Inflammatory and Reactive Lesions of the Breast

Inflammatory and Reactive Lesions of the Breast Laura C. Collins, M.D. Vice Chair of Anatomic Pathology Professor of Pathology Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA

Topic for Discussion Inflammatory lesions of the breast Mammary duct ectasia Lymphocytic mastopathy Granulomatous lesions Squamous metaplasia of lactiferous ducts (SMOLD) IgG4-related mastitis Reaction to mammary implants Mimics of inflammatory/reactive lesions

Mammary Duct Ectasia A misunderstood entity! Not simply ectatic ducts

Mammary Duct Ectasia Primarily peri- and post-menopausal women Clinical presentation Pain, nipple discharge, nipple retraction, mass May mimic carcinoma Mammography Ductal pattern of calcification, may simulate that of DCIS

Mammary Duct Ectasia Initially confined to large subareolar ducts but later may involve an entire segment Gross: Dilated, thick-walled ducts filled with pasty, yellowbrown secretions (may be mistaken for DCIS with comedo necrosis) Variably fibrotic intervening stroma

Mammary Duct Ectasia Microscopic features: Early: inspissation of lipid-rich secretions, periductal inflammation (with prominent plasma cells), foamy histiocytes (in secretions, duct wall, epithelium), granulomatous or xanothogranulomatous features Late: Duct dilatation/ectasia, periductal fibrosis, obliteration of duct lumens

Proposed Pathogenesis Inspissation of secretions, leakage Inflammation Fibrosis Duct dilatation

Alternatively, are inflammatory lesion and duct ectasia separate entities? Differences in age, smoking hx

Ectatic Ducts = Mammary Duct Ectasia Ectasia of extralobular ducts common 30-40% of women >50 years Clinically evident mammary duct ectasia uncommon

Ectatic ducts, not duct ectasia!

Lymphocytic Mastopathy Primarily young to middle-aged women Most commonly associated with type I diabetes (diabetic mastopathy) Similar histologic changes seen in association with other autoimmune diseases, type II diabetes, and in men May present as a palpable mass or mammographic abnormality May be multiple and bilateral Recurrences in up to one third

Histologic Features of Lymphocytic Mastopathy Keloidal fibrosis Periductal, perilobular and perivascular lymphocytic infiltrates (primarily B cells) Epithelioid myofibroblasts

Lymphocytic Mastopathy Pathogenesis?Autoimmune reaction?resistance of collagen to degradation due to glycosylation and increased cross-linking

Granulomatous Lesions Most often result from same causes as granulomatous lesions in other organs (infection, sarcoid, reaction to foreign materials, reaction to carcinoma) Some due to lesions unique to the breast (duct ectasia, idiopathic granulomatous mastitis, cystic neutrophilic granulomatous mastitis)

Histologic Features of Granulomatous Lesions Granulomatous Lesion Mycobacterial, fungal, parasitic infections Sarcoid Mammary duct ectasia Reaction to foreign materials Features Granulomas resemble those seen in comparable infections in other sites; may be necrotizing or non-necrotizing Non-necrotizing granulomas in inter- and intra-lobular stroma Periductal granulomas; may have xanthogranulomatous features Foreign body-type granulomas; foreign body giant cells; foreign material Reaction to carcinoma Non-necrotizing granulomas

Tuberculous Mastitis

Sarcoid involving the breast

Idiopathic Granulomatous Mastitis (Granulomatous Lobular Mastitis) Usually presents as a mass in young parous women, often related to recent pregnancy May clinically simulate carcinoma Histologic features Lobulocentric granulomas, often with neutrophils, microabscesses

Cystic Neutrophilic Granulomatous Mastitis (CNGM) Recently recognized entity Presents as mastitis in parous or lactating women Patients often febrile with leukocytosis Nipple inversion or retraction common; fistulas can occur

Cystic Neutrophilic Granulomatous Mastitis (CNGM) Lobulocentric granulomas, often with neutrophils or areas of microabscess formation Empty (cystic) spaces of dissolved lipid surrounded by neutrophils distinguish CNGM from IGM Giant cells may also be present

Cystic Neutrophilic Granulomatous Mastitis (CNGM) Faint rod-like structures may be identified within cystic spaces On Gram stain these bacteria are more easily identified as gram positive rods consistent with Corynebaceria C. kroppenstedtii are most commonly implicated Treatment not yet established

Idiopathic Granulomatous Mastitis vs Cystic Neutrophilic Granulomatous Mastitis Overlap in clinical features Overlap in histologic features Many cases previously diagnosed as idiopathic granulomatous mastitis probably represent examples of cystic neutrophilic granulomatous mastitis in which cysts/bacteria were not identified Johnstone, Pathol, 2017

Squamous Metaplasia of Lactiferous Ducts (SMOLD) Squamous epithelium normally extends into nipple duct orifices for 1-2mm

Squamous Metaplasia of Lactiferous Ducts (SMOLD) Squamous epithelium normally extends into nipple duct orifices for 1-2mm If epithelium extends more deeply, keratin may accumulate, fill and obstruct duct (similar to epidermal inclusion cyst) Duct rupture results in extrusion of keratin and inflammatory reaction

Squamous Metaplasia of Lactiferous Ducts (SMOLD) May occur at any age Highly associated with smoking Presents as red, painful mass near nipple; usually diagnosed clinically as abscess Antibiotics and I and D generally ineffective Also known as recurrent subareolar abscess, Zuska s disease

Squamous Metaplasia of Lactiferous Ducts (SMOLD) Treatment requires complete excision of effected duct(s) Inadequate excision may result in recurrences and/or fistula formation

