti-neutrophil cytoplasmic antibodies (ANCA, 76.2 U/mL) (Table 1). We consulted with our immunology department because we considered a diagnosis of ANCA-associated vasculitis, and atezolizumab was discontinued. The patient’s clinical progression over time is shown in Fig. 4. CT showed that the previously noted lung nodule had increased in size, and a cavity had formed within the nodule, suggesting necrosis (Fig. 4). Although the size of both the mediastinal lymph nodes and the breast abscess had increased compared with prior to the administration of atezolizumab and bevacizumab (Fig. 4), the intrahepatic lesions had disappeared. Additionally, the patient had developed left otitis media and pleural effusion. Bronchoscopic biopsy of the lung nodule identified granulomatous inflammation with macrophages, eosinophils, and neutrophils in the pulmonary interstitium (Fig. 3). Neither dirty necrosis, vasculitis nor alveolar hemorrhage were detected in these specimens. We could not detect plasma cell infiltration to lung tissues implying IgG4-related disease. There were no apparent malignant findings derived from HCC. We reached a diagnosis of GPA on the basis of the fact that the patient’s symptoms affected two organs (ear and lung) and the presence of vasculitis (pleurisy), as well as the pathological findings of necrotizing granulomatous inflammation and c-ANCA-positivity. Her clinicopathological findings reached score 10 and met the criteria of GPA (score 5 or more) in 2022 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification [6]. The symptoms in the patient’s breast and lung improved dramatically after initiating prednisolone 50 mg/day in-hospital (Fig. 4). The steroid dosage was successfully tapered with subsequent good control of the vasculitis, even without immunosuppressive drugs. On day 22 after admission (at a prednisolone dose of 30 mg/day), the patient developed obstructive jaundice due to intrahepatic relapses and underwent endoscopic nasobiliary drainage. She subsequently developed a fever, and we identified β-D-glucan-positivity, with intraocular mycosis and candidemia. Treatment with antifungals was ineffective, and unfortunately, the patient developed hepatic encephalopathy and died on day 46 of hospitalization.

Fig. 1.

Mammography showing a marginal serrated mass in the middle and outer right breast (category 4); left image: mediolateral oblique view, right image: craniocaudal view

Fig. 2.

Ultrasonography showing a 19-mm irregularly shaped hypoechoic mass in the DE area of the right breast

Fig. 3.

Histopathology of both the excisional biopsy of the right breast mass (a) and bronchoscopic biopsy of the right lung mass (b). Hematoxylin and eosin staining of both biopsy tissues showed granulomatous inflammation with severe infiltration of inflammatory cells, suggesting GPA. Pathological findings of vasculitis were not detected in the areas of these specimens

Table 1.

Laboratory findings

WBC	5920	× 103/μl	TP	7.4	g/dL
RBC	389	× 106/μl	Alb	2.8	g/dL
Hb	13.1	g/dL	TSH	34.89	μIU/mL
Ht	38.9	%	FT4	0.9	ng/dL
PLT	14.2	× 104/μl	FT3	1.5	pg/mL
PT	56	%	AFP	2	ng/mL
Na	134	meq/L	PIVKA-II	15	mAU/mL
K	3.6	meq/L	T-SPOT	(-)
Cl	101	meq/L	C-ANCA	76.2	U/mL
BUN	13	mg/dL	P-ANCA	< 1.0	U/mL
Cre	0.49	mg/dL	ACE	22.9	IU/L
T-Bil	0.7	mg/dL	Urine gravity	1.022
AST	57	U/L	Hematuria	(-)
ALT	30	U/L	Proteinuria	( ±)
Glu	114	mg/dL
CRP	1.94	mg/dL

ANCA, anti-neutrophil cytoplasmic antibodies; ACE, angiotensin-converting enzyme

Fig. 4.

The patient’s clinical progression over time, showing the relationship between when the drugs were administered and the clinical symptoms of GPA. Computed tomography of the right breast (upper images), lung (middle images), and mediastinal lymph nodes (lower images) at three time points are compared: before atezolizumab and bevacizumab (left), at the time of the GPA diagnosis (middle), and after steroid therapy (right). GPA granulomatosis with polyangiitis; PSL prednisolone: CNB core needle biopsy

Discussion

This case report highlights the importance of considering granulomatous mastitis as a potential symptom in the context of autoimmune diseases, especially during ICI therapy. The diagnosis in this case at the time of the first examination in our department was breast abscess, which was supported by the results of the core needle biopsy. The persistent antibiotic-resistant inflammation led to surgical drainage and open biopsy, which revealed necrotizing granulomatous mastitis. We considered concurrent autoimmune diseases because the patient was older than those with typical idiopathic granulomatous mastitis, and she had received several ICIs for metastatic HCC. Notably, a cough and bloody sputum arose 3 weeks after the appearance of the breast mass. CT showed that the right lung nodule had developed a cavity, and bronchoscopic biopsy revealed granulomatous inflammation, not metastatic disease from HCC.

