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• Postoperative lesions:
  1. ordinary scar, +- hypertrophic
  2. ceroid granuloma: epithelioid granulomatous mass reacting to fatty breakdown products which happen to produce AFB+ staining ceroid [LMC-01-6219]
• Traumatic lesions:
  1. fat necrosis
  2. lipid granuloma: histiocytes, foam cells, cholesterol clefts as evidence of organization of an area of hemorrhagic fat necrosis or a hematoma [LMC-01-6518]
• Myoepithelial lesions²:
  1. adenomyoepithelioma: increased glands and ME cells (looks a little biphasic); increased mitoses but benign nature reflected in lack of pleomorphism & necrosis [LMC-01-3364; LMC-03-2112B]
  2. fibromyoepithelioma: fibroadenoma with excessive ME cells [LMC-03-2112A]
• Myofibroblast tumors:
  1. CD34 marks myofibroblasts (MF) (The Breast J. 7(4):263-265, 7-8/2001)¹⁰
  2. myofibroblastoma or myofibroma: rare circumscribed (FA-like) nodule of broad bands of hyalinized collagen and haphazard arrangement of short spindle-cell fascicles of myofibroblasts...treat by excision.¹⁰[LMC-03-2112A]
     • collagenized variant : PASH-like (myofibroma)(vs. fascicular var. PASHLMC-03-5182)
     • epithelioid variant: this variant...when "collagenized"...can mimic invasive lobular ca.
     • cellular variant:
     • infiltrative (not a discrete tumor) variant:
     • myxoid variant:
  3. Pseudoangiomatous stromal hyperplasia (PASH...since about 2000)
     • PASH usually fibroadenoma-type imaging features and comes to Bx because of rapid growth of some or because FNA or core Bx done and not fibroadenoma (FNA smears can suggest phyllodes tumor).
     • Confidently diagnosable by:
       • imaging studies: no.
       • FNA: no (cytology is like fibroadenoma).
     • core biopsies: yes...if proper components are portrayed richly enough; but, there can be small patches of PASH amongst or on the edge of other lesions so concordance needs to consider if core findings make sense for the size of the lesion (a single 1 cm core may not adequately represent a 3 cm lesion.
       • What is PASH?: is an exaggeration of physiological menstrual change and usually & very common as a small, focal change in a variety of breast situations² ; but it can lead, rarely, to the need for bilateral mastectomy¹⁵ and even recurr in axilla.
       • PASH Histology: stroma has interconnected cracks and slits with increased nuclei...resembles angiomatous change² ; the cells are myofibroblasts (MF) & usually CD34 positive¹⁰. Can have some giant cells (giant cells can even predominate ) and mitotic activity.
       • PASH Variants:²
         1. Macro: palpable or fibroadenoma-like nodule ("nodular variant of PASH", see below)  vs. a more diffuse change ("lesion of diffuse PASH")[LMC-01-7312; 8179; LMC-02-152; LMC-02-5976; LMC-04-7564; LMC-04-9271]
         2. Micro: "fascicular" histological pattern: MF cells prolif. & group [LMC-01-4353B; LMC-01-6272]
         3. Micro: "myomatous" histo. pattern: MF cells have maximally expressed cytoplasm.
       • PASH Treatment:
         1. unsure/variable, but surgical: some have suggested from complete excision to wide local excision^1,10.
         2. if recurs: the histo. features are same as original and same as those not recurring^1,10.
  4. Other:
     • intramammary lipoma or circumscibed lipomatous intrusion of subdermal fat.
     • mammary parenchymal ridge...invariably as a diagnostic excisional biopsy of a palpable abnormality which is occult by ultrasound & mammography...histology of normal breast.
     • leiomyoma.
     • myxoma
     • vascular tumors: angioma, hemangioma, hemangiopericytoma, aneurysm, etc.[LMC-04-9406].
     • angiomyolipoma [LMC-91-6739] (epithelioid angiomyolipoma can be HMB-45 positive) .
     • granular cell tumor (granular cell myoblastoma):
       • only rarely malignant. 
       • cured by local excision^{1, 5}...some say wide¹⁰.
       • [not sure why couldn't be just followed in the right patient][LMC-91-6741; S-01-4822 core bx & LMC-01-5058 lumpectomy].

