Breast-nonmalignant
Last revised 17 June 2009
Last major update October 2008
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Table of Contents - Breast-nonmalignant
General: primary references, WHO classification, embryology, neonatal, thelarche, normal anatomy, normal histology, pregnancy/lactation, pubertal macromastia
Congenital anomalies: amastia/hypoplasia, accessory glandular tissue, aplasia, athelia, nipple inversion, supernumerary
Procedures: biopsy marking devices, cautery artifact, core biopsy, cytology, MRI directed, open biopsy/frozen section, reduction mammoplasty
Inflammatory / infectious / parasitic: acute mastitis/abscess, duct ectasia, fat necrosis, foreign body reaction, fungi, giant cell arteritis, granulomatous mastitis, hemorrhagic necrosis, infarct, lupus mastitis, lymphocytic mastitis, Mondor's disease, nephrogenic systemic fibrosis, ossification, parasites, plasma cell mastitis, polyarteritis nodosa, reactive spindle cell nodule, sarcoidosis, silicone implants, tuberculosis
Fibrocystic disease: general, apocrine metaplasia, chronic inflammation, collagenous spherulosis, columnar cell lesions, cystic hypersecretory hyperplasia, cysts, epithelial ductal hyperplasia, fibroadenomatoid change, fibrosis, microcalcifications, pseudolactational hyperplasia, radial scar
Adenosis: general, adenomyoepithelial, blunt duct, microglandular, sclerosing, tubular
Benign (usually) tumors/changes: adenomyoepithelioma, amyloid tumor, angiolipoma, apocrine adenoma, atypical or benign vascular proliferations post-radiation, Carney’s syndrome, chondrolipoma, clear cell “sugar” tumor, cylindroma, ductal adenoma, eccrine spiradenoma, fibroadenoma, fibromatosis, galactocele, granular cell tumor, gynecomastia-like, hamartoma, hemangioma, hemangiopericytoma, inflammatory pseudotumor, juvenile xanthogranuloma, lactating adenoma, leiomyoma, lipoma, lymphangioma, mucocele, myoepithelioma, myofibroblastoma, nipple adenoma/florid papillomatosis, nodular mucinosis, papilloma, phyllodes, pleomorphic adenoma, pseudoangiomatous stromal hyperplasia (PASH), sclerosing lobular hyperplasia, subareolar sclerosing duct hyperplasia, syringomatous adenoma of nipple, tubular adenoma
Atypical hyperplasia: flat epithelial atypia, atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH)
Go to Breast-malignant chapter (DCIS, invasive carcinoma, other malignancies, miscellaneous, children, males)
Primary references for Breast chapter
American Journal of Clinical Pathology (AJCP), January 2000 to October 2008
American Journal of Surgical Pathology (AJSP), March 1977 to October 2008
Archives of Pathology and Laboratory Medicine (Archives) [free full text, no registration always]; January 1976 to September 2008
BMC Clinical Pathology [free full text, no registration always]; December 2003 to 19 September 2008
Cytojournal [free full text, no registration always]; July 2004 to 30 September 2008
Human Pathology (Hum Path), March 1970 to October 2008
Modern Pathology (Mod Path) [free full text, no registration after 1 year]; January 1988 to September 2007 / October 2008
Rosen: Tumors of the Mammary Gland (AFIP Fascicle, 3rd series, volume 7); 1994
Rosai, J: Ackerman’s Surgical Pathology (9th Ed), Mosby, 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Tavassoli: Tumours of the Breast and Female Genital Organs (WHO, 2003)
Websites (images): Digital Atlas of Breast Pathology, Johns Hopkins Breast Center, National Institutes of Health, Online Management of Breast Diseases, PathologyResources.com (online version of AFIP fascicle 3rd Series), PathoPic
Virtual slides: University of Iowa, USCAP, vSlides
Journal search terms: “breast” and each topic below; last searched October 2008
Please refer to these primary references for more detailed discussions and additional images
WHO classification of breast tumors
2003 classification: Table
References: Wikipedia
Breast is considered an epidermal gland because it develops as diverticula of epidermis into dermis
Breast is also considered a modified and highly specialized apocrine gland
Mammary gland development begins at week 4, when ectoderm and underlying mesoderm proliferate and differentiate into skin
Week 4: paired ectodermal thickenings called mammary ridges or milk lines develop along ventral embryo and extend in curvilinear convex pattern from axilla to medial thigh; ridges will eventually disappear except at 4th intercostal space on anterior thorax, where mammary gland develops
Week 5: remnant of mammary ridge ectoderm proliferates and is termed primary mammary bud
Week 7: primary mammary bud grows downward into underlying dermis
Week 10: primary mammary bud branches into secondary buds
Week 12: secondary mammary buds start lobule development
Week 20: small lumina develop with mammary buds that coalesce and elongate to form lactiferous ducts
Month 5: areola is formed by ectoderm
Drawings: milk lines #1; #2; lifetime mammary gland development
Micro images: various images
References: eMedicine, UC Davis
Identical in males and females
Nipple is small pit in center of areola, becomes everted shortly after birth due to proliferation of mesenchyme underlying the areola
Breast enlargement (uni- or bilateral) is present in up to 70% of neonates due to neonatal prolactin production, caused by falling levels of maternal estrogens; associated with production of “witch’s milk” in males and females
Continued breast stimulation (squeezing or massaging breasts) may cause hypersecretory state to persist
Milk secretion: resembles colostrum; contains water, fat, cellular debris
Clinical images: 12 day old boy
Micro: duct dilation without acini
Micro images: AFIP - neonatal breast ectasia with dilation of mammary ducts
Rapid growth of breasts at onset of puberty, usually age 10-11 in females
Signifies entry into Tanner stage II of development (Arch Dis Child 1976;51:170)
Growth is due to fat deposition, periductal connective tissue and elongation and thickening of ductal system; growth may be sporadic
Influenced by estrogens, growth hormone and prolactin, but not progesterone
Excision of initial subareolar disc will lead to amastia after puberty
Premature: if prior to 9 years; may be isolated, or part of (central) precocious puberty if other signs of puberty are present; no lobules present (BMC Pediatr 2008;8:27)
Tanner staging: Stage I; Stage II; Stage III; Stage IV; Stage V
Clinical images: premature thelarche
Gross: initially rubbery subareolar discoid mass; may be asymmetric
Micro: prior to puberty, breasts of both sexes have ducts with variable branching lined by cuboidal epithelium, no lobules, no necrosis (AFIP, Section 3.1, p. 11); at puberty in females, lobules develop
Micro images: premature thelarche (9 year old girl with premature breast enlargement): AFIP - proliferation of ducts without lobules; intraductal epithelial hyperplasia with uniform cells and prominent nuclei
References: Wikipedia
Also called mammary gland
Covered by skin and subcutaneous tissue
Separated from pectoralis muscle by fascia
Note: 2005 study changed commonly held views (J Anat 2005;206:525, Wikipedia)
Composed of terminal duct lobular units (TDLU, terminal duct and lobule, has secretory function) plus mean 18-23 large ducts which drain into mean 5-9 ductal orifices (Cancer 2004;101:1947), often through a common opening (Breast Cancer Res Treat 2007;106:171, Eur Surg Res 2006;38:545); large ducts subdivide into segmental ducts, subsegmental ducts and then lobules; lactiferous sinuses are apparently an artifact, and do not actually exist (J Anat 2005;206:525)
Nipple: mean diameter 11-13 mm, mean height 0.9 cm, mean diameter of areola is 4 cm (Aesthetic Plast Surg 2008 Jul 15 [Epub ahead of print], Am J Surg 2007;194:433)
Montgomery's tubercles: areolar protuberances (10-20), more prominent during pregnancy; composed of ducts and sebaceous apparatus (Archives 1982;106:60)
TDLU: site of origin of fibrocystic changes, hyperplasia, carcinoma (including most ductal carcinomas)
Ducts: site of origin of solitary papillomas, duct ectasia, rarely ductal carcinoma
Regional lymph nodes: (a) axillary - interpectoral [Rotter’s] nodes and lymph nodes along axillary vein and its tributaries, (b) internal mammary - in the intercostal spaces along the edge of the sternum in the endothoracic fascia; supraclavicular lymph nodes are not considered regional
Lymph nodes: occur normally in any quadrant; but should biopsy in cancer patients (Hum Path 2001;32:178); may be more than one sentinel node (Ann Surg Oncol 2008;15:863)
Drawings: breast anatomy #1; #2; Netter drawing #1 (anatomy-but ampulla does not actually exist); #2 (blood supply); #3 (lymphatics); regional lymph nodes-schematic; radiograph of lymphatics; tracing of lymphatics; supraclavicular fossa
Gross images: nipple orifices, some cannulated with guide wires; collecting vessels and lymphatics after dye injection into cadaver
Micro images: perforating lymphatic
References: eMedicine
Major ducts: lined by pseudostratified columnar epithelium (extralobular) or double layer of cuboidal epithelium (intralobular); extralobular ducts are surrounded by well developed layer of elastic tissue
Terminal duct lobular unit (TDLU): ductules (acini) with lobular architecture and intralobular connective tissue
Ductules (lobular ducts): lined by inner layer of columnar or cuboidal epithelium (secretory and absorptive) and outer basal layer of myoepithelium (myofilaments oriented parallel to long axis of duct)
A continuous basement membrane follows contour of duct and ductules
Occasional neuroendocrine cells are present
Ochrocytes (histiocytes containing lipofuscin pigment) occur in 15-20% (J Pathol 1975;117:39)
Intralobular connective tissue: loose myxomatous stroma with fibroblasts, lymphocytes, macrophages, vessels; hormonally responsive; no elastic fibers
Interlobular connective tissue: denser, more collagenous than intralobular connective tissue; becomes more fatty after age 18 years
Nipple: contains numerous sebaceous glands independent of hair follicles, dense fibrous stroma containing erectile smooth muscle tissue, stratified squamous epithelium resembling skin but with increased melanin pigment, Toker cells (clear cells basally located in the epidermis, identifiable in 10% of normal nipples, but hyperplastic in 27% of these and atypical in 12%, Hum Path 2008;39:1295); stratified squamous epithelium extends into duct lumens for short distance
Areola: contains sebaceous glands
Menstrual cycle related changes: proliferative phase breast has small lobules with few terminal duct structures, rare mitotic figures, condensed intralobular stroma; secretory phase breast has larger lobules, more terminal duct structures, basal epithelial cell proliferation and vacuolization, stromal edema (breast fullness), increased mitotic figures; stromal lymphocytes increase at end of secretory phase; followed by desquamation, apoptosis, atrophy, shrinkage (AJSP 1986;10:382)
Pregnancy related changes and lactation: see below
Clear cell change: clear cytoplasm contains glycogen, may represent metaplastic change towards eccrine sweat glands
Post-menopausal: largely adipose tissue with few residual ducts, acini or vessels; atrophy of glandular component is normal with age, may be microcystic (but not considered fibrocystic disease); in elderly women, residual estrogenic stimulation maintains vestigial remnants of lobules; elastosis (excess elastic fibers) found in 50% of women age 50+ years without breast disease, either diffusely in stroma, around vessels or around ducts; marked perivascular elastosis is suggestive of malignancy (Archives 1991;115:1241)
Males: testosterone causes involution of male mammary gland, except in testicular feminization syndrome (no testosterone receptors)
Normal histology of breast (continued)
Micro images: subgross (click on #10-left); normal lobules #1; #2; #3; #4; #5; two layers #1; #2; #3; terminal duct lobular unit #1; #2; #3; various images; epithelial cells have ER+ nuclei #1; #2; epithelial cells have PR+ nuclei; E-cadherin #1; #2; aging #1; #2
AFIP - clear cell change #1; #2; myoepithelial hyperplasia with clear, round myoepithelial cells displacing glandular epithelial cells
myoepithelial cell stains - smooth muscle actin; calponin #1; #2; p63+ #1; #2; CD10, smooth muscle actin, S100; type IV collagenase (upper left)
metaplasia: AFIP - myoid metaplasia derived from myoepithelial cells (HHF+); squamous metaplasia arising in duct
post-treatment: normal acini (see also Breast malignant chapter-treatment effect)
menstrual cycle stages: stage 1 (days 0-5, eosinophilic luminal secretions), stage 2 (days 6-15, vacuoles in myoepithelial cells, can distinguish ductal and myoepithelial cells), stage 3 (days 16-24, prominent myoepithelial vacuoles), stage 4 (days 25-28, extensive stromal edema)
nipple: with pilosebaceous units; nipple and lactiferous duct #1; #2; lactiferous ducts #1; #2
Cytology images: normal breast #1; #2; #3
