Cystic neutrophilic granulomatous mastitis

Introduction

Granulomatous lobular mastitis with lobulocentric non-necrotising granulomas (A, B). Cystic neutrophilic granulomatous mastitis showing neutrophil-lined cysts within granulomas (C) and Gram-positive coryneform bacilli present within the cysts (D).

“Granulomatous mastitis” is a lumper’s term that can refer to any disease with giant cells, and indeed many studies fail to separate these out. “Granulomatous lobular mastitis” (GLM) is a splitter’s term referring to the specific (idiopathic) inflammatory diagnosis rendered when the granulomatous inflammation is lobulocentric and after other specific causes of mammary granulomas have been excluded (including duct ectasia, SMOLD, sarcoidosis, Wegener’s, tuberculosis, fungi). Cystic neutrophilic granulomatous mastitis (CNGM) is a distinctive histological pattern seen in some cases of GLM and is associated with Corynebacterium infection, a gram positive rod. Recognising CNGM is important so as to avoid multiple biopsies (which may propagate the disease) and to expedite the commencement of appropriate antibiotics (in what can be a protracted disease).

Diagnosing CNGM changes management, because it implies Corynebacterium infection, whether or not there is microbiological corroboration. The landmark study was by a New Zealand group in 2003. They identified 34 cases with tissue samples of inflammatory breast lesions with positive microbiological (28) or histological (6) evidence of Corynebacterium species. By demonstrating (1) pure growth (in 40/52 positive cultures), (2) a strong leukocyte response (significant neutrophils in all 34 cases), and (3) organisms in the clinical material (Coryneform species [palisading, V-shapes] visualised in 14/34 cases); they satisfied Funke’s criteria for associating Corynebacteria with a disease entity, namely CNGM. They cultured Corynebacteria in 52/116 samples and performed 16S rRNA gene sequencing on 24—identifying lipophilic Corynebacteria in 20/24 and Corynebacteriua kroppenstedtii in 14/24. Because lipophilic Corynebacteria are fastidious, standard microbiological cultures are likely to be negative, and are not required for the diagnosis of CNGM.

As an emerging entity CNGM remains under-diagnosed. In 2011 when the second case series of CNGM was published, the authors commented that “we were unable to find a citation of this report [Taylor et al] in any standard breast pathology or general pathology textbook”. Moreover, in the most recent 2018 case series of CNGM, only 2/7 cases were recognized as CNGM, the others being signed out with descriptive diagnoses such as “acute and chronic inflammation with non-necrotising granulomas”.

Clinicopathological features

Our clinicopathological understanding of CNGM is based on 90 cases across six studies. Like GLM, CNGM presents as a palpable mass in parous reproductive-aged women that frequently mimics malignancy, with women of Māori and Pacific Islander ethnicity being over-represented (77%) in the original New Zealand study. No defined macroscopic lesion is usually seen and the microscopic findings are diagnostic (described below). The clinical course tends to be protracted (3-12 months in the most recent study) and treatment is based on surgical drainage and/or excision with antibiotics tailored to lipophilic Corynebacteria. Timely recognition of CNGM is required to avoid multiple biopsies before these appropriate antibiotics are initiated.

Microscopic features

All six case series describe the distinctive microscopic features of CNGM. GLM is characterised by lobulocentric granulomas (masked in confluent disease) and CNGM is distinguished by cystic spaces (<1mm but larger than adipocytes), lined by neutrophils, within granulomas; frequently associated with neutrophilic microabscesses. The cystic spaces are consistent with dissolved lipid, being Oil Red O positive. Gram positive rods are reported in 49/90 cases (with at least 16 only seen on review), mostly in low numbers (<10 bacteria), only in the cystic spaces (suitable for lipophilic species), and often with Coryneform features (palisading, V shapes). Given the distinct histology of CNGM, most authors recommend raising the definite possibility of Corynebacteria infection in the report—even without visualising organisms on the gram stain.

Pathogenesis

Regarding pathogenesis, it may be that static secretions predispose to GLM and CNGM, since essentially all affected women have undergone lactational change and both duct ectasia and limited breastfeeding are associated with the diseases. Milk secretions may provide a suitable culture for lipophilic species, as well as being inflammatory in their own right. Furthermore, CNGM—an infection—may be the result of seeding of non-pathogenic flora into the breast tissue, and indeed needle core biopsy worsened 3/7 and 4/12 cases in two studies, and nipple piercing preceded two further cases. Therefore, recognising the specific diagnosis of CNGM may help to avoid potentially harmful repeat biopsies.

References

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