25. September 18.00 Granulomatous Mastitis 18.30 Low grade intraductal proliferations ADH vs DCIS 19.00 Special types of breast cancer: clinical & molecular correlates 19.40 Breast pathology post neoadjuvant chemotherapy 20.20 Predictive marker update & multiparameter molecular markers

Granulomatous Mastitis September 25, 2018 Megan L. Troxell MD/PhD

Granulomatous mastitis Differential diagnosis: Infectious (TB, fungal, cat scratch, bacterial) Bug stains (AFB/Fite, GMS and Gram) Idiopathic Diagnosis of exclusion Autoimmune Sarcoid Rheumatoid nodules/RA GPA/vasculitis Rule out carcinoma Infarct SMOLD (Squamous Metaplasia of Lactiferous Ducts) IgG4 related disease?? (Biopsy site/foreign body) Renshaw. AJCP 2011. 136:424-427

‘Idiopathic’ granulomatous mastitis Young women, esp. post lactation Mass lesions, painful, treatment refractory Surgery Immunosuppression (steroid, methotrexate) Antibiotics (non-targeted) May heal in 6-12 months without treatment Histology: lobulocentric granulomatous inflammation Also during pregnancy; different than lactation associated acute mastitis; Idiopathic ”lobular”

Granulomatous & necrotizing mastitis AJCP. 2011; 136:424-427 Granulomatous & necrotizing mastitis Distinctive cystic spaces lined by polys Spaces larger than adipocyte Gram + organisms (corynebacterium) Bugs are IN THE SPACES Lipophilic, requires Tween to grow Rx with tetracycline, doxycycline (2+ weeks) Taylor. Pathology 2003:35:109-19. NZ study with culture data Small # bugs, over reactive immune reaction

33 year old with breast mass The mammogram just shows density in the upper outer quadrant, no discrete mass. The ultrasound shows an irregular hypoechoic mass with suggestion of finger-like projections extending into the surrounding tissue. Mammogram: no discrete mass Ultrasound: irregular hypoechoic, finger like projections into surround

CNGM

Polys can be few around space, or more numerous

CNGM

Guatemala case (not shown, one with H&E bugs but no Gram stain from 2015; more acute & granulomatous, abscessy)

CNGM histologic pattern lipophilic bacteria Granulomatous mastitis Pattern Age (range) Child bearing Gram+ bugs? D’Alfonso AJSP CNGM 34 (25-49) nd 5/12 Troxell AJCP 33 (19-47) 4.75 y ago 16/19 Other GM 47 (29-71) 14 y ago 0/16 CNGM: More polys (neutrophils) CNGM with eosinophils Hispanic ethnicity in OR; can also be fewer polys! 66% Hispanic GNGM vs 14% other GM D’alfonso most or all cores Acute and granulomatous/histiocytic

Microbiology perspective Taylor & Paviour 1993-2002 “..granulomatous mastitis can be associated with Corynebacteria infection, particularly infection by C. kroppenstedtii.” 34 breast specimens with Corynebacteria spp. 13 C. kroppenstedtii. Described lobular GM with suppurative lipogranulomas 79% Maori or Islander (NZ) C. kroppenstedtii 1998 Difficult to grow Lipophilic; requires Tween Lacks mycolic acid at cell membrane Long incubation (72+ hr) Difficult to determine Abx susceptibility May be disregarded as skin flora/contaminant Tauch. Int J.ID 2016;48:33-9 37/42 (88%) C. Kropp from breast isolates Taylor: Controls similar histology, but no bacterial isolates (probably same disease) Many are pure isolates; Described cystic space Johnstone and UNC have similar studies (starting with micro then looking at tissue) Ten were identified as Corynebacterium kroppenstedtii, two as Corynebacterium tuberculostearicum, two as Corynebacterium amycolatum, one as Corynebacterium CDC group G2, one as Corynebacterium accolens and one as Corynebacterium minutissium. The C. amycolatum isolates and the C. minutissium isolate were the only non-lipophilic corynebacteria identified. The seven isolates speciated biochemically were classified as C. kroppenstedtii (4), Corynebacterium CDC Group D2 (1), Corynebacterium CDC Group G2 (1) and C. minutissium (1). C. kroppenstedtii was identified from 13 different women.

Granulomatous: Non-CNGM Granuloma & eosinophilic Post XRT for cancer TB (T-cell lymphoma) Hispanic ethnicity in OR Troxell et al. AJCP.2016;145:635-645 Stromal ‘idiopathic’ bilateral

Several groups have suggested granulomatous mastitis= IgG4 sclerosing disease of breast

No, not all IgG4+ is IgG4 RSD Several groups have suggested granulomatous mastitis= IgG4 sclerosing disease of breast No, not all IgG4+ is IgG4 RSD

Lymphoplasmacytic infiltrate, mass-forming AJSP 2009;33:1058-64 Lymphoplasmacytic infiltrate, mass-forming Stromal sclerosis and loss of breast lobules NO GRANULOMAS!! 3 of 4 with multiple masses, elevated serum IgG or IgG4 IgG4+ also in some lymphomas

IgG4 ?granulomatous mastitis IgG4+ plasma cells not specific for IgG4-RSD in other organs Granulomas unusual in IgG4-RSD in other organs Granulomatous mastitis is NOT IgG4-RSD (in my opinion) Cheuk et al IgG4+/hpf IgG4-R mastitis 272-495 Lymphocytic mastopathy 0-5 Granulomatous mastitis 5-398 Our study CNGM 6-58 Other GM 0-22 Our study Cheuk Chan had lymphocytic mastopathy and granulomatous mastitis as controls Our CNGM 2/9 with >30/hpf

GM literature problematic IgG4+ plasma cells not specific for IgG4-RSD in other organs Allen, Kleer. Breast J. 2016;22:501-9 What about cystic neutrophilic pattern? Polys? Bugs? Clinical? 17/43 IgG4 seems high Egypt & morocco 17 IgG4/8 GM/18 indet.

Core biopsy: granulomas

Same case: epithelioid histiocytes?

Same case: epithelioid histiocytes? Keratin stain: ILC with granulomas

Conclusions Recognize CNGM pattern Do Gram (bacterial) stain along with AFB, fungal stain Look in the ‘microcysts’ for bacterial organisms Stain multiple blocks Antibiotics for Corynebacterium “lipophilic antibiotics with a high volume of distribution …..doxycycline and trimethoprim-sulfamethoxazole; clarithromycin and rifampicin” Johnstone Pathology. 2017;49:405–12. CNGM is major subset of ‘idiopathic’ or ‘lobular’ GM Speculation: immune response out of proportion to indolent chronic bacteria? I raise possibility even if bugs not ID’ed; put in ddx in right clinicopath context Working on projects to compare immune infiltrates

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