Virtual slides: infant breast; normal breast #1; #2; #3
Videos: normal breast
Positive stains - basement membrane: laminin, type IV collagen, reticulin
Positive stains - epithelium/luminal cells: CK 8/18, CK 19, CK7, EMA (apical region of active secretory cells), milk fat globule membrane antigen, lactalbumin, E-cadherin
Positive stains - myoepithelial cells: smooth muscle actin, CK5/6, CK14, CK17, S100, p63 (nuclear staining, AJSP 2001;25:1054),
CD10 (Mod Path 2002;15:397), E-cadherin and P-cadherin (J Pathol 1993;169:245), calponin, smooth muscle myosin heavy chain, maspin, type IV collagenase
Positive stains - Toker cells: ER, PR; also CK7, EMA
Negative stains - myoepithelial cells: EMA, ER, PR, p53, HER2 (AJCP 2003;120:161)
Negative stains - Toker cells: CD138, p53; also p63
EM images: acini; glandular and myoepithelial cells
DD: atypical Toker cells may resemble Paget’s disease, but Toker cells are usually ER+, PR+, CD138-, p53-, HER2-, Paget’s cells are opposite (Hum Path 2008;39:1295)
Pregnancy / lactation - breast
See also lactating adenoma, pseudolactational hyperplasia
Changes in breast usually begin at time of first missed menstrual period (gestational week 4)
Changes are due to progesterone, estrogens, prolactin and placental lactogen secretion in third trimester
Intralobular ducts form buds that become secretory alveoli with grape-like clusters and scant stroma; epithelial cells accumulate cytoplasmic organelles to sustain postpartum lactation; glands have dilated lumina, contain lipid secretory vacuoles with large, apical nuclei resembling Arias Stella reaction; may have clear cell change in ductal or lobular epithelium; these changes may also occur without pregnancy or hormonal manipulation (see pseudolactational hyperplasia)
Prolactin stimulates alveolar epithelium to produce and secrete casein, alpha-lactalbumin and lipids
Lactation: increase in number of lobules and number of acini within each lobule; reduction in interlobular and intralobular stroma; myoepithelial cells are present but difficult to identify; luminal epithelial cells are secretory and have cytoplasmic vacuoles; after lactation ends, lobules involute over several months and are infiltrated by lymphocytes and plasma cells
Crying or suckling causes hypothalamus to produce oxytocin, causing contraction of myoepithelial cells, which expels milk
When nursing stops, prolactin level drops, causing milk production to stop
Lactation may cause macromastia - erythematous, edematous, painful breasts with variable ulceration of overlying skin; usually recurs with subsequent pregnancies
Drawings: breast during lactation; breast lobules during lactation
Micro: acinar proliferation with minimal intra- and interlobular connective tissue
Micro images: first trimester; third trimester; 8th month (AFIP); ectatic acinar lumens are lined by vacuolated epithelium and contain secretion, typical of late third trimester (AFIP); lactational change #1; #2; #3; #4; various images
Virtual slides: hyperplasia of pregnancy; lactating breast #1; #2
Videos: hyperplasia of pregnancy #1; #2
Pubertal (virginal) macromastia
Also called gigantomastia
Occasionally breasts undergo rapid and massive enlargement at puberty, instead of development over several years
If unilateral, usually due to multiple fibroadenomas
Rarely familial with congenital anonychia (lack of nails, J Adolesc Health 2004;35:151)
Treatment: reduction mammoplasty usually needed; may recur (Ann Plast Surg 2001;46:517); tamoxifen may be helpful
Clinical: diffusely enlarged breasts with flattening of nipples
Micro: abundant connective tissue separating ducts, usually poorly developed or no lobules; may resemble gynecomastia
Micro images: AFIP - 15 year old girl with massive bilateral enlargement of breasts, dense connective tissue, only minimal lobular development
References: Stanford University
Gestational gigantomastia
Much less common than pubertal macromastia
References: Plast Reconstr Surg 2006;118:840
Congenital anomalies of breast
Amastia / hypoplasia of breast tissue
Uncommon; unilateral or bilateral
Amastia: no glandular tissue (breast bud), nipple or areola
Hypoplasia: small rudimentary breasts; also called micromastia
Amastia and hypoplasia are both associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, OMIM 173800, eMedicine), also damage to breast bud by surgery (Postgrad Med J 2003;79:235) or radiation (Acta Oncol 1989;28:519, Pediatr Radiol 1989;19:124)
Clinical images: amastia in 11 year old girl; hypoplasia (left image)
Treatment: breast augmentation surgery (Semin Pediatr Surg 2008;17:161)
Accessory glandular tissue of breast
See supernumerary nipples / breasts below
Nipple and areola present, but no glandular tissue
Associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, OMIM 173800, eMedicine)
Treatment: surgery (Acta Chir Plast 2001;43:39)
Breast glandular tissue, but no nipple or areola
Very rare
Associated with Poland syndrome (musculoskeletal deformities of chest wall and ipsilateral upper extremity, OMIM 173800, eMedicine)
Case reports: female infant who died shortly after birth (Am J Med Genet A 2007;143:1231), bilateral athelia and congenital jejunal atresia (Clin Dysmorphol 2006;15:37)
Affects males and females
Occurs in 3% of women, 87% are bilateral (Aesthetic Plast Surg 1999;23:144)
Familial in 50%
Usually caused by fibrous bands and hypoplastic ductal system tethering nipple in inverted position
Also associated with large, pendulous breasts
Interferes with nursing, may be confused with cancer
Grade I, II or III (Plast Reconstr Surg 1999;104:389)
Treatment: surgery (Plast Reconstr Surg 2007;119:1178, Aesthetic Plast Surg 2008;32:641), continuous elastic outside distraction (Ann Plast Surg 2005;54:120)
Clinical images: inverted nipple; grade I; grade II; grade III; man with inverted nipples
Supernumerary nipples / breasts
Also called pseudomamma
Persistent epidermal thickenings along milk line from axilla to perineum/vulva due to clusters of primordial breast cells that fail to involute
Ectopic tissue may be combinations of breast glandular tissue and nipple
Often not noticed until pregnancy
Occurs in 2-6% of females and 1-3% of males; may be more common on left side in males (Eur J Pediatr 1998;157:821)
Classified into 8 levels of completeness (Wikipedia, eMedicine)
Polythelia (3+ nipples) is more common than polymastia (ectopic breast tissue)
Sites (nipples): thorax or abdomen (65%), axilla (20%); back, buttock, face, neck are less common
Sites (glandular tissue): axilla most common
May undergo same disease or physiologic processes as other breast tissue, including lactation (J Reprod Med 1994;39:657)
Associated with renal disease in some studies (7% vs. 1% in controls, Int J Dermatol 1996;35:349, Scand J Urol Nephrol 2008:1 but not all, Pediatr Dermatol 2001;18:291); also associated with hematologic disorders (Pediatr Hematol Oncol 2004;21:461), mitral valve prolapse (Am J Cardiol 2000;86:695)
Case reports (disease in supernumerary nipples or breast): carcinoma in vulva (Cancer 1976;38:2570), fibroadenoma (J BUON 2007;12:285), hamartoma (Breast 2006;15:135), metaplastic carcinoma (South Med J 2002;95:462), mucinous adenocarcinoma of vulva (Archives 2002;126:1216), Paget’s disease (Virchows Arch 1998;432:289), secretory carcinoma (Archives 2001;125:1372)
unusual sites - face (J Pediatr Surg 1997;32:1377), foot (Dermatol Online J 2006;12:7), male perineum (Urology 1997;50:122)
other case reports - occurrence in three generations (Eur J Pediatr 2001;160:375)
Drawing: usual sites
Clinical images: nipples anterior to axilla; nipple on foot #1; #2; accessory breast tissue of lower abdomen; post-partum axillary mass; accessory nipple and bilateral accessory breasts in axilla
Micro: supernumerary nipple has same features as regular nipple, including hyperpigmentation, slight hyperkeratosis, pilosebaceous structure of Montgomery tubercles, smooth muscle, Toker cells (J Cutan Pathol 2003;30:256), possibly breast lobules and ducts
Micro images: normal breast tissue in axilla of 12 year old girl; normal breast tissue and breast carcinoma in vulva (slow loading); fibroadenoma in axillary supernumerary breast; mucinous adenocarcinoma in vulva; secretory carcinoma in axilla
References: eMedicine
Procedures involving breast\
See also Breast-malignant chapter under grossing
Devices mark the site of radiographic biopsies for future localization and resection
Either pellets of resorbable polylactic acid/polyglycolic acid copolymers or plugs of bovine collagen; both contain metallic clips for long-term radiographic marking; pellets are placed within biopsy cavity to fix clip in place and reduce clip migration away from biopsy site; collagen plugs may also promote hemostasis
Note: 4% of patients experience intraoperative clip loss (AJR Am J Roentgenol 2008;190:W196)
Clinical images: devices and radiographs; Gel Mark Ultra ®, MammoMark™
Gross: pellets resemble soft grains of rice; collagen plugs are spongiform with variable hemorrhagic changes
Micro:
pellets - initially hypocellular fibrotic reaction around empty spaces (processing dissolves the polymer), then multinucleated giant cell reaction with eosinophilic material in marker core
collagen plugs - eosinophilic, hyalinized, acellular material with lymphocytic and eosinophilic infiltrate that gradually penetrates into the core; no prominent multinucleated giant cell reaction; may resemble amyloidosis
References: AJSP 2005;29:814, AJR Am J Roentgenol 2003;181:1295
Electrocautery instruments reduce bleeding and risk of hematoma
Radiofrequency ablation may be used for local destruction of tumor cells (Int J Clin Pract 2008;62:816)
Thermal distortion may make it difficult to distinguish hyperplasia and DCIS, to assess histologic grade or margin status, or to interpret immunostaining
Micro images: AFIP - parallel linear cracks typify cautery artifact; blurred cell outlines, hyperchromatic nuclei and parallel linear cracks
other - epithelial distortion (fig 9A, 9B); artifact may make specimen uninterpretable
References: Am J Surg 2001;182:384 (laser treatment), Ann Surg 1986; 204: 612
See also discussion of core biopsies under specific diagnoses
Percutaneous large core needle biopsy using stereotactic mammography or ultrasound guidance is routinely used to evaluate clinically occult breast lesions, and is an alternative to open biopsy for many patients
Recommended as initial diagnostic procedure in patients with highly suspicious mammograms, due to improved pathologic margins and fewer surgical procedures (Breast J 2008;14:471)
Has led to reduction in surgical interventions after benign or negative diagnoses (Eur J Cancer 2008 Jul 14 [Epub ahead of print])
Overall high level of inter-pathologist agreement (AJSP 2004;28:126)
Diagnostic performance is comparable to excisional specimens (Int J Cancer 2008;122:468) but tumor grade in invasive carcinoma may differ (AJSP 2003;27:11, Am J Surg 2008 Jul 8 [Epub ahead of print])
Core biopsy is favored over fine needle aspiration because core biopsy: (a) is useful for evaluating cytologic and architectural characteristics and diagnosing invasive carcinoma (Diagn Cytopathol 2007;35:681); (b) is more reliable (Acta Radiol 2008;49:863); (c) reduces additional biopsies (Acta Oncol 2008;47:1037); imprint cytology may be useful for rapid diagnosis (Cytopathology 2008;19:311)
Not associated with significant bleeding in patients on anticoagulant therapy (AJR Am J Roentgenol 2008;191:1194)
Cytopathologists may be able to perform ultrasound guided FNAs and core biopsies (Diagn Cytopathol 2008;36:317)
Note: may be an alternative to surgery for some lesions (Breast 2008 Sep 29 [Epub ahead of print], Radiology 2008;248:406)
First generation: computer-assisted stereotactic mammography or ultrasound used to localize target lesion, then automated spring-loaded biopsy gun, usually with 14-gauge cutting needle
Second-generation: includes Mammotome (Breast Cancer 2007;14:292, World J Surg Oncol 2007;5:83); uses vacuum assistance to draw tissue into the needle and permits use of larger-caliber needles (8 to 11 gauge) and more thorough sampling of lesions (thicker, longer, multiple specimens with single needle insertion)
Core biopsy of breast lesions (continued)
Processing: should routinely obtain 3-5 deeper levels; 5 levels recommended to detect ADH and atypical proliferations, (Archives 2001;125:1055) or minimally invasive carcinoma (Archives 2004;128:996); see also Mod Path 2001;14:350
Reducing false negatives: need radiologic-histologic correlation - must determine if histologic results provide a sufficient explanation for the imaging features - if not, lesion may not have been adequately sampled; follow up imaging is also helpful (Radiographics 2007;27:79)
Some recommend routine radiologic examination of cores for microcalcifications and deeper levels if microcalcifications are not in slide