FIBROUS STROMAL/INFLAMMATORY/METABOLIC:
• "lymphocytic mastitis", "diabetic mastopathy"³:
  • associations with: diabetes, hypothyroidism, Hashimoto's,  autoimmune diseases, arthropathy [LMC-01-3472, 4346, 5885].
  • gross & histology:
    • circumscribed mass or nodule.
    • sclerotic, keloid-like collagen stroma.
    • patches of polyclonal B lymphocytes: stroma vs. periductal (lymphocytic ductitis) [LMC-04-4761] vs. perivascular vs. intralobular (lymphocytic lobulitis) and maybe even lymphoid nodule formation...followed by glandular atrophy.
    • some cases have epithelioid histiocytes or fibroblasts, isolated and clustered; some lymphocytic/mononuclear perivasculitis which is predominantly B cell.
• Fibroma: there may be no significant difference between this and "fibrous tumor", below.
• Fibromatosis (rare): lacks aggressive behavior of "desmoids" but dense collagen bands & recurs if not removed with clear margins⁹; alternative terms in literature are "extra-abdominal desmoid", "low-grade or grade I fibrosarcoma", and "aggressive fibromatosis"...usually presents as hard, palpable lesion, often subareolar, ages 13-80, spindled cells and collagen...sometimes keloidal...treatment said to be wide local excision¹⁰.
• Fibrous tumor: markedly decreased or absent breast epithelial components in a benign collagenized mammary stroma...usually premenopausal...usually fairly discrete¹⁰ [LMC-02-4632].
• Fibrous pseudotumor: fibrosis and evidence of some chronic inflammation (could be nearly fully fibrosed fat necrosis [LMC-03-1587/2701]).
• idiopathic localized scleredema: (otherwise sometimes called liposclerosis) in the breast, it is associated with clinical findings such as pain & swelling and mammographic findings of increased fibroglandular vdensity and implies a stromal reaction to lymphatic obstruction. But the term is reserved for cases in which obstruction could not be found. Our case (B07-248) seemed benign on post-incisional-biopsy follow-up, but metastatic breast cancer was found a year later.
• Nodular fasciitis like lesion:[LMC-02-1233].
• Plasma cell mastitis: is first & foremost a mammographic lesion...histology must be concordant with mammography.
• granulomatous mastitis:
1. infectious: following the damage of a bacterial abscess [16 weeks pregnant L09-6255], and in mycobacterial & fungal mastitis.
2. foreign body
3. "lobular granulomatous mastitis" [L09-5239].
4. idiopathic granulomatous mastitis¹⁷: highly associated withpostpartum period...as much as 3 years so [L08-3228].
• Epithelium-poor lesion of fibrocystic mastopathy: [LMC-03-5840].
• ANDI lesions (Anomaly of Normal Breast Development and Involution¹¹): all other benign stromal lesions, not otherwise specified. [LMC-04-4761] This includes anomalous developmental ridges, non-diabetic fibrous areas, etc. (and many would include the whole realm of fibrocystic mastopathy).

EPITHELIAL LESIONS:

• Skin: we have seen one plastic surgery case with hypertrophy of apocrine sweat glands of the axilla such that excision was made thinking that there was bilateral axillary breast tissue [L09-1436].
• Adenoma: circumscribed mass of tubular elements & scant stroma
  1. adenoma/tubular adenoma: hardly any stromal participation & usually in young women [LMC-00-6928; LMC-03-1798].
  2. lactating adenoma: during pregnancy or postpartum period and may become discrete due to chronic inflammation and, therefore, is more like a "lactational pseudotumor" [LMC-07-384].
  3. focal pregnancy like change: lactational histology in non-lactating patient.
  4. apocrine adenoma: nodule of solid/pap. & cystic apocrine metaplasia⁷.[LMC-05-7991; L10-9406]...if high-H-score p53 nuclear positivity & elevation of Ki67 on core biopsy, it may be best to excise.
• Adenosis: excessive quantities of ductules/tubules.
  1. sclerosing adenosis
  2. (simple adenosis, NOS)
  3. adenosis tumors, see below under biphasic
  4. blunt duct adenosis: hypercellularity of terminal ducts, remindful of tubular (this is its importance), but overall retains an oval nuclear shape.
• Radial scar: radial sclerosing lesions have about a 25% association with carcinomas, especially tubular ca.; at least 2-cell layer epithelial radiations look drawn or puckered toward center & with axis tending parallel with the radiation & no "infiltration of fat"...and often have some at least mild, usual hyperplastic change; fibrosis is more central & often with elastosis¹⁴.[LMC-05-8748]
• Hyperplasia: excessive epithelial proliferation into lumens (epitheliosis); qualitative and quantitative assessment of architecture and cytology.
  1. ductal/intraductal (originate primarily in TDLUs): [see DIN system]
     • usual ductal hyperplasia (UDH): k903 stains & can be mozaic/mixed¹³: (heteromorphic, uneven, nuclear streaming...like fish in a school, and any cribriform bridges look non-rigid, unstretched & irregularly fenestrated & with peripheral fenestrations):
       1. simple
       2. complex
     • atypical ductal hyperplasia (ADH...d-AH): a mix of UDH & DCIS in a duct profile (sort of like pre-low-grade DCIS); or, UDH that histologically mimics DCIS with cribriform areas of secondary lumina (residual spaces) whose bridges are not "rigid" enough and/or with cellularity that is not monomorphic enough. K903 absent or decreased¹³ in the atypical areas while UDC area positive¹⁹.
     • columnar cell lesion...change (CCC), hyperplasia (CCH), FEA : is a separate situation of dilated TDUs without & with increased epithelium. [algorithmic DDX chart] Can be multifocal and bilateral and usually targeted for biopsy because of microcalcification; & micro-cystic increase in enlarged crowded columnar epithelium which has apocrine change with snouts...CCC if not multilayered & CCH if 2 or more cells thick¹³. Because the entity has been previously thought to be associated with tubular carcinoma or lobular neoplasia, excisional biopsy is warranted...but certainly not mandatory...when there is a core biopsy diagnosis...as with d-AH. If epithelium atypical...nuclei more round...& epithelium  noncomplex, referred to then as "flat epithelial atypia" (FEA)¹³ though cells not "flat". At UCLA, in Rosen's book, and Schnitt's hospital, surgeons respond to the core biopsy diagnosis with excision of the lesion¹². If incidentally found on excisional biopsy, be sure that all non-fatty component has been processed; studies as of 4/2005 fail to declare increased risk of breast cancer...but would seem to mark the patient to stay committed to breast self exams & yearly mammography. A special variant is the HELU lesion (hyperplastic enlarged lobular units) which typically has microcalcification (originally "blunt duct adenosis")²¹. Columnar complexity moves one into UDH-like vs. ADH-like vs. d-CIS.

       "¹²I discussed your case and concerns with several breast pathologists in our department. We all felt that this is a very difficult and extremely confusing area. In our institution, if a needle core biopsy contains a columnar cell change or columnar cell hyperplasia with atypia (no matter mild, moderate or severe; some people group these two---CCC with atypia and CCH with atypia together and call them flat epithelial atypia or FEA), surgeons will do excisional biopsy. Rosen (in his book) and S. Schnitt recommended the same. I went to the USCAP meeting at Banff in late July '04, and S. Schnitt gave a talk in CCC/CCH and FEA etc. at the meeting. I have a CD of his talk and if you are interested I can send you his part of power point presentation to you as an attachment. As to atypia:

       "¹²Presence of several mitoses alone in one duct unit without any other associated cytological and architectural atypia may not be enough for atypia. In your case, we felt that it may simply represent a CCC with increased mitosis (? may have something to do with menstrual cycle and estrogen level). Many of us try not to put too much weight on mitosis alone unless there are some associated cytological (roundness of nuclei, prominent nucleoli, loss of polarity and orientation, nuclear crowding or jumbled up nuclei, nuclear hyperchromasia, etc.) and architectural atypia. In addition, if the duct unit contains one or two layers of epithelial cells, we usually call it CCC. Likewise, if there are more than two layers of epithelial cells but do not meet formal criteria of ADH, we call it CCH. If there are associated atypia, we call it CCC with atypia or CCH with atypia (Schnitt's group calls both FEA). I believe there are more than 10 different terms used to describe the same change, to name a few, ELUCA (enlarged lobular unit with columnar alteration, Dr. Page's group at Vanderbilt) and CAPSS [columnar alteration with prominent snouts and secretions], etc.¹²" .
       