GM is a rare inflammatory condition of the breast that was first reported by Kessler and Wolloch in 1972 [2]. There is a high prevalence of GM in parous women, usually within 5 years after pregnancy [1, 2]. Some cases of GM develop after infection with organisms such as Mycobacterium tuberculosis or Corynebacterium species, and others present with concurrent autoimmune disease and respond well to steroid therapy [1]. Recent research has focused on autoimmune etiologies of GM. Autoimmune mastitis has four histological patterns: lymphocytic infiltrates, ductal ectasia, GM, and vasculitis [3], which overlap [1, 3]. For example, GPA and eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) are both characterized by GM and vasculitis, and immunoglobulin G (IgG)4-related diseases are characterized by GM with lymphocytic infiltrates [1, 3]. Behçet’s disease presents as ductal ectasia with GM and vasculitis [1, 3], and patients with sarcoidosis develop granulomas without vasculitis or necrosis [1, 3]. Because the differentiation of autoimmune mastitis using only histological diagnosis is very difficult, clinical examinations are useful. These examinations include testing for ANCA for GPA and EGPA, angiotensin-converting enzyme (ACE) for sarcoidosis, IgG4 for IgG4-related diseases, and antinuclear antibodies for idiopathic GM [3]. In this case, we found neither pathogenic nor acid-fast bacteria. We were able to exclude the possibility that GM and the lung nodule arose from tuberculosis infection because of the lack of supporting pathological results and the negative T-SPOT result. We considered GPA after detecting c-ANCA-positivity and biopsied the enlarging lung nodule.

GPA is an ANCA-associated vasculitis that affects small vessels [1, 3]. GPA is characterized by systemic necrotizing granulomatous vasculitis that predominantly affects the upper respiratory tract, with crescentic glomerulonephritis [1, 3]. Therefore, typical clinical findings are seen mainly in the otorhinolaryngologic area and kidney. Breast involvement is very rare and is seen in only 2.3% of patients with GPA [4]. We found only 37 detailed cases of GM with GPA in the literature [3, 4, 7–17]. The median age for all patients was 50 years (range: 25–81 years), which was older than the susceptible age for idiopathic GM. Fourteen cases (38%) developed their first symptom in their breasts. Treatment strategies comprised immunosuppressive therapy with corticosteroids (70%), cyclophosphamide (51%), and other immunosuppressants. In comparison, a review of 193 cases of autoimmune mastitis by Goulabchand et al. reported that GPA was a relatively frequent cause (19%), after sarcoidosis (34%) [3]. Therefore, clinicians should consider evaluating ACE and ANCA when they encounter patients with suspected autoimmune mastitis. Notably, our patient experienced a painful breast mass as her first symptom of GPA. Therefore, we should be aware of unrecognized autoimmune mastitis and consider additional testing.

irAEs are becoming common with increased use of ICIs. Most irAEs are mild to moderate but require appropriate treatment and may be fatal [5]. Rheumatic irAEs, such as inflammatory arthritis, vasculitis, and sarcoidosis are less common than other irAEs [5], which makes rheumatic irAEs difficult to recognize. The reported incidence of rheumatic irAEs is 0.7–5.1% [5]. Additionally, unlike non-rheumatic irAEs, the inflammation associated with rheumatic irAEs may persist even after cessation of ICI therapy, and these irAEs require long-term management [5]. Notably, the GPA in our patient was a suspected rheumatic irAE.

In a cohort study comparing patients with GPA and other AAVs with healthy controls, the authors found single nucleotide polymorphisms in the CTLA-4 gene and PDCD1, the gene encoding PD-1 [18]. The authors also reported that the presence of these variants was associated with disease severity [18]. These polymorphisms reduce the expression or the inhibitory function of CTLA-4 and PD-1 and lead to T-cell hyperreactivity, contributing to the pathogenesis of GPA [18]. This suggests the hypothesis that people with these polymorphisms are predisposed to develop AAVs easily as an irAE when they receive ICIs for cancer treatment. In this case, we did not investigate her genetic polymorphism of CTLA-4 and PD-1. However, considering the possibility that some patients arising rheumatic irAE may have genetic potentials in molecules involved in inhibition of T-cell receptor signaling, in some era, we may consider to screen these polymorphisms to predict the risk of rheumatic irAE, such as the examination of UGT1A1 polymorphism before introducing irinotecan.