Minimal invasion in core biopsies (1 mm or less) is usually associated with invasive tumors of 1 cm or more at excision (Archives 2004;128:996)
Rarely, mastectomy (or excisional biopsy) after malignant core biopsy will show no cancer (Mod Path 1997;10:1209)
Immunostains for ER, PR and HER2 show 85-95% concordance with excision specimens (Acta Oncol 2008;47:38, Pathology 2007;39:391)
Complications: (a) seeding/displacement of normal epithelium along needle tract, particularly with papillary lesions, which may simulate malignancy (Archives 2005;129:1465), (b) seeding of tumor cells along needle tract (Breast Cancer Res Treat 2008;110:51), particularly intracystic papillary carcinoma (J Clin Pathol 2002;55:780), (c) reactive spindle cell proliferation (see below), (d) epidermal inclusion cysts (image)
Reporting system of UK National Health Service Screening Programme (J Clin Pathol 2004;57:897)
- B1 - normal tissue/inadequate sample (comment on microcalcifications and specimen adequacy)
- B2 - benign lesion (specify)
- B3 - uncertain malignant potential (includes radial scar, some papillary lesions, ADH, lobular neoplasia)
- B4 - suspicious of malignancy (suggestive but not diagnostic due to scanty material or artifacts)
- B5 - malignant; specify if invasive or not, if possible; indicate grade of DCIS
Clinical images: Mammotome
Micro images: displaced epithelial cells #1; #2-intracystic papillary carcinoma; core biopsy with atypical hyperplasia (various)
References: eMedicine, Breast fine needle aspiration cytology and core biopsy; a guide for practice 2004
See also discussion under specific diagnoses
Usually refers to fine needle aspiration (FNA); also imprints of core biopsies (Cytopathology 2008;19:311) or cytology touch imprints for evaluating margins (quick, easy, inexpensive, no frozen section artifact, doesn’t sacrifice tissue, can sample entire margin, Archives 2002;126:846)
Relatively quick with minimal equipment needed
Uses 23 or 27 gauge needles (Breast 2006;15:567)
Rapid cell blocks may be superior to on site evaluation (Diagn Cytopathol 2008;36:523)
Fine needle aspiration (FNA): 90% sensitive, 95%+ specific; false positives are often florid epithelial hyperplasia; difficult to differentiate ADH or invasive carcinoma from DCIS, papillary carcinoma from fibroadenoma (Archives 2000;124:1667)
False negatives: more common for tubular carcinoma, lobular carcinoma (Cancer 2008;114:111) or low grade ductal carcinoma, often due to small tumor size causing sample error (Cytopathology 2008;19:279); also less sensitive for tumors with extensive fibrosis, DCIS, cribriform carcinoma; also for women age 35 and under with malignancy (Pathology 2008;40:359)
Ductal lavage cytology: sensitive in detecting intraductal malignancies (Breast Cancer Res Treat 2008 Oct 10 [Epub ahead of print]); may be useful in distinguishing benign versus malignant lesions in patients with unilateral, spontaneous nipple discharge (Int Surg 2003;88:83); presence of epithelial cells in nipple aspirate fluid is associated with higher risk for subsequent breast cancer (Breast Cancer Res Treat 2006;98:63); limited value in screening high risk patients overall (Am J Surg 2007;194:463)
Recommendations: first line diagnostic modality for benign appearing lesions, with core biopsy for indefinite cases (Br J Cancer 2008;98:1182, Cytopathology 2008;19:271)
Negative FNA should not rule out biopsy if clinical suspicion of malignancy persists, but negative cytology, negative clinical examination and negative radiologic findings together have a negative predictive value close to 100% (Breast J 2004;10:487)
Breast aspiration fluid CEA concentration may be helpful in determining malignancy (Archives 2004;128:1251)
p63 immunostaining may be useful to categorize cases problematic by Pap staining (AJCP 2007;128:80)
Cytopathologists may be able to perform ultrasound guided FNAs and core biopsies (Diagn Cytopathol 2008;36:317)
FNA artifacts: displaced epithelium which simulates stromal and vascular invasion (AJSP 1994;18:896, Mod Path 1995;8:380), hemorrhage, infarction, necrosis, hemosiderin deposition (AJSP 1994;18:1039)
Cytology of breast lesions (continued)
Cytology: malignancy - detailed analysis of a single morphologic characteristic has limited diagnostic value (Cancer 2005;105:152)
helpful features are cohesive clusters of tumor cells with irregular margins; pleomorphic cells with enlarged and hyperchromatic nuclei, mitotic figures, necrosis, microcalcifications, usually no naked nuclei, usually no apocrine metaplasia
In elderly patients, background of single epithelial cells with atypia and absence of bipolar nuclei in the background have a strong association with malignancy (Pathology 2008;40:573)
Cytology images: displaced epithelium #1; #2-simulating vascular invasion; #3-displaced papillary carcinoma
cytology imprints from core biopsy - malignant #1; #2; #3; #4; benign
DD of malignancy: (a) gynecomastia with chemoradiation induced atypia (Archives 2002;126:613), micro image; (b) tissue infarction (Diagn Cytopathol 2008;36:586), (c) herpes zoster / chicken pox infection (Acta Cytol 2008;52:337)
References: protocol instructions for fine needle aspirations-JCAHO (Cytojournal 2007;4:19)
Widely used in US (AJR Am J Roentgenol 2008;191:332)
Magnetic resonance imaging (MRI) is used to screen high risk women for breast cancer (AJR Am J Roentgenol 2003;181:619, Cancer 2005;103:1898) and to evaluate extent of disease
MRI cannot verify that suspicious lesion is in specimen (unlike traditional radiography), because MRI requires IV injection of gadolinium and uptake into suspicious area, which cannot be done after specimen has been excised
Low (87%) sensitivity for diagnosing mammographically detected microcalcifications (AJR Am J Roentgenol 2006;186:1723)
Recommended to submit entire specimen for microscopic examination because usually no gross findings (Hum Path 2007;38:1754)
Complete removal of MRI target does not ensure complete histologic excision of the cancer (AJR Am J Roentgenol 2008;191:1198)
References: eMedicine
Open biopsy and frozen section of breast
Perform excisional biopsies for tumors 2.5 cm or less; incisional biopsies for diagnosis if tumors are larger
Historically, open biopsy with positive frozen section led to mastectomy; currently, even if frozen section is positive, there is a delay after biopsy to give patient time to evaluate options
First priority of open biopsy or frozen section is accurate histologic diagnosis - sufficient tissue must be obtained for permanent sections
If frozen section is suspicious for DCIS, use all remaining tissue for permanent sections
Don’t do frozen section if mass is 1 cm or less or if calcifications only/no mass (Cancer 1997;80:75), because frozen block may contain artifacts and no tissue will be left for permanent sections without artifacts
Frozen section can be helpful to evaluate margins (Ann Surg Oncol 2007;14:2953, World J Surg 2008 Oct 4 [Epub ahead of print]), to confirm a cytologic diagnosis, or to assess sentinel lymph nodes (World J Surg Oncol 2006;4:26, Eur J Surg Oncol 2008 Sep 9 [Epub ahead of print]); probably not helpful if grossly benign (Mod Path 1994;7:762)
False positives with frozen section: sclerosing lesions (radial scar, sclerosing adenosis, ductal adenoma), ductal hyperplasia, papillary lesions, fat necrosis; often cannot exclude invasion in DCIS
False negatives with frozen section: post-chemotherapy tumor, well differentiated papillary carcinoma, lobular carcinoma, tubular carcinoma (Chin Med J (Engl) 2007;120:630)
References: Archives 2005;129:1565
Also spelled mammoplasty
Common surgical procedure performed for cosmetic purposes or relief of pain
Must examine tissue carefully since most have some pathologic change, most commonly fibrocystic disease (Plast Reconstr Surg 2005;115:729)
Carcinomas present in 0.5 to 1.5% (usually microscopic), ADH/ALH in 1-2%, moderate/florid hyperplasia, sclerosing adenosis or papilloma in 10% (AJCP 2003;120:377); frequency of neoplasia increases with patient age (Int J Surg Pathol 2008;16:25)
Micro images: invasive ductal carcinoma; lobular carcinoma; DCIS
References: eMedicine
Inflammatory / infectious / parasitic lesions of breast
Associated with lactation and cracks in nipple
Mastitis occurs in 5-15% of post-partum primiparous women, 3% with mastitis have an abscess (BJOG 2004;111:1378)
Also associated with eczema, nipple dermatoses and post-reduction mammoplasty
Bacteria often not isolated from culture
Pregnancy related infections usually due to Staphylococcus; usually unilateral, often MRSA (Arch Surg 2007;142:881)
Streptococcus usually causes diffuse infections leading to scarring, but is uncommon today
Nonpregnancy related infections are usually polymicrobial
May cause fistulous tract between duct and surface of areola
Zuska’s disease: periareolar abscess associated with squamous metaplasia of lactiferous ducts (J Am Coll Surg 1994;178:29)
Case reports: Brucellosis (Breast J 2006;12:375), Enterococcus faecalis (Indian J Pathol Microbiol 2005;48:507), Fusarium (Indian J Med Microbiol 2005;23:198), Gordonia bronchialis (J Clin Microbiol 2005;43:3009), Prevotella (Int J Syst Evol Microbiol 2007;57:883), Streptococcus group B abscess (Archives 1987;111:74), post-partum presentation with widespread symmetrical inflammatory polyarthropathy and marked synovitis (Scand J Rheumatol 2000;29:133), with acute tubulo-interstitial nephritis and uveitis syndrome (Acta Paediatr 2004;93:135)
Treatment of abscesses: incision and drainage, but may recur (Gynecol Obstet Fertil 2007;35:645); also ultrasound guided treatment (Radiology 2004;232:904), antibiotics/nisin (J Hum Lact 2008;24:311)
Clinical images: acute mastitis; abscess (Fusarium)
Micro: central cavity with neutrophils and secretory material surrounded by inflammatory cells and eventually fibrosis
Micro images: AFIP - Staph abscesses are sharply demarcated, bacteria are in central cavity (AFIP); squamous metaplasia of lactiferous ducts #1-plug of keratin debris fills orifice of lactiferous duct, which has metaplastic squamous epithelium; #2-squamocolumnar junction is displaced, mild periductal lymphocytes are present; other - acute mastitis
Cytology images: neutrophils in acute mastitis
References: Wikipedia
Also called periductal mastitis, although some believe they are different entities (Br J Surg 1996;83:820)
Usually women in reproductive years; may be a response to stagnant colostrum
Painful, erythematous, subareolar mass, may have fistulous tract; associated with smoking (Int J Clin Pract 2005;59:1045), possibly pituitary adenomas and increased prolactin levels (AJSP 1988;12:130)
Recurrences may cause nipple inversion or discharge, resembling carcinoma
Late stage is ductitis obliterans or mastitis obliterans with total occlusion of ducts (Breast J 2007;13:599)
Case reports: causing bloody nipple discharge in 2 year old boy (Turk J Pediatr 2005;47:379), 13 year old girl (J Natl Med Assoc 2004;96:543), associated with Bechet’s disease (Saudi Med J 2001;22:1030)
Treatment: excise duct and fistulous tract in continuity
Gross: nipple discharge in 20%; skin retraction from fibrosis may mimic cancer; dilated large ducts with fatty (cheesy) material in lumen
Micro: dilated large ducts with fibrous thickening of wall, elastic fibers in wall and foamy macrophages in lumen; often calcifications; keratin goes deep within ductal system causing dilation and rupture of duct with intense chronic and granulomatous inflammation; may have associated epithelial hyperplasia or apocrine metaplasia
Cytology: paucicellular, with few scattered, cohesive clusters of ductal epithelial cells with mild atypia and peripheral myoepithelial cells; also CD68+ macrophages with finely vacuolated cytoplasm (Acta Cytol 2001;45:1027)
Micro images: AFIP - ducts are dilated with sparse secretions, lower duct is partially disrupted releasing material into stroma and causing periductal fibrosis and elastosis; dilated duct has amorphous stasis material and lymphoid nodules at sites of secondary duct branching; periductal lymphocytes, thickened basement membrane and lack of cells in duct contents; narrowed duct lumen due to periductal collagen and elastic tissue
other - dilated ducts with foamy macrophages and periductal inflammatory infiltrate; late stage with hemosiderin-laden macrophages; foamy macrophages below luminal epithelium; other images #1; #2; #3; #4; periductal scarring (late) #1; #2
References: Stanford University
Simulates carcinoma clinically and mammographically
May be associated with duct ectasia, fibrocystic change, trauma (including surgery), brachytherapy or radiation (Int J Radiat Oncol Biol Phys 2007;69:724), injections of Depixol (J BUON 2002;7:281), low molecular weight heparin (Age Ageing 2005;34:193) or methylene blue dye (Int Semin Surg Oncol 2005;2:26)
Frozen sections difficult to obtain due to high fat content of specimen