     • Ductal carcinoma in-situ  (DCIS...d-CIS): (see DIN chart)
     • as to ADH, above: the minimal criteria to make a diagnosis of at least low grade DCIS are¹³:
     1. cytology: monotonous uniform round cells; round nuclei which are equidistant; maybe a subtle increase in N/C & maybe nuclear hyperchromia. Some HG DCIS positive¹³!.
     2. architecture: solid; or, arcade/cribriform rigidity and punched out lumena spare duct periphery; or, micropapillary.
• Intraductal paillomatosis: from microscopic fibroepithelial papillomata in minimally dilated ducts, to one or many larger visible lesions causing galactogram filling defects, to even florrid papillomatosis lesions forming palpable masses of very large size (such as 10 cm).
• periductal mastitis: until very late, this usually presents with nipple discharge, & histology is a heavy periductal active chronic inflammation which can be duct-destructive, leading to some granulomatous inflammation and even intraductal granulomatous inflammatory polyp formation (galactogram filling defects [L07-879]), & leading to duct ectasia & periductal scarring and becoming a palpable mass .
• Lobular (LIN):
  • hyperplasia (LH): mild increase in lobular cellularity...no "filling"¹⁹.
  • atypical lobular hyperplasia (ALH...l-AH): moderate or greater lobular cellularity short of appearing to really distend the lobular profile and/or less than half of the TDLU is "filled" by lobular cells.
  • lobular carcinoma in-situ. (greater than half of TDLU "filled" with lobular cells¹⁹).
• Cysts:
  1. common: simple lining as in fibrocystic mastopathy.
  2. apocrine: simple, but apocrine, lining as in fibrocystic mastopathy.
  3. intracystic papilloma [S-02-11932].

BIPHASIC (epithelium and stroma increased significantly) LESIONS ⁶:

• Fibrocystic mastopathy (FCM): Dr. Rosen credits Boston surgeon, J. C. Warren with the initial "naming" of this disorder in a1907 publication as "abnormal involution"²⁰ (a condition of faulty coversion with advancing age of the younger female fibroglandular breast parenchyma into a predominantly fatty parenchyma).
  • FCM NOS.
  • tubular adenosis: longitudinal tubules without lobulocentric orientation (but with basement membranes and ME cells) and potentially a problem vs. tubular ca.⁷
• Fibroadenoma type tumors:
  • the two standard fibroadenoma histological patterns:
    • stroma is intracannalicular.
    • stroma is pericannalicular.
  • Fibroadenoma variants:
    • mitoses: can easily find mitoses up to 3/10 hpf where stroma with "active nuclei"¹⁸.
    • sampling: without reasonably careful & thorough sampling, you can miss the foci that take you to the "worse diagnosis"¹⁸.
    • juvenile: in an adolescent & has rapid growth & causes affected breast to be 2-4x size of other & stretches skin & displaces nipple; increased stromal cellularity and epithelial-component concentration as larger tubules & with fewer lobulations & yet fairly few mitoses¹⁸.
    • giant: >8-10cm &/or >500 grams.
    • hypercellular: ⁷[LMC-02-1976; L08-2947; L09-2622] excision recommended⁷; no leaf-like, no fat within, no metaplasia, surprisingly few mitoses in view of cellularity, & no margin infiltration¹⁸.
    • tubular:⁷ [LMC-01-6167; LMC-03-6457].
    • with minor benign phyllodes-like component: "leaves" not cellular [LMC-05-6124; L08-3262].
    • phyllodes tumor (cystosarcoma phyllodes [PT or CP]):
      1. benign: there are no truly reliable factors to distinguish this from a variant fibroadenoma (though Hx of rapid growth and size greater than 4 cm. probably favor it). But, phylloid "leaves" plus some at least focal loss of circumscription help "make" the diagnosis. Median age of 45 years. Dx from benign vs. malignant rests on (1) predominantly on mitotic activity, being very careful to check stromal areas immediately periductal²⁰ (benign rarely greater than 1-2 mitoses per 10 hpfs), (2) stromal cellularity (benign rarely more than moderately cellular), and (3) character of tumor border as determined from an adequately sampled, excised tumor, remembering that benign can be invasive (don't conclude benignancy until this excisional exam!). Benign does not metastasize, and has a 20% local recurrence rate after excision⁷. One more likely to find mast cells admixed in the stroma of benign.
      2. borderline: can consider it a low-grade PT/CP; more tendency to a "pushing" border than "malignant" & <4cm size and <3/10 hpf mitoses; only mild nuclear atypia and no "sarcomatoid" foci
      3. malignant: consider it a high-grade PT/CP; only 0.18% of all breast malignancies; small ones can have a gross cut surface that looks entirely benign; usually quite large, but 50% are 1-4cm¹⁸; but some cases as small as 2 cm⁷ [more]. Benign epithelium within the sarcomatous tumor makes it PT/CP and not carcinosarcoma of breast¹⁸.
  • Fibromyoepithelioma: fibroadenoma with excessive ME cells [LMC-03-2112A].
  • Fibroadenomatoid mastopathy^1,7: a localized tumor up to 5 cm. diameter composed of lobules of increased size (due to tubule, stroma, or mixed increase...often looking like miniature fibroadenomata); has also been called "sclerosing lobular hyperplasia⁸"; excision recommended¹ [LMC-01-5754...looks like "fibroadenomatoid mastopathy" were there such an entity; LMC-01-6254 & it has a small fibroadenoma in it; S-02-6694 plus fibrosis].
• Adenosis masses⁸:
  • radial scar:
  • sclerosing adenosis: more often postmenopausal; adenosis includes increase in ME cells, more so in sclerosing types; benign epithelial proliferative lesions can involve perineural spaces...look for ME cells⁷
  • adenosis tumor: a palpable mass; (usually premen. and imaging usually suggests fibroadenoma); all "adenosis" is lobulocentric⁷[LMC-02-6420; L09-3028].
• The nodular variant of PASH (above): when it includes an increased tubular component¹ [LMC-01-7312]
• Hamartoma: discrete round or discoid masses (often can be "shelled out", ranging from 1-17 cm. greatest diameter & of varying quantities of ductal & stromal components (fibrous and fatty⁸) and myxoid.
  • myoid hamartoma: significant/predominant component of smooth muscle^8,10
  • adenolipoma: like an ordinary lipoma, palpable well-circumscribed masses, but containing variable microscopic quantities of small ducts and lobules⁸ 
• Other:
  • "masses" of fibrocystic mastopathy (may need to use IHC to r/o the stromal component as myofibroblastic)[LMC-01-5252]
  • pleomorphic adenoma (mixed tumor) [LMC-01-6434] caution...one could confuse with a very low grade metaplastic carcinoma.