We reviewed the literature and found only four cases with GPA induced by ICI therapy for metastatic cancer (Table 2) [19–22]. Three patients received pembrolizumab (anti-PD-1 antibody) therapy, and one received dual therapy with ipilimumab (an anti-CTLA-4 antibody) and nivolumab (an anti-PD-1 antibody). Evidence supporting GPA onset was seen 7–21 days after ICI initiation. In our case, the onset of the breast mass was 120 days after the first dual ICI (durvalumab and tremelimumab) therapy and 14 days after initiation of the additional ICI (atezolizumab). However, considering that the lung granuloma, previously diagnosed as a metastatic lesion, appeared just before the additional ICI therapy, the GPA symptoms might have started 90 days after the initiation of durvalumab and tremelimumab. We might achieve an improvement if we had reconfirmed the diagnosis of this lung nodule, i.e. metastatic disease or not, because her other metastatic sites except lung were stable.

Table 2.

Characteristics of five patients with GPA after immunotherapy reported in previous studies

No	Author	Year	Age	Gender	Primary disease	ICI	Symptoms	Duration from ICI to symptom onset (days)	c-ANCA (U/ml)	Diagnostic examination	GPA Treatment	GPA outcome	Cancer treatment after GPA
1	Brom	2016	56	F	Melanoma	Pembrolizumab	Lung nodule Proteinuria Fever and purpura	7	Positive	Biopsy of skin ANCA	PSL pulse and cyclophosphamide	Remission	Not assessed
2	Sibille	2019	64	M	Lung cancer	Pembrolizumab	Muscle pain	10	178	Biopsy of pleura, skin and lung ANCA	PSL pulse	Relapsed after 8 month and treated with PSL	Chemotherapy
3	Nabel	2019	56	M	Urothelial cancer	Pembrolizumab	Lung nodule Fatigue and arthritis	7	204	Biopsy of lung	PSL	Relapsed after 4 months and remission by rituximab	Chemotherapy
4	Hung	2021	66	F	Melanoma	Ipilimumab + nivolumab	Hemoptysis Proteinuria Headache, arthritis and purpura	21	1501	Biopsy of kidney ANCA	PSL pulse, rituximab and infliximab	Remission but suffered from secondary diabetes mellitus and renal failure	Not assessed
5	Ours	2025	75	F	Hepatic cell carcinoma	1. Durvalumab + tremelimumab 2. Atezolizumab + bevacizumab	Mastitis Cough and blood sputum	1. 120 2. 14	76	Biopsy of breast and lung ANCA	PSL	Good response but secondary mycosis	BSC

ICI immune checkpoint inhibitor; GPA granulomatosis with polyangiitis; PSL prednisolone; BSC best supportive care

Previous studies reported that various organs were affected, and ours is the first report, to our knowledge, of mastitis with GPA as a possible irAE. In previous studies of ICI-associated GPA, all patients received immunosuppressive therapy, mainly prednisolone [19–22]. Although the reported remission induction rate of general GPA is up to 80%, relapse occurs frequently (41%), and the 5-year overall survival rate is only 45–76% because of secondary renal failure or chronic respiratory failure [23, 24]. In these reports, GPA relapsed in two patients after several months and required additional immunosuppressants [19, 20]. Case 4 and our case developed secondary organ failure or infection (lung). In the view of cancer therapy, besides Cases 2 and 3 restarted chemotherapies after remission of GPA, the general condition of our case could not allow further treatment for cancer. GPA arising as a rheumatic irAE is reported to show a good response to steroid therapy and prudent readministration of ICI is not always impossible under a good control of GPA [5]. When treating GPA in patients with cancer, it is important to consult with immunologists to avoid potentially fatal secondary complications and consider a good strategy for cancer treatment.

In conclusion, we reported a case of rare mastitis with GPA induced by ICIs. When encountering atypical GM, it is important to recognize the possibility of systemic autoimmune disease.

Authors’ contributions

Drafting the manuscript: CM. Clinical treatment: CM, AW, and TK. Pathological diagnosis: YM. Writing–review and editing: RT, YS, NM, MT, YS, TY, and TT. Critical revision of the manuscript and supervision of the study: KS.

Funding

The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study did not receive any specific funding.

Data availability

The data that support the findings of this study are available from the corresponding author, CM upon reasonable request.

Declarations

Conflict of interest

Takahiro Kodama, Tetsuhiro Yoshinami, and Kenzo Shimazu received lecture fees from AstraZeneca and Chugai. Takahiro Kodama received research funding from AstraZeneca. The other authors declare no conflicts of interest.

Ethical approval

This case report was performed in accordance with the guidelines of the Declaration of Helsinki and its later amendments. Ethical approval was not required according to the policies of our institution as this was a report of a single case and no identifiable patient data were disclosed.

Informed consent

Consent to participate and for publication were obtained from the patient.