Clinical images: skin and fat necrosis due to methylene blue dye; due to coumadin
Gross: opaque, bright yellow
Gross images: hemorrhagic fat necrosis
Micro: partially necrotic adipose tissue with foamy macrophages, multinucleated giant cells and chronic inflammatory cells; often hemosiderin deposits, fibrosis and calcification; occasional metaplastic squamous epithelium
Micro images: giant cells and microcalcification; necrotic adipocytes and calcification; with metaplastic squamous epithelium with keratin whorls (AFIP); irregular fatty spaces and foamy macrophages; foamy macrophages and calcifications #1; #2; #3; #4; giant cells; giant cells engulfing lipid; pap stain (inset Giemsa)
Cytology images: fat necrosis #1; #2; #3
Virtual slides: traumatic fat necrosis
Videos: traumatic fat necrosis
Foreign body reaction of breast
See also fat necrosis, reactive spindle cell nodule of breast, silicon breast implants
Also called biopsy site changes
Usually localized; occurs 1-2 weeks after trauma, surgery or radiation
Clinically resembles carcinoma due to skin retraction
Case reports: injections - carbon for biopsy tracking (Clin Radiol 1998;53:845), gear oil (Indian J Pathol Microbiol 2007;50:373), hydrophilic polyacrylamide gel (Hong Kong Med J 2007;13:137), paraffin (Breast 2006;15:540), petroleum jelly (South Med J 2008;101:422)
Gross: localized to subcutaneous tissue; may be nodular, fibrotic, orange-brown (due to hemosiderin); up to 1 cm
Micro: not encapsulated; fibrosis, foreign body giant cells, chronic inflammatory cells, fat necrosis, calcification, cholesterol clefts (needle like empty spaces, due to substances dissolved during processing), hemosiderin; may see a foreign body
Micro images: foreign body reaction to suture material; biopsy site changes with fibrosis and hemosiderin deposition; fibrosis and multinucleated giant cells; small blood vessel proliferation and giant cells; collagen plug inside biopsy cavity #1; #2; asteroid body; granulation tissue; fig 1e: cholesterol clefts, secretory material (thin arrows), perivascular fibrosis (arrowheads); post-gunshot wound
Virtual slides: foreign body reaction to silicon
Videos: foreign body reaction
Report of saline filled breast implant contaminated with Curvularia in 5 patients (J Infect Dis 2005;192:170)
Case reports: immunosuppressed patient with breast nodule due to coccidiomycosis (Archives 1991;115:1064), cryptococcus in HIV+ patient (J Infect 2008;57:82), fusarium (Indian J Med Microbiol 2005;23:198), Histoplasma capsulatum causing granulomatous mastitis (Hum Path 1989;20:47, Archives 2006;130:e1), bilateral male breast enlargement due to Trichophyton rubrum (Breast 2006;15:263)
Micro images: Fusarium - clinical image and FNA smears; Histoplasma capsulatum - fig 1: necrotizing granulomatous inflammation; fig 2/3: histiocytes contain multiple intracellular organisms with peripheral clearing; fig 4: GMS shows yeast with narrow-based buds and nonbudding yeast
Giant cell arteritis of breast
Usually post-menopausal women with firm mass that mimics carcinoma
May be systemic manifestations, but no temporal artery involvement
Case reports: 56 year old woman with breast tenderness but no systemic complaints (Med Princ Pract 2004;13:234), bilateral involvement (Am J Med Sci 2008;335:489)
Micro: involvement of small and medium sized arteries with transmural and perivascular infiltrate of lymphocytes, histiocytes and giant cells; elastic stain shows fragmentation of elastic fibers in vessel wall
Micro images: AFIP - intramammary arterial lumen is mostly obliterated by subintimal and mural inflammation, including giant cells (arrows); transmural necrotizing inflammation of medium sized mammary vessels, with elastic stain showing partial destruction of elastic layer
DD: polyarteritis nodosa, Wegener’s granulomatosis
References: Hum Path 1987;18:1186
Granulomatous mastitis (idiopathic)
Rare; young women with inflammatory breast processes (Ann NY Acad Sci 2007;1108:603)
Diagnosis of exclusion
Median age 36 years, not related to smoking (J Am Coll Surg 2008;206:269)
Possibly due to Corynebacterium (Pathology 2003;35:109, J Clin Microbiol 2007;45:1666)
Case report: 20 year old woman with large ulcer (The Internet Journal of Surgery 2007;13(2)), 35 year old woman with tender breast mass (Jpn J Clin Oncol 1997;27:274), 36 year old woman with mass (Int Semin Surg Oncol 2007;4:21)
Treatment: no consensus-observation, glucocorticoids, surgery (Am Surg 2007;73:798); may recur or be locally aggressive
Clinical images: appearance of second lump post-biopsy; firm mass with multiple sinuses
Gross: firm/hard faintly nodular mass
Gross images: resembles infiltrating ductal carcinoma; ulcer replaces breast tissue
Micro: granulomatous inflammation centered on lobules with lymphocytes, plasma cells, epithelioid histiocytes, multinucleated giant cells; may be neutrophils; necrosis in 11%
Cytology: abundant epithelioid histiocytes and neutrophils, variable granulomas, usually no necrosis (J Clin Path 2003;56:519)
Micro images: granulomatous inflammation centered on breast lobules #1; #2; #3; inflammatory reaction in lobules with giant cells (AFIP); nonnecrotizing granulomas with giant cells #1; #2; multinucleated giant cells; granulomatous inflammation
Cytology images: epithelioid histiocytes in an inflammatory background #1; #2; #3; atypical cells, suspicious for carcinoma
Negative stains: GMS and PAS for fungi or mycobacteria
DD: systemic granulomatous disease (Wegener's granulomatosis, sarcoidosis), infections (mycobacteria, fungi, cat scratch disease, Archives 1989;113:473), granulomatous angiopanniculitis (involves subcutis and extends into breast, Hum Path 1989;20:1084), foreign body reaction, fat necrosis
References: Archives 1994;118:822, Pathology 2004;36:254
Hemorrhagic necrosis in breast
Unusual complication of warfarin therapy (Ann Surg 1972;175:647)
Warfarin causes hemorrhagic necrosis of skin in 0.1 to 1.0% of patients (Br J Plast Surg 2000;53:624)
Rapid onset after initiation of therapy
Associated with protein S/C deficiency
Case reports: resembling inflammatory carcinoma (J Postgrad Med 2004;50:268)
Treatment: may require mastectomy
Clinical images: hemorrhagic necrosis of breast
Micro: widespread necrosis with multiple small vessel thrombi
Micro images: venous thrombosis and necrotizing arteritis; necrotizing arteritis; intimal necrosis of artery
Associated with intraductal papilloma, fibroadenoma, pregnancy-like hyperplasia, lactating adenoma, phyllodes tumor
May be spontaneous (J Clin Pathol 1975;28:937), but also associated with fine needle aspiration (Archives 1996;120:1069)
Special stains (reticulin or trichrome) may demonstrate residual fibrous structure
Case reports: infarcted lactating adenoma (AJR Am J Roentgenol 1999;173:933)
Clinical images: infarcted lactating adenoma
Micro: necrosis and ghost cells, hemosiderin; usually no thrombi are identified
Cytology: initially degenerated cells with smudged nuclei, ghost cells and necrotic debris; later fibroblasts, ductal cells and necrotic debris (Diagn Cytopathol 2006;34:373)
Micro images: AFIP - infarct in post-partum breast with lactational change #1; #2 with outlines of ductules in infarcted tissue other - sharply circumscribed border; partial infarction of hyperplastic lobules; coagulative necrosis of hyperplastic lobules (reticulin stain); infarct with foamy macrophages; partial luminal obliteration of medium sized vessels (elastic stain); organizing thrombus in vein; infarcted lactating adenoma #1; #2 (note zonal pattern); #3
A subset of breast-limited lupus panniculitis
Case reports: 33 year old woman with SLE and acute breast pain (J Obstet Gynaecol Res 2008;34:919), 44 year old woman with lupus nephritis but no systemic disease (AJR Am J Roentgenol 2002;178:1233)
Treatment: usually medical, not surgical
Micro: necrotizing vasculitis, fat necrosis with microcalcifications
Micro images: perivascular lymphocytic infiltrate; dense fibrosis with calcifications
Also called diabetic mastopathy or sclerosing lymphocytic mastitis/lobulitis if prominent fibrosis
Uncommon; usually women; often associated with type I / insulin dependent diabetes (Diabetes Care 2000; 25:121) or other autoimmune disease, but may occur in type II diabetes or non-diabetes
May occur in men, associated with gynecomastia (Pathol Res Pract 1997;193:197)
Rarely associated with DCIS
No increased risk of lymphoma
Case reports: 66 year old woman with multiple bilateral masses (AJSP 2006;30:1330), associated with lymphoepithelioma-like carcinoma (Archives 2001;125:669)
Treatment: excision; often recurs (30%, AJCP 2000;113:541)
Gross: clinically palpable mass, usually subareolar; gray-white, smooth cut surface; often bilateral
Micro: ill defined lesion of dense intralobular, perilobular and perivascular lymphocytes with lobular atrophy and sclerosis (keloidal fibrosis), B cell lymphoepithelial lesions, lymphoid follicles with germinal centers; also histiocytes and fibroblasts; epithelioid fibroblasts may be mistaken for carcinoma or granular cell tumor (Mod Path 1994;7:49); variable fat necrosis, noncaseating granulomas; no changes in overlying epidermis
Cytology: clusters of ductal cells, lymphocytes and epithelioid fibroblasts in fragments of dense connective tissue (Acta Cytol 1997;41:1349)
Micro images: perivascular lymphocytic infiltrate sparing lobules (AFIP); keloid-like fibrosis and prominent lymphoid infiltrate around breast ducts/lobules #1; #2; #3; lymphoepithelial lesion; keloidal fibrosis; CD20+/CD3- lymphocytes (B, not T cells); various images
findings in men - periductal lymphocytes and dense collagenous stroma #1; #2
Positive stains: B cell markers
Molecular: lymphocytes are not clonal (Mod Path 2003;16:223)
DD: MALT lymphoma (clonal), sinus histiocytosis with massive lymphadenopathy, gigantomastia (perilobular lymphocytic infiltrate is CD3+, different clinical findings, J Clin Endocrinol Metab 2005;90:5287)
References: Hum Path 1994;25:819, Hum Path 1992;23:780, Mod Path 1995;8:349, Radiology 2001;219:797 (similar clinical findings in men), Stanford University
Rare; thrombophlebitis of superficial veins of breast and adjacent thoracoabdominal wall
Sudden onset of firm, painful, nodular cord beneath skin
Self-limited, only rarely recurs
May be related to trauma, such as radical mastectomy, but not associated with breast cancer
Case reports: after core biopsy (AJR Am J Roentgenol 2002;179:185)
Treatment: anti-inflammatory drugs, excision of thrombosed vein or no treatment (Eur J Gynaecol Oncol 2005;26:213)
Clinical images: cord on lateral breast #1; #2; cords between breast and abdomen; 53 year old man #1; #2; shallow linear depression
Micro: phlebitis with thrombosis; late recanalization occurs
References: eMedicine
Nephrogenic systemic fibrosis in breast
Previously called nephrogenic fibrosing dermopathy
Recently described systemic fibrosing disorder primarily affecting patients with chronic renal insufficiency
Skin involvement may resemble peau d'orange
Only one case reported to date involving breast
Case reports: bilateral breast changes resembling inflammatory carcinoma (Archives 2007;131:145)
Micro images: fibrocollagenous thickening of dermis with clefts in reticular dermis and perivascular plasmacytic dermal infiltrate; fibroblast like cells and stromal mucin (Alcian blue+); spindle cells are CD68+ and CD34+
Uncommon; present in benign lesions and 1% of breast cancers
Due to cholesterol granuloma (Pathol Res Pract 2008;204:353), fibroadenoma (Radiology 1989;172:671), fasciitis ossificans (Pathol Res Pract 2007;203:737, Archives 2004;128:e29), implant capsules (Aesthetic Plast Surg 1985;9:43), metaplastic carcinoma (Breast 2008;17:314), osteosarcoma, post-radiation therapy (Br J Radiol 2002;75:460), saline implants (Plast Reconstr Surg 2001;107:356) or silicone (Ann Plast Surg 1998;41:348)
Micro images: fasciitis ossificans - fig 1: spindle cell stroma and unremarkable mature lamellar bone; fig 2: lamellar bone is rimmed by osteoblasts
Parasitic infestation of breast
Cysticercosis of breast (parasites)
Due to larvae of Taenia solium (tapeworm), a major public heath problem in developing countries
Case reports: 15 year old girl with breast lump (Med Trop (Mars) 2007;67:179)
Gross images: cyst of Taenia solium in breast biopsy (AFIP)
Micro: fibrous walled cyst covered by several layers of epithelioid cells with eosinophils, occasional giant cells (AJSP 1999;23:1276)
Cytology: parts of parasite may be identifiable (Acta Cytol 1996;40:653); also spiked spherules and inflammatory cells (Acta Cytol 1989;33:659)
Echinococcal cyst of breast (parasites)
Also called hydatid cyst
See also discussion in Liver-non tumor chapter
Due to infestation by larval form of Echinococcus granulosus, endemic in sheep rearing countries
Rare, but consider in differential diagnosis of a breast mass in endemic regions
Case reports: diagnosis by fine needle aspiration (Rev Med Interne 2007;28:336), masses in pancreas and breast (JOP 2004;5:368)