REFERENCES:

1. Rosen's Breast Pathology [text], Paul Peter Rosen, 1997
2. Rosen lecture, 8th Annual Seminar in Pathology, Pittsburgh, 6 May 2001
3. Tavassoli, 15th annual Pathology Symposium, Augusta, Ga. 22 April 2001
4. AFIP fascicle #2, McDivitt & Stewart, 1968
5. Ackerman's Surgical Pathology, Juan Rosai, 8th Ed., 1996.
6. Pathology of The Breast, Tavassoli, 2nd Ed., 1999.
7. Rosen PP, Breast Pathology: Diagnosis by Needle Core Biopsy [atlas/text], 1999.[EBS's office]
8. Breast Pathology: Benign Proliferations, Atypias & In Situ Carcinomas [atlas/text], Fechner RE, Mills SE, 1990.
9. Carter, Darryl, Interpretation of Breast Biopsies, 4th Edition, 2003.
10. Rosen PP, Rosen's Breast Pathology 2nd Ed, 1004 pages, 2001.
11. Stephen Ketterwell, MD's website in Glasgow, Scotland...The Breast Clinic.
12. Fan, Xuemo, pathologist friend of Karen Xu's @ UCLA Med. Ctr, via e-mail of 30 Sept. 2004.
13. Scnitt SJ, "Intraductal Proliferative Lesions: Pathologic Features and Clinical Significance of Columnar Lesions and Flat Epithelial Atypia,  MUSC McKee-PT Seminar, 4 April 2005 (EBS attended...has handout).
14. Silverberg  SG, Atlas of Breast Pathology, 206 pages, 2002.
15. Singh KA, et. al. "Pseudoangiomatous Stromal Hyperplasia. A Case for Bilateral Mastectomy in a 12-Year-OLd Girl", The Breast J. 13(6):603-606, Nov/Dec 2007 [EBS's office].
16. Thorncroft K, et. al. "The Diagnosis and Management of Diabetic Mastopathy", The Breast J. 13(6):607-613, Nov/Dec 2007 [EBS's office].
17. The Breast Journal 10(4):318-322, 2004.
18. DDX page compiled by EBS from Arch. Path & Lab Med 7/88 p752, 3rd Ed. Haagensen p269-312, McDivitt AFIP fascicle 2nd series p117, and 5/95 ASCP CME course KH went to 5/95.
19. Schnitt SJ, breast cancer topics, Gordon R. Hennigar Memorial Lecture, S. C. Society of Pathologists fall meeting, Grove Park Inn, Asheville, N. C. 12 Sept. 2009.
20. Rosen PP, Rosen's Breast Pathology 3rd Ed, 1116 pages, 2010.
21. Visscher DW (Mayo Clinic, Rochester), 18th Annual Seminar in PAthology, Pittsburgh, April/May 2011.

(posted March 2002; latest addition 3 May 2011)