Squamous Metaplasia of Lactiferous Ducts (SMOLD) Initial surgical specimen often I and D of presumptive abscess Specimens may be small and show non-specific findings Search carefully for keratin and for ducts with squamous metaplasia Subsequent excisions usually contain more diagnostic features

Part of a growing family of IgG4-related diseases characterized by mass-forming lesions due to: Dense lymphoplasmacytic infiltrates with lymphoid follicles and prominent component of IgG4+ plasma cells Stromal sclerosis with atrophy of lobules Elevated serum IgG4 Other sites may be involved Favorable clinical outcome AJSP, 2009

Mod Pathol 2012 Three major histologic features Dense lymphoplasmacytic infiltrate Fibrosis, at least focally in a storiform pattern Obliterative phlebitis Other histologic features: Phlebitis without obliteration of lumens Increased eosinophils Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance (counts vary by organ:10-200/hpf; ratio >40%)

Cheuk, AJSP, 2009

Reactions to Mammary Implants Fibrous capsule Reaction to silicone gel leakage Capsule, breast, axillary lymph nodes Synovial-like metaplasia Breast implant-associated anaplastic large cell lymphoma?mesenchymal tumors?carcinomas

Squamous Metaplasia of Implant Capsule

Silicone lymphadenitis

Breast Implant-Associated Anaplastic Large Cell Lymphoma Presentation Late onset seroma, capsular contraction, mass Median time to development ~10 yrs (range 1-39 yrs) Median age 51 yrs (range 28-87 yrs) Significant association with textured implants Clemens, Plast Recon Surg, 2017 de Boer, JAMA Oncol, 2018

Breast Implant-Associated Anaplastic Large Cell Lymphoma RR of BIA-ALCL in patients with textured implants is 67x higher than in general population But absolute risk is extremely low 1 in 35,000 at age 50 1 in 12,00 at age 70 1 in 7,000 at age 75 Clemens, Plast Recon Surg, 2017 de Boer, JAMA Oncol, 2018

Breast Implant-Associated Anaplastic Large Cell Lymphoma Large, pleomorphic cells in seroma fluid or implant capsule T-cell or null lineage CD30+ Majority ALK-negative Absence of genetic abnormalities at ALK (2q23)

Arada, 2014 CD30

Breast Implant-Associated Anaplastic Large Cell Lymphoma Differential Diagnosis Inflammation Recurrent carcinoma, particularly invasive lobular carcinoma

Breast Implant-Associated Anaplastic Large Cell Lymphoma Treatment and course If confined to capsule, treated conservatively» Removal of implant Most have indolent clinical course (98% 5 year survival)» Patients presenting with mass appear to have worse outcome (?chemotherapy) Must exclude systemic ALCL (may account for some cases with more aggressive clinical course) ~20% have lymph node involvement; more commonly seen when BIA-ALCL extends beyond capsule; can be a mimic for Hodgkin lymphoma; OS reduced to ~75% in patients with LNI

Breast Implant-Associated Anaplastic Large Cell Lymphoma Possible etiologies Chronic T-cell stimulation either due to:» Micromotion/friction of textured implant surface» Response to bacterial biofilm Ralstonia sp. implicated; non-fermenting Gram negative bacillus found in soil and water Similarities with H. pylori Interestingly, macrotextured implants were developed in the 1980 s to improve integration of implant with host tissues; widespread use began in 1990s and first report of BIA-ALCL was in 1996, with many more being reported in the 2000 s

Kim, Plast Reconstr Surg, 2015 Nava, Plast Reconstr Surg, 2018 20 experts from multiple disciplines agreed on the following: Late seromas >1 year after implant should always be evaluated Fluid sent for culture, cytology, flow cytometry and cell block evaluation by hematopathologist Surgical removal of implant and capsule Clinical f/u every 6 months for 5 yrs with US for 2 yrs Absolute risk of BIA-ALCL is very low and BIA-ALCL is biologically indolent, but is a clinically important complication of breast reconstruction/augmentation surgery

BIA-ALCL listed as a new provisional entity distinguished from other ALK- ALCL Non-invasive disease with excellent outcome Some would argue should be considered a lymphoproliferative disorder rather than lymphoma Swerdlow, Blood, 2016

Implant-Associated Mesenchymal Tumors Balzer, 2009 24 cases reported to date Seen with both saline and silicone implants 2/3 fibromatoses, 1/3 sarcomas Cause and effect relationship between implants and mesenchymal lesions not established Some patients who developed sarcomas had received XRT for breast cancer

Implant-Associated Carcinomas Case reports (including squamous cell carcinoma) No relationship between breast augmentation and increased breast cancer risk in two epidemiologic studies

Fibromatosis Mimics of Inflammatory and Reactive Lesions Mimic Fibromatosis-like metaplastic carcinoma Spindle cell (metaplastic) carcinoma Scar Scar Inflammatory/Reactive Lesion Nodular fasciitis Hematopoietic/Lymphoid lesions Invasive lobular carcinoma Histiocytoid carcinoma Inflammation Inflammation Fat necrosis

Fibromatosis Scar

Fibromatosis-like Metaplastic Ca Scar

Spindle Cell Ca Nodular Fasciitis

CLL

Lymphocytic mastopathy CLL

Extramedullary hematopoiesis

Cytokeratin AE1/AE3/Cam 5.2

Histiocytoid ca Fat necrosis

Take Home Message Although relatively uncommon, pathologists should be familiar with the spectrum of the important inflammatory and reactive lesions of the breast, and of the lesions that may mimic them