Treatment: complete excision
Clinical images: ruptured cyst and part of germinative membrane
Micro images; germinative layer (fig 3, inset)
References: eMedicine
Filariasis of breast (parasites)
Usually involves lymphatics or lymph nodes, rare in breast
May occur years after leaving endemic area
Case reports: breast mass 3 years after visit to India (Archives 1987;111:757), granuloma in breast (Indian J Pathol Microbiol 2008;51:85), Nigerian woman visiting US (Radiology 2002;222:515), dirofilariasis in Hong Kong diagnosed by FNA (Diagn Cytopathol 2002;26:22)
Micro: adult worms, preserved or degenerating; granulomatous inflammation with eosinophilic abscesses
Cytology: eosinophils, ova, embryonated eggs (Indian J Pathol Microbiol 2006;49:365)
Micro images: gravid female worm of Wurcheria bancrofti in exudate surrounded by fibrosis (AFIP); transverse section of adult filarial worm with granuloma
References: eMedicine #1, #2
Myiasis of breast (parasites)
Infestation of body by larva of Diptera (flies with 2 wings)
Larvae usually occupy skin and subcutis, but potentially any organ; cause abscess and rarely granulomatous response to dead larvae
Dermatobia hominis (human botfly) is obligate Diptera that needs to feed on a host to complete its development; indigenous to Central and South America, occasional reports in USA (Radiology 2001;218:517)
Cordylobia anthropophaga (Tumbu fly) is endemic in Nigeria (BMC Surg 2004;4:5); often multiple infestations in breast, also affects lips of breast fed infants (Int J Dermatol 2006;45:1069)
Clinical images: breast infested by Tumbu fly larvae; extracted Tumbu fly larvae; human botfly larvae extracted from a dog
Case reports: 54 year old woman with breast mass due to chronic granulomatous response to botfly (Archives 1999;123:829)
Micro: chronic granulomatous response, dead larvae
Micro images: botfly - respiratory spiracles; granulomatous response around a spine
DD: ticks (have legs and mouth and don’t burrow deeply into skin), Tunga penetrans (flea with legs, almost always involves feet, has cuticle > 20 microns, lacks a spine)
Sparganosis of breast (parasites)
Infection with larval tapeworm of genus Spirometra (Stanford University)
Case reports: 17 cm worm (Korean J Parasitol 2002;40:187), 20 cm actively moving worm (Korean J Parasitol 2006;44:151), 38 year old man (J Formos Med Assoc 2005;104:127)
Clinical images: worm arising from 2 cm breast nodule at surgery
Considered a variant of periductal mastitis/duct ectasia with prominent plasma cell component
Associated with pregnancy, occurs a mean 4 years after cessation of lactation
Resembles carcinoma clinically
Very few recent articles in English medical literature using this terminology
Clinical: firm mass, 2-3 cm, with nipple discharge and retraction; often axillary adenopathy
Case reports: 35 year old woman with breast abscess (Postgrad Med J 1958;34:654), bilateral involvement (Br Med J 1949;1:94)
Treatment: excision to avoid ulceration and fistulas
Gross: dilated ducts with creamy secretion
Micro: hyperplasia of ductal epithelium with markedly diffuse plasma cell infiltrate of ducts and lobules; often granulomatous reaction
Cytology: prominent plasma cells and histiocytes; also hyperplastic epithelial cells
Micro images: infiltrate of plasma cells, macrophages, lymphocytes (AFIP)
Polyarteritis nodosa of breast
See also giant cell arteritis of breast
Also called periarteritis nodosa
Case reports: two cases (Histopathology 1993;23:535), presenting as an isolated breast lesion (Br J Dermatol 1999;141:1117)
Micro: vasculitis of medium and small arteries; medium arteries have intimal fibroplasia, fragmentation of internal elastic lamina and inflammatory cellular infiltration; small arteries have fibrinoid vasculitis
Micro images: site unknown-intimal hyperplasia
Reactive spindle cell nodule of breast
Usually after core biopsy or fine needle aspiration
Similar tumors in bladder, prostate, other GU sites, but few publications in breast
Associated with biopsy of complex sclerosing lesions and papillary lesions (AJCP 2000;113:288)
May be due to exuberant reparative process
Gross: up to 1 cm, nodular, not encapsulated
Micro: spindle cells with mild/moderate nuclear pleomorphism, small vessel proliferation, foam cells, lymphocytes, hemosiderin; no/rare mitotic figures
Positive stains: spindle cells - smooth muscle actin, muscle specific actin
DD: inflammatory myofibroblastic tumor, nodular fasciitis, myofibroblastoma, fibromatosis, low grade spindle cell carcinoma, low grade sarcoma
Abnormal breast examinations or mammograms in 2% of sarcoidosis patients, granulomas in 1% (Sarcoidosis Vasc Diffuse Lung Dis 2001;18:301)
Occasionally begins in breast and remains localized for long periods
Note: sarcoidosis may also mimic metastatic breast cancer (Clin Breast Cancer 2007;7:804)
Case reports: systemic disease and breast mass (Eur Rev Med Pharmacol Sci 2006;10:47, free full text)
Micro: noncaseating, epithelioid granulomas with multinucleated giant cells; no/rare necrosis
Cytology: epithelioid cells and lymphocytes
Micro images: stromal granulomas sparing lobules (AFIP); non-necrotizing granulomatous inflammation #1; #2; #3; #4
DD: mycobacteria, fungi, foreign material, granulomatous mastitis
References: Archives 1984;108:673, Hum Path 1985;16:851, Hum Path 1985;16:185
Used for breast construction post-mastectomy or for breast augmentation
Do not cause systemic disease, but can leak and rupture, causing local scarring, infection and disfigurement
Recommended to photograph and describe surface of removed implant for possible litigation (Mod Path 2000;13:1050)
Can chemically identify silicon inclusions with Raman spectroscopy (Mod Path 1999;12:714)
Several reports of anaplastic large cell lymphoma adjacent to implants (Mod Path 2008;21:455, Archives 2003;127:e115, AJSP 2008;32:1265)
Case reports: capsular synovial metaplasia mimicking silicone leak of breast prosthesis (J Med Case Reports 2008;2:277), leaky implant associated with Kikuchi-Fujimoto disease (Archives 1996;120:380), synovial metaplasia of periprosthetic breast capsule (Archives 1994;118:249); follicular lymphoma and adjacent granulomatous response to foreign material next to silicone implant (AJSP 1995;19:712)
Gross images: silicon implant (diagrams)
Micro: chronic inflammatory response (plasma cells, B and T cells and foamy macrophages) with fibrotic capsule around the implant causing contracture of prosthesis; lining cells may resemble synovium (synovial metaplasia, Mod Path 1994;7:310), gel may seep through intact implant shells; may have foreign body reaction with sinus tracts; numerous cystic spaces and vacuoles may exist where silicon dissolves during processing
Micro images: injected silicone (AFIP) - refractile silicone and giant cell reaction #1; #2 (arrow at doubly-refractile silicon) polyurethane implant (AFIP) - polyurethane (arrow) and silicone (round globules)
silicone implants - dense fibrosis and chronic inflammatory cells in capsule (AFIP); giant cell reaction and silicone #1; #2; #3; #4; #5; capsular synovial metaplasia
Virtual slides: foreign body reaction
References: AJSP 1995;19:433, Mod Path 1999;12:706, Mod Path 1994;7:728, Hum Path 1985;16:19, eMedicine, Wikipedia
Axillary lymph nodes and silicone
Due to implantation of bag-gel prosthesis for mammary augmentation or migration of injected silicone
Either an incidental finding or causes painful / enlarged lymph node
Case reports: rupture of high cohesive gel implant (J Plast Reconstr Aesthet Surg 2006;59:885), evidence of silicon migration (Br J Plast Surg 2005;58:1027)
Micro: usually foamy macrophages (scattered or sheets), refractile droplets of clear material consistent with silicone, granulomatous inflammation (Histol Histopathol 1997;12:1003), occasionally foreign polygonal fragments consistent with polyurethane
Cytology: birefringent material with foreign body giant cells in lymphoid background (Acta Cytol 1999;43:1163)
Micro images: fig 1b: histiocytes with variably sized cytoplasmic vacuoles
DD: sinus histiocytosis with massive lymphadenopathy
References: AJSP 2005;29:506, AJSP 1988;12:484, Archives 1981;105:371
Rare in general, but common in India (The Internet Journal of Tropical Medicine 2005;2(2))
Usually unilateral without pulmonary involvement (ANZ J Surg 2006;76:234)
For breast cancer patients with granulomatous axillary lymphadenitis, PCR may be required to rule out TB in endemic regions (Pathol Res Pract. 2007;203:699)
Case reports: coexisting with ductal carcinoma (World J Surg Oncol 2008;6:29), mimicking breast cancer (J Med Case Reports 2008;2:34)
Clinical images: resembles breast carcinoma
Gross: multiple sinuses
Micro: granulomas with Langhans giant cells and caseous necrosis (often)
Cytology: foamy histiocytes, neutrophils, necrotic debris
Micro images: AFIP - granulomatous inflammation of major lactiferous duct with epithelial necrosis; granulomatous inflammation and Langhans giant cells
other - granuloma with central necrosis and epithelioid histiocytes #1; #2-also Langhans giant cells and prominent lymphocytes; acid-fast bacilli; ductal carcinoma plus epithelioid granuloma (upper right)
Fibrocystic disease of breast
Fibrocystic disease of breast - general
Also called fibrocystic change
A general category for numerous entities, detailed below
Cystic features are usually prominent, but there may not be fibrosis
Not necessarily a disease that requires treatment, but Rosai favors "fibrocystic disease" over “fibrocystic change” because the constellation of findings fulfills the criteria for a disease, similar to nodular hyperplasia of the prostate
Common in women ages 25-45 years, more common in Americans/Europeans than Japanese or South American women
More common in women with polycystic ovaries (based on radiology, not histology, Minerva Ginecol 2000;52:321)
Benign, not neoplastic, but may be confused with malignancy
Usually bilateral, although one breast may be affected more than the other
Associated with hormonal imbalance (increased estrogen to progesterone ratio); decreased risk with oral contraceptives, perhaps due to balanced supply of estrogens and progesterone
Either proliferative (adenosis, hyperplasia) or nonproliferative (cysts)
The specific proliferative disease present determines the relative risk for subsequent carcinoma, varying from 1x (no increased risk) to 5x for atypical ductal hyperplasia (AJSP 2003;27:836)
Gross images: cysts surrounded by fibrous tissue #1; #2; #3
Micro: primarily affects the terminal duct lobular unit, not the large ducts; see specific types below
Micro images: various images
Virtual slides: #1
See also apocrine (adenomyoepithelial) adenosis, apocrine adenoma
Common, associated with dilated ducts and cysts
Apocrine cysts may contain fluid under pressure
Benign, but risk factor (low) for cancer (Cancer Epidemiol Biomarkers Prev 2007;16:467)
Highly complex papillary apocrine change: rare, often coexists with ADH (Cancer Epidemiol Biomarkers Prev 1996;5:29)
Micro: cells resemble apocrine sweat glands, are enlarged with abundant eosinophilic cytoplasm and apical snouts, often supranuclear vacuoles, medium sized nucleus but prominent nucleoli; changes may be partial/incomplete; may have more atypical features in sclerosing adenosis
Cytology: atypical apocrine metaplasia with signet ring cells (such as from sclerosing papilloma) may resemble mucinous carcinoma (Acta Cytol 2002;46:749)
Micro images: subgross #1; #2; apocrine metaplasia #1; #2; #3; #4; #5; #6; #7; #8; #9; #10; #11; with epithelial hyperplasia; papillary epithelial hyperplasia; papillary proliferation; strong androgen receptor staining #1; #2; #3; CK19+; GCDFP-15+; negative for ER alpha; negative for progesterone receptor (positive internal control in normal breast at upper left); highly complex papillary apocrine change #1; #2; #3
Cytology images: apocrine metaplasia #1; #2; #3; #4
Positive stains: PAS (coarse glycolipid granules), GCDFP-15, androgen receptor (J Clin Pathol 1999;52:838); c-myc (nuclear staining, but no amplification by FISH, Breast 2002;11:466)
Negative stains: ER, PR, p53, low Ki-67 (Mod Path 2000;13:13)
Molecular: loss of heterozygosity in 53% (Am J Pathol 2000;157:323)
Chronic inflammation of breast
Common
Associated with cyst rupture and release of secretions into stroma
DD: mammary duct ectasia, foreign body reaction, lymphocytic mastitis
Collagenous spherulosis of breast
Rare variant of epithelial ductal hyperplasia first described in 1987 (AJSP 1987;11:411)
Almost always an incidental finding, only rarely presents as a mass
Associated with intraductal papilloma, sclerosing adenosis and radial sclerosing lesions
Benign, but often mistaken for intraductal or invasive carcinoma
Also seen in salivary gland tumors
Case reports: involvement by LCIS (AJSP 1995;19:1366), in adenomyoepithelioma (J Clin Pathol 2004;57:83), with DCIS (Pathologica 2002;94:317)
Gross: usually multifocal, 1 to 3 mm
Micro: intraluminal clusters of eosinophilic or rarely basophilic (“mucinous spherulosis”, Archives 1999;123:626), collagen-rich spherules within spaces between epithelial and myoepithelial cells or intraductal; usually an incidental finding; associated with LCIS (25%) and microcalcifications (25%, AJSP 2006;30:20)
Cytology: hyaline pink globules surrounded by benign myoepithelial cells in Giemsa stained smears (Cytopathology 2002;13:116)
mucinous spherulosis - cribriform structures with lightly basophilic material embedded in loosely mucinous acellular background; intermediate to large, round hyaline spherules are naked or surrounded by myoepithelial cells; Diff-Quik stain shows fibrillary radial appearance (Diagn Cytopathol 2006;34:626)
Micro images: AFIP - collagenous spherulosis #1; #2
other - collagenous spherulosis #3; #4; #5; #6; #7; basophilic spherules (mucinous spherulosis); tubular adenosis with features of collagenous spherulosis; adenoid cystic carcinoma (first column) vs. collagenous spherulosis (second column); p63; c-kit
Positive stains: myoepithelial cells - smooth muscle actin, smooth muscle myosin heavy chain, calponin, p63 (nuclear staining, examine at high power, Mod Path 2006;19:1351)
Negative stains: myoepithelial cells - c-kit/CD117
EM: epithelial cells and myoepithelial cells plus associated basement membrane-like material (Breast J 2000;6:199)
EM images: fig 7B: amorphous material with thick fibrils showing periodic banding
DD: adenoid cystic carcinoma (denser and tightly nodular material is rarely degenerated, stromal invasion, CD117+ luminal cells, calponin and smooth muscle actin negative, may have collagenous spherulosis like structures, Pathol Int 2004;54:332), signet ring carcinoma
References: Stanford University
Columnar cell lesions of breast
See also flat epithelial atypia
Also called blunt duct adenosis, columnar alteration with prominent apical snouts and secretions, columnar metaplasia, enlarged lobular units with columnar alteration (AJSP 2005;29:105)
Frequent finding in breast biopsies for mammographic calcifications (AJSP 1998;22:1521); may be associated with lobular neoplasia in these patients (AJCP 2008;130:254)
May be associated with atypical hyperplasia, but otherwise no significantly increased risk of breast carcinoma (Cancer 2008 Sep 24 [Epub ahead of print])
Appears to be a clonal (neoplastic), nonobligate, intermediate step in development of some forms of low grade DCIS and invasive carcinoma (AJSP 2005;29:734); present in 95%+ cases of tubular carcinoma (AJSP 2007;31:417, Adv Anat Pathol 2008;15:140)
Recommended to merely note the presence of this lesion if no atypia, to identify ADH or DCIS if present, and to submit additional tissue / obtain additional levels if atypia is present (AJSP 2002;26:1095)
Classifications below with atypia (types 3-6) have lowest diagnostic reproducibility (J Clin Pathol 2005;58:705)
Classification: Schnitt (Adv Anat Path 2003;10:113) modified by Simpson (AJSP 2005;29:734)
[All have variable dilated acini, cytoplasmic snouts and intraluminal secretions; several types may coexist in same breast]
Type 1 (columnar cell change): 1-2 cell layers; columnar cells have uniform ovoid/elongated nuclei perpendicular to basement membrane; no/inconspicuous nucleoli; may have apical snouts but usually not prominent
Type 2 (columnar cell hyperplasia): >2 stratified cell layers with variable nuclear crowding and cellular micropapillations, but no complex architectural patterns (i.e. no rigid bars, bridges or well-formed micropapillary structures); cytology similar to type 1 but may have hobnail cells; associated with intraluminal calcification
Type 3 (columnar cell hyperplasia with architectural atypia): >2 stratified cell layers with complex architectural patterns (micropapillary, tufts, fronds, arcades, rigid bridges or punched out spaces); type 2 cytology
Type 4 (columnar cell hyperplasia with cytologic atypia): type 2 architecture; mild to moderate cytologic atypia, may resemble tubular carcinoma
Type 5 (columnar cell hyperplasia with cytologic and architectural atypia): type 3 architecture; type 4 cytology
Type 6 (columnar cell change with cytologic atypia): 1-2 cell layers; type 4 cytology
Columnar cell lesion of breast (continued)
Xray: ossifying-type calcifications-a peculiar, infrequent type of calcification found in mammary duct lumina, with a central core of calcification and a rim of ossifying-type matrix reminiscent of osseous tissue but not lined by osteoblasts or osteocytes (Archives 2002;126:995)
Treatment: excision is recommended if atypia found at core biopsy (Am Surg 2007;73:984)
Micro: distended, unfolded terminal duct lobular units lined by tightly packed columnar epithelial cells with prominent apical cytoplasmic snouts and intraluminal secretions; cells may have clear cytoplasm; variable cytologic atypia and architectural complexity (see classification); may be associated with ADH or low grade DCIS
Cytology: flat sheets of cells with enlarged nuclei, distinct cell borders, finely granular cytoplasm; usually few myoepithelial cells; resembles papillary neoplasms and well differentiated adenocarcinoma (Diagn Cytopathol 2007;35:73)
atypical features: cohesive 3D clusters of enlarged polygonal epithelial cells mixed with myoepithelial cells centrally and palisading columnar cells peripherally; often bipolar nuclei and apical snouts (Diagn Cytopathol 2004;31:370)
Micro images: columnar cell change - #1; #2; #3; #4; #5; #6; #7; #8; with microcalcifications #1; #2; #3; #4; ossifying-type calcifications (dense basophilic, smooth, round calcifications surrounded by ossifying matrix); with calcium oxalate crystals #1; #2; ”blunt duct adenosis” #1; #2; adenosis with columnar cell change #1; #2; with DCIS
columnar cell hyperplasia - #1; #2; #3; #4; #5; #6; psammomatous calcification; in mucocele-like tumor #1; #2
columnar cell hyperplasia with atypia - #1; #2; columnar cell change with flat epithelial atypia #1; #2
Virtual slides: columnar cell change with atypia
Positive stains: ER (strong, Breast J 2005;11:326), PR, CK19; also bcl2, Ki-67 increased but less than carcinoma (Hum Path 2007;38:284)
Negative stains: CK 5/6, CK14, 34betaE12, HER2, p53
Molecular: no mutational changes in simple columnar change; progressive accumulation of allelic damage with atypia, DCIS or invasive carcinoma, involving 9q, 10q, 17p and 17q (Mod Path 2006;19:344)
DD: cystic hypersecretory hyperplasia (secretions, but no apical snouts), apocrine metaplasia
References: Stanford University
Cystic hypersecretory hyperplasia of breast
Associated with pregnancy-like (pseudolactational) hyperplasia (AJSP 2000;24:1670)
Either asymptomatic with mammographic abnormality or palpable mass
May coexist with atypia or DCIS of cystic hypersecretory type, so sample generously
Case reports: 48 year old woman with mass exhibiting atypia (Archives 2003;127:e389)
Treatment: wide excision (Cancer 1988;61:1611); if atypia present at core biopsy, excise entire lesion because DCIS is often present (AJSP 2004;28:789)
Gross: resembles juvenile papillomatosis of the breast; large, ill-defined, firm to rubbery, spongy mass of fibrous tissue containing multiple small cysts; also abundant thick, sticky mucin within the cysts
Gross images: dilated cysts with gelatinous type material #1; #2
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Micro: cystically dilated ducts of various sizes with colloid-like material, often with parallel fracture lines, retraction halo and overlapping due to processing; ducts are lined by flat, orderly, columnar epithelial cells with eosinophilic cytoplasm, nuclei are round/oval, vesicular, bland; atypical features are epithelial crowding, enlarged nuclei lacking normal polarization, hyperchromasia and rare mitotic figures
Micro images: cysts lined by flat cuboidal epithelium contain eosinophilic material #1 (AFIP); #2; #3; #4; intraluminal secretions show fine, parallel cracks and shrinkage of the cyst content with peripheral scalloping; hyperplasia (fig 2A/2B), DCIS and invasive carcinoma
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atypia - focal atypical epithelium between cysts (AFIP) #1; #2 (AFIP); fig A: MRI shows 5 cm mass; fig B: dilated epithelial cysts with colloid-like material; fig C: epithelium is flat or cuboidal; fig D: focal areas of cellular atypia and mitotic figures
DD: cystic hypersecretory DCIS or invasive carcinoma
Very common
May arise from lobular acini that coalesce
Usually multifocal and bilateral
Associated with calcifications, apocrine metaplasia
Cysts with cloudy or turbid cyst fluid should have cytologic analysis
Excision required after aspiration if no fluid, bloody or tenacious fluid, or mass persists (Am Fam Physician 2003;68:1983)
Blue dome cysts: based on gross appearance
Type 1 cysts: Na/K ratio of 3 or less; increased breast cancer risk; associated with higher levels of estrogen, melatonin, epidermal growth factor and DHEA-S and lower levels of TGF-B2 than type 2 cysts (Breast Cancer Res Treat 2007;103:331)
Type 2 cysts: Na/K above 3: reduced breast cancer risk, although patients may have both types of cysts, and type 2 cysts can be associated with cancer (Breast 2005;14:37)
Gross: variable size, usually visible grossly, contains clear or yellow fluid
Gross images: unopened cyst #1; #2; #3; large hemorrhagic cysts #1; #2; extensive cystic disease; cyst and fibrous tissue #1; #2
Micro: lined by double layer of flat/cuboidal cells or no lining, may rupture and elicit inflammatory response with foamy macrophages, cholesterol clefts, fibrosis; variable apocrine metaplasia
Micro images: subgross #1; #2 (arrow points to terminal duct of fully unfolded epithelial cyst filled with secretion, other cyst is partially unfolded); two cysts hanging from duct tree; early cystic change #1; #2 (arrows point to broken walls of distended ductules); multiple broken walls in lobule converting into cyst; multiple dilated cysts #1; #2; papillary hyperplasia; squamous metaplasia of epithelium lining cyst (AFIP); calcifications in cystically dilated ducts
Virtual slides: multiple dilated cysts
DD: duct ectasia (elastic tissue in wall, macrophages in lumen), cystic hypersecretory hyperplasia (colloid-like secretions)
References: Am Fam Physician 2003;68:1983 (aspiration procedure)
Epithelial ductal hyperplasia of breast
Definition: benign ductal proliferative lesion that typically has secondary lumens and streaming of central proliferating cells
Also called usual ductal hyperplasia, intraductal hyperplasia, hyperplasia of usual type, papillomatosis (but this term may be confused with papillomas or florid papillomatosis of nipple), epitheliosis
May be due to increase in mitotic rate of epithelial cells compared to apoptotic rate, causing an increased number of epithelial cells within preexisting glandular components (Hum Path 1998;29:1539, Breast Cancer Res 2001;3:276)
Appears to derive from a CK5+ committed stem cell lesion with the same differentiation potential as normal breast, in contrast to ADH/DCIS, which display a differentiated glandular immunophenotype (CK8/18/19+, CK5-, J Pathol 2002;198:458)
Overall may have slightly increased risk for invasive carcinoma with relative risk of 1.5-2.0 (Archives 1998;122:1053); high ERalpha/ERbeta ratio lesions are more likely to progress to breast cancer (AJSP 2005;29:1593)
Micro: streaming (parallel arrangement) of central cells with indistinct cell borders; irregularly shaped and sized secondary lumens, often peripheral; tufts of cells project into lumina; peripheral elongated clefts (not round, not central), irregularly shaped bridges connect opposite portions of wall with nuclei parallel to long axis of the bridge (not Roman bridges); cells have acidophilic and granular cytoplasm, oval normochromatic nuclei with slight overlap, small or indistinct nucleoli; myoepithelial cells and foamy macrophages are present; individual cells are well supported by their stroma; variable apocrine metaplasia, intraluminal or stromal calcifications, intranuclear round eosinophilic bodies (helioid inclusions); occasional fibrosis, elastosis or chronic inflammation; rarely necrosis; no/minimal mitotic figures; no psammoma bodies, no atypia, no prominent nucleoli
Perineural invasion is rare, usually associated with sclerosing adenosis or radial scar (Hum Path 2001;32:785, Archives 2000;124:465)
Mild hyperplasia: 2-4 epithelial layers; no increased risk for invasive carcinoma
Moderate hyperplasia: 4 or more epithelial layers; 1.5 to 2x increased risk for invasive carcinoma, higher if age 50+ years
Florid hyperplasia: epithelium almost completely fills duct but with fenestrations (irregular lumina at periphery) and papillomatosis; 1.5 to 2x increased risk for invasive carcinoma
Gynecomastia-like hyperplasia: micropapillary, resembles gynecomastia of male breast
Thyroid-like hyperplasia: resembles tall cell variant of papillary thyroid carcinoma (see also Tall cell-like tumors in Breast-malignant chapter)
Epithelial ductal hyperplasia (continued)
Cytology: may rarely be hyperchromatic with increased N/C ratio and loss of 2 cell layers; however, be cautious if radiologic imaging and physical exam are not definitive for malignancy (Breast Cancer 2007;14:388)
Micro images: AFIP - distention of duct by cellular proliferation with irregular and slit-like spaces; oval/spindled epithelial cells mixed with elongated myoepithelial cells with dense chromatin #1; #2; spindled epithelial cells are parallel to long axis of intraductal cellular bridges, cell bridges merge to form secondary lumina, myoepithelial cells are present along borders of duct; micropapillary ductal hyperplasia with parallel arrangement of most cells and uniform nuclei; secondary lumina have irregular shapes; apocrine metaplasia forming secondary lumina with foam cells; secondary lumina adjacent to basement membrane are more rounded than smaller central lumina, and cell population is heterogeneous
other - perineural invasion; more epithelial hyperplasia #1; #2; #3; #4; #5; #6; #7; #8; #9; #10; usual ductal hyperplasia (CK903+) versus ADH (CK903-)
Cytology images: ductal hyperplasia #1; #2; #3-incorrectly called malignant (fig 1A/2A); with apocrine metaplasia #1; #2; #3
Virtual slides: epithelial hyperplasia
Videos: epithelial hyperplasia
Positive stains: 34betaE12 keratin (strong, AJSP 1990;14:939), CK 5/6 (Hum Path 2006;37:787), E-cadherin, S100 (weak), ER
Fibroadenomatoid change of breast
Also called fibroadenomatoid hyperplasia, fibroadenomatoid mastopathy
An incidental finding, usually in a background of fibrocystic change
Incidence of 11% (Pathology 1987;19:393, Malays J Pathol 1991;13:101)
Radiology: suspicious, granular, clustered microcalcifications on screening mammography (AJR Am J Roentgenol 1998;171:1331)
Micro: resembles microscopic foci of fibroadenoma without an actual mass and without the typical circumscription of a fibroadenoma; exhibits proliferation of intralobular connective tissue; often coexists with dilated ducts, epithelial hyperplasia, adenosis, calcifications
Micro images: fig 1/2
Also called hyaline fibrosis of stroma
Common finding (2-7% of core needle biopsies, Radiology 2000;216:255, AJR Am J Roentgenol 2001;177:573); also associated with diabetes (Gen Diagn Pathol 1997;143:49), radiation therapy (Eur J Cancer 2008 Aug 29 [Epub ahead of print]), Cowden’s syndrome (Exp Dermatol 1998;7:380)
May be associated with a reduced risk for progression to breast cancer (Clin Cancer Res 2007;13:5474)
Gross images: fibrosis
Micro: stromal proliferation with obliteration of ducts and acini
Micro images: fibrous tissue with dilated ducts and reduced lobules; mass-like fibrosis with entrapped ducts and lobules #1; #2; #3; discrete lobulocentric focus of fibrous tissue (arrows); narrow bands of fibrous tissue (arrow) surrounding ducts (arrowhead) and lobules; irregular patches of fibrous tissue (arrows) mixed with fat; stromal fibrous nodule #1; #2-subgross
Presence of microcalcifications on mammography has led to detection of breast tumors as small as 1-2 mm
Microcalcifications are present in 50% of carcinomas versus 20% of benign breast disease, but only 20% of “suspicious” microcalcifications are actually malignant
Microcalcifications are either calcium phosphate (basophilic, nonbirefringent) or calcium oxalate (seen with polarized microscopy, not H&E, AJSP 1990;14:961, Archives 1989;113:1367, Mod Path 1992;5:146)
Pathologists must detect microcalcifications in glass slides that correspond to those in radiographs - if not present, submit additional tissue, obtain additional levels or use polarized microscopy to look for calcium oxalate (Pathologica 2007;99:5); exhaustive searching for microcalcifications yields a small increase in specific diagnostic information but with a high technical cost (Mod Path 2001;14:350)
Note: microcalcifications may be missing from biopsy due to retrieval failure (Radiology 2006;239:61)
Note: recommended to examine all vacuum assisted breast biopsy specimens histologically, even those without microcalcifications (Eur Radiol 2008;18:925)
Detection of calcium phosphate microcalcifications is reduced with glyoxal fixative (Hum Path 2004;35:1058)
Calcium oxalate microcalcifications of breast
Calcium oxalate crystals are typically within benign cysts or terminal ductules that are histologically apocrine or GCDFP-15 positive; are associated with LCIS, but only rarely with invasive carcinoma (AJSP 1991;15:586)
Calcium oxalate crystals may be present in centrifuged fixative (AJSP 1997;21:255)
Radiologic BI-RADS (Breast Imaging Reporting and Data System of American College of Radiology) classification:
Category 0 - need additional imaging evaluation; category 1 - negative; category 2 - benign finding; category 3 - probably benign finding-short term interval followup suggested; category 4 - suspicious abnormality-biopsy should be considered; category 5 - highly suggestive of malignancy-appropriate action should be taken
References: American College of Radiology
Microcalcifications of breast (continued)
LeGal classification of microcalcifications
Type 1 - annular; type 2 - regularly punctiform; type 3 - too fine for precizing the shape, type 4 - irregularly punctiform; type 5 - vermicular (Bull Cancer 1984;71:57)
Case reports: Case of the week #25, gold salts within intramammary nodes may simulate microcalcifications (Hum Path 1988;19:992)
Micro images: calcium oxalate calcifications - with polarized light (AFIP) #1; #2; without polarized light (AFIP) #1; #2; #3; #4
mammography category 3 (probably benign) - Xray and histology images (figs 2-4, 7)
calcium phosphate calcifications - #1
benign lesions with microcalcifications - AFIP - ADH; sclerosing adenosis #1; #2; other - columnar cell change #1; #2; cystically dilated ducts; fat necrosis; mucocele-like lesion;
malignant lesions with microcalcifications - DCIS-comedo type; LCIS involving adenosis; invasive ductal carcinoma with DCIS
Virtual slides: microglandular adenosis with microcalcifications
Positive stains: von Kossa for calcium phosphate
References: eMedicine
Pseudolactational (pregnancy-like) hyperplasia of breast
See also pregnancy/lactation, lactating adenoma
Women, mean age 44 years, range 38-52 years, not lactating, not pregnant
Identified in needle localization and core biopsies due to calcifications or presence of a mass (overall, 2-3% of breast biopsies)
Often multifocal
Associated with phenothiazine or other medications (AJCP 1987;87:23)
Associated with / may merge with cystic hypersecretory hyperplasia
May have associated ADH or DCIS (AJCP 2004;122:714) but invasive carcinoma is rare (AJSP 2004;28:789); recommend excision if atypia found in core biopsy (AJSP 2000;24:1670)
Micro: glands and terminal ducts with little or no secretion; glandular cells are swollen with abundant pale or clear, finely granular or vacuolated cytoplasm; luminal cytoplasmic borders of glandular cells are frayed with small cytoplasmic blebs extending into lumen that may contain nuclei; small, uniform, round and darkly stained nuclei
Micro images: AFIP - expanded acinar glands; cells have abundant pale cytoplasm but no secretion; micropapillary pattern of columnar cells with luminal cytoplasmic buds
other - cells have finely vacuolated cytoplasm #1; #2
References: Stanford University
Definition: benign lesion with stellate architecture and prominent fibroelastosis that resembles invasive carcinoma
Initially described in 1977 (AJSP 1977;1:155)
Also called complex sclerosing lesion (larger lesions), sclerosing ductal lesion, sclerosing adenosis with pseudoinfiltration
Common; incidence has increased with mammography (J Clin Pathol 2003;56:721)
Associated with 2x increased risk of breast cancer, may be due to coexisting proliferative disease (Cancer 2006;106:1453, Breast Cancer Res Treat 2008;108:167 but see N Engl J Med 1999;340:430); may be associated with metaplastic carcinoma (Mod Path 2003;16:893)
Xray: stellate abnormalities (“black star”) may resemble invasive ductal carcinoma or tubular carcinoma; often bilateral
Xray images: characteristic findings
Treatment: local excision and follow up or possibly vacuum assisted excision (Breast 2008 Sep 29 [Epub ahead of print])
Core biopsy: excision recommended since associated carcinoma is relatively common (AJSP 2004;28:1626, AJSP 2002;26:1095, Breast Cancer Res Treat 2008;107:371)
Case reports: with DCIS and invasive carcinoma (Breast Cancer 2006;13:107)
Gross: stellate with central sclerosis and elastosis, resembles invasive ductal carcinoma, usually 1 cm or less; may be firm, irregular, with yellow streaks and flecks (due to elastotic stroma)
Gross images: central sclerosis and elastosis resembling carcinoma; subgross image
Micro: “flower head” pattern on low power; high power shows central fibroelastotic zone of basophilic elastic material in walls of obliterated ducts and elsewhere, with radiation of compressed tubular structures with 2 cell layers (including myoepithelium) and hyalinized stroma; variable amounts of epithelial hyperplasia, adenosis and cysts; perineural invasion occasionally noted
Cytology: fine needle aspiration often inadequate (J BUON 2002;7:137); bland epithelial clusters and bipolar naked nuclei; also frequent apocrine cells, papillary clusters, foam cells and fibrillary elastoid material; features are nonspecific, but suggest benign diagnosis (Diagn Cytopathol 1997;17:353); may also be atypical / malignant features if additional lesions present
Radial scar of breast (continued)
Micro images: central fibrosis and elastosis with radiating fibrous bands and dilated ducts #1; #2; #3; #4; #5; #6; fibrosis, elastosis and ductal hyperplasia; various images #1; #2; with tubulolobular carcinoma
AFIP - adenosis surrounds central area of fibrosis and elastosis with entrapped ducts; cysts are commonly present at periphery; squamous metaplasia; central angular glands are suggestive of tubular carcinoma, but peripheral duct hyperplasia and cysts are not typical; elastic stain highlights central elastosis
Virtual slides: case report (#1a)
Positive stains: elastic stains (von Gieson); myoepithelial cells - p63, CD10 and 1A4 (Appl Immunohistochem Mol Morphol 2006;14:71)
DD: invasive carcinoma, tubular carcinoma (no peripheral duct hyperplasia and cysts, negative for myoepithelial markers)
References: Stanford University
Adenosis of breast
Any hyperplastic process primarily involving glands (i.e. an increased number of glandular components)
See subtypes below
Common, benign, often accompanied by fibrosis
Micro: loosely structured proliferation of acinar or tubular structures, with epithelial and myoepithelial layers, surrounded by basement membrane
Micro images: low power shows a somewhat lobular architecture; enlarged lobules; epithelial and myoepithelial cells; adenosis with columnar cell change #1; #2; various images; reticulin stain demonstrates continuous basement membrane around glands (AFIP)
Adenomyoepithelial adenosis of breast
Also called apocrine adenosis or secretory adenosis (Stanford School of Medicine)
Apocrine adenosis is defined as adenosis with apocrine metaplasia in >50% of adenosis area
Uncommon
Appears to be a precursor to adenomyoepithelioma (Histopathology 1987;11:305, AJCP 1988;89:308, Virchows Arch A Pathol Anat Histopathol 1984;405:55)
May be premalignant, based on loss of heterozygosity, allelic imbalance (Cancer Detect Prev 2001;25:262) and clonality (Histopathology 2001;38:221)
Some believe these lesions have variable myoepithelial cells and are a form of microglandular adenosis (AJSP 2003;27:1052)
Case report: associated with adenocarcinoma (Pathol Int 1994;44:475)
Micro: multiple foci of haphazardly arranged ducts with eosinophilic granular secretions; resembles microglandular adenosis but with larger and more irregularly shaped glands, taller lining epithelial cells with eosinophilic granular cytoplasm and bland basal nuclei, identifiable myoepithelial cells; has infiltrative growth pattern; may have mild atypia; often associated with adenomyoepithelioma
Cytology: often highly cellular; cells have apocrine metaplasia with occasional prominent nucleoli and pleomorphism resembling carcinoma, but minimal hyperchromasia; naked nuclei are present (Diagn Cytopathol 2007;35:296)
Micro images: AFIP - appears infiltrative; ducts lined by apocrine cells with large nuclei and prominent nucleoli; cells have vacuolated cytoplasm, large nuclei and prominent nucleoli;
other - confined within a lobule; apocrine adenosis (“B”); expansion of lobular units with marked apocrine metaplasia #1; #2; #3; with sclerosing adenosis #1; #2; androgen receptor positive
apocrine adenosis with atypia - focal three-fold variation in nuclear size; cytologic atypia present
Positive stains: EMA, actin (myoepithelial cells), GCDFP-15 (AJSP 1993;17:99), androgen receptor (J Clin Pathol 1999;52:838), PAS for basement membrane (Mod Path 1993;6:318)
Negative stains: ER, PR
EM: distinct basal lamina present
DD: sclerosing adenosis with apocrine metaplasia, tubular adenosis, microglandular adenosis, apocrine carcinoma
Microglandular adenosis of breast
Also called microglandular hyperplasia
Rare; benign, although associated with carcinoma (AJSP 1986;10:237) and may evolve into carcinoma (Int J Surg Pathol 2000;8:303), often adenoid cystic carcinoma (AJSP 2003;27:1052)
Case reports: invasive carcinoma arising within microglandular adenosis (Archives 2003;127:77)
Treatment: complete excision to rule out invasion (AJSP 2008;32:544) and close followup, particularly if atypical features (AJSP 1983;7:137); may recur if incompletely excised
Gross: palpable mass or small localized lesion; infiltrative and ill defined; usually 3-4 cm
Micro: haphazardly infiltrating collection of small uniform, rounded, open glands with eosinophilic secretions, irregularly distributed in fibrous or adipose tissue; glands lined by single layer of cuboidal/flat cells with vacuolated/granular cytoplasm and bland nuclei, no apocrine snouts, no nucleoli, no/variable myoepithelial layer, but thick basement membrane
atypical microglandular adenosis: pleomorphic glands and microacini; budding glandular units and luminal bridging, mild cytologic atypia, reduced intraluminal secretions, occasional mitotic figures
Cytology: sparse cellularity, monotonous population of medium sized cells with vacuolated clear cytoplasm, round and uniform nuclei, small nucleoli; also clear cells that are solitary or clustered with spindly fibroblasts (Diagn Cytopathol 1993;9:72)
Micro images: haphazard glands apparently infiltrating stroma; ducts lined by single cells and containing secretory material #1; #2; small round, regular glands, some dilated, within adipose tissue; smooth round glands with bland nuclei and focally vacuolated cytoplasm surrounded by delicate fibrous tissue but no myoepithelium; fig 1-microglandular adenosis; fig 2-atypical microglandular adenosis (arrows point to atypical glands); microglandular adenosis with ALH; case report with associated invasive and intraductal carcinoma #1; #2
AFIP - multilayering of epithelium with granular cytoplasm; small round infiltrative glands #1; #2
Virtual slides: with microcalcifications; extensive; with invasive ductal carcinoma
Positive stains: CAM 5.2, AE1, S100 (Archives 2007;131:1397), p63 (secretory epithelium, Histopathology 2005;47:611), CK 8/18 and EGFR (AJSP 2008;32:544), PAS+ diastase resistant secretions; variable smooth muscle actin, vimentin, type IV collagen and laminin (around glands)
Negative stains: EMA, GCDFP-15, ER, PR, HER2, p53; low Ki-67
EM: thick basement membrane around epithelium; electron-lucent cytoplasm, sparse organelles (AJSP 1983;7:731)
DD: tubular carcinoma (stellate growth pattern, desmoplastic stroma, glands vary in size and shape with angulated “tear-drop” appearance; lined by cells with prominent apical snouts and without a surrounding basement membrane; EMA+, S100-, Archives 2007;131:1397), invasive ductal carcinoma with a microglandular adenosis pattern (Ann Diagn Pathol 2004;8:39), apocrine adenosis (larger glands lined by luminal tall columnar cells with apocrine features and surrounded by flat myoepithelial cells)
References: Stanford University
Confused with carcinoma by new pathologists
Mean age 30 years
Increased risk of cancer of 1.5 to 2x (Cancer 1989;64:1977); also coexists with cancer
Rarely involved by LCIS and may be mistaken for invasive carcinoma (Mod Path 1991;4:31)
Associated with clustered microcalcifications (mimics cancer in mammograms)
Adenosis tumor/nodular adenosis: palpable mass (AJR Am J Roentgenol 2000;175:31)
Myoepitheliosis: rare; sclerosing adenosis with predominance of myoepithelial cells, presents as multifocal microscopic lesions (AJSP 1991;15:554); cells may have longitudinal nuclear grooves
Case reports: occurrence in sentinel axillary nodes (Archives 2008;132:1439)
Gross: multinodular, cuts with increased resistance; gritty but no chalky yellow-white foci or streaks
Micro: low power diagnosis; increase in glandular elements plus stromal proliferation that distorts and compresses glands; maintains lobular architecture at low power with rounded and well defined nodules; more cellular centrally than peripherally; increased numbers of distorted and compressed acini, dilated at periphery; often microcalcifications, apocrine metaplasia
Two cell layers are present, but myoepithelial cells may vary from being prominent to indistinct; also intralobular fibrosis, proliferation of small ductules, elastosis and apocrine metaplasia; florid changes are associated with pregnancy; rarely penetrates walls of veins or perineural spaces; no necrosis, no pleomorphism
Cytology: moderate to markedly cellular, with small to large groups of benign epithelial cells in acinar sheets and scattered individual epithelial cells; also small foci of dense hyalinized stroma (Acta Cytol 2001;45:353, Diagn Cytopathol 2008;36:496)
Micro images: subgross; low power #1; #2; #3; #4; #5; #6; high power; small ducts with microcalcifications #1; #2; late stage with increasing fibrosis and decreasing acini #1; #2; sclerosed stroma; core biopsy with microcalcifications #1; #2; core biopsy with sclerosing adenosis and radial scar; adenosis tumor #1; #2; #3; #4; #5; sclerosing adenosis with features of microglandular adenosis; myoid differentiation #1; #2-smooth muscle actin; presence in sentinel nodes; HHF35; CK5/6 AFIP - ducts dilated at periphery; small ducts with microcalcifications #1; #2; retention of myoepithelial-type cells but loss of ductal epithelium; small bland ducts adjacent to nerve; with small intraductal papilloma; invagination into cystic duct; with LCIS #1; #2; #3; #4 (normal glands in upper right); with LCIS and microinvasion #1 (arrows); #2
Virtual slides: sclerosing adenosis with apocrine metaplasia; ALH involving sclerosing adenosis
Positive stains: myoepithelial cells - smooth muscle actin, p63, calponin, HHF35, CK 5/6; basement membrane (surrounds tubules) - laminin and type IV collagen
DD: invasive carcinoma (not lobular at low power, cells have marked atypia, no myoepithelial cells)
Uncommon benign breast lesion that may mimic invasive carcinoma or coexist with invasive or in-situ carcinoma (AJSP 1996;20:46)
Micro: haphazard proliferation of elongated tubules that are narrow, noncrowded, occasionally branching, not lobular; some tubules extend into fat; tubules contain basophilic or eosinophilic secretions and microcalcifications; tubules are lined by bland ductal cells and surrounded by myoepithelium; may be infiltrative similar to microglandular adenosis
Micro images: AFIP - mildly irregular tubules within stroma; tubules appear to branch in 3 dimensions; two cell layers
other - tubular adenosis with features of collagenous spherulosis
Positive stains: myoepithelium - HHF35, S100
DD: invasive carcinoma (tubular carcinoma), adenomyoepithelial adenosis (no tubular configuration), microglandular adenosis (no myoepithelial cells), sclerosing adenosis (lobular architecture, crowded tubules)
References: Stanford University
Benign (usually) tumors / tumor like-changes
Definition: proliferation of variable myoepithelial cells around small epithelial lined spaces
Somewhat uncommon
Mean age 60 years
Usually benign, although may recur locally; benign appearing tumors rarely metastasize to lung (Archives 2006;130:1349)
Page recommends that cases with malignant histology not be called adenomyoepithelioma but be defined by the histology of the malignant component (AJSP 2005;29:1294)
Case reports: cellular tumor (AJSP 1983;7:863), with collagenous spherulosis (J Clin Path 2004;57:83), intracystic tumor (Breast Cancer 2007;14:429); malignant adenomyoepithelioma #1 (Archives 2000;124:632); #2 (Archives 2004;128:235), #3 with matrix production (Pathol Res Pract 2007;203:599), #4 with malignant myoepithelial component and p53 mutation (Pathol Int 2006;56:211); #5 transforming to osteosarcoma and carcinoma and causing death (AJSP 1998;22:631)
Treatment: complete local excision; may recur with incomplete excision
Gross: small (mean 1-2 cm), firm, well circumscribed; may have satellite nodules
Gross images: unusually large bisected tumor with central cavity with bosselated contour (AFIP)
Micro: well circumscribed, may be encapsulated; proliferation of epithelial and myoepithelial elements; aggregated lobules of glands with tall lining epithelium with scant cytoplasm and hyperchromatic nuclei surrounded by myoepithelial cells with clear cytoplasm; glandular component is dominant; apocrine metaplasia may be present, also adenomyoepitheliomatous hyperplasia
Malignant appearing cases have local invasion, high mitotic rate, severe atypia (AJSP 1992;16:868)
Cytology: moderate to highly cellular with large clusters of epithelium and myoepithelium; myoepithelium appear as small clusters or dispersed cells with epithelioid morphology, intranuclear or intracytoplasmic vacuoles, often naked bipolar nuclei; tubular structures occasionally found; mild to moderate nuclear atypia present; metachromatic fibrillary stroma occasionally found; no mitotic figures, no necrosis; often classified incorrectly as fibroadenoma, suspicious for malignancy or malignant (Cancer 2006;108:250)
Micro images: proliferation of epithelial and myoepithelial elements #1; #2; #3; #4; #5; myoepithelial cells are difficult to identify; myoepithelial cells are calponin+ (fig I, description is under H)
AFIP - intraductal bands of pale myoepithelium separate adenomatous ductal epithelium; myoepithelial cells with clear cytoplasm crowd glandular epithelium and expand into stroma; overgrowth of myoepithelium in two nodules separated by stromal band; myoepithelial cells in small clusters have replaced most ductal elements; foci of glands with luminal secretions; isolated myoepithelial cells with clear vacuolated cytoplasm; transition between adenomatous and myomatous growth; AE1+ glandular cells (myoepithelial cells are negative); myoepithelial cells are focally actin+;
Adenomyoepithelioma of breast (continued)
Micro images - benign histology but malignant behavior: benign appearing tumors that metastasized to lung; lung metastases with benign histology-H&E, ER+, smooth muscle myosin heavy chain+
malignant histology: various images; S100+ in benign areas; keratin+ epithelial cells; fig A: biphasic growth with dark areas of hyperchromatic cells with high N/C ratio and pale zone of large polygonal pale cells with ill-defined cytoplasm and vesicular nuclei; fig B: mitotic figure (arrow); fig C: AE1-AE3 staining of epithelial component; fig D: S100 staining of myoepithelial component
Virtual slides: benign tumor with case report
Cytology images: branching groups of benign ductal and myoepithelial cells resemble fibroadenoma, inset shows tubular structures; metachromatic fibrillary stroma accompanying cells, inset-myoepithelial cells surround hyaline globule, resembling collagenous spherulosis (Pap stain); ductal cells shows moderate atypia (nuclear pleomorphism, irregular nuclear contours, occasional prominent nucleoli), arrow points to myoepithelial cell (Pap stain); Diff-Quik shows myoepithelial cells with vacuolated cytoplasm, spindled myoepithelial cells and naked bipolar nuclei, arrow points to inclusion in myoepithelial cell; myoepithelial cells as single cells with intact cytoplasm, some plasmacytoid, others are clear cells
Positive stains: epithelial component - keratin (AE1-AE3), CEA, variable ER; myoepithelial component - p63 (AJSP 2001;25:1054), S100
Negative stains: PR
Molecular: case report with t(8;16)(p23;q21) (Cancer Genet Cytogenet 2005;156:14)
DD: adenosis tumor, tubular adenoma, nipple adenoma, intraductal papilloma
References: Hum Path 1987;18:1232, Stanford University
May occur late in systemic amyloidosis, rheumatoid arthritis, myeloma, Waldenstrom’s macroglobulinemia
80% occur in right breast
Clinical examination needed to differentiate primary and secondary amyloid tumors
Rarely is confined to breast
Case reports: with myeloma (AJR Am J Roentgenol 2000;175:1590), rheumatoid arthritis (South Med J 2008;101:199), sclerosing lymphocytic lobulitis / diabetic mastopathy (Breast 2006;15:281), Sjogren’s syndrome (JBR-BTR 2006;89:313); amyloidosis/(bilateral masses (Archives 2004;128:e67)
Gross: 5 cm or less, firm, gray-white, opalescent
Micro: amorphous eosinophilic deposits in fat, stroma or vessels; may cause ductal atrophy, form rings around individual fat cells, have associated multinucleated giant cell reaction or osseous metaplasia (J Clin Path 2002;55:634)
Cytology: amorphous acellular material with scattered plasma cells, lymphocytes, stromal cells and epithelial cells; rare multinucleated giant cells; metachromatic by modified Wright’s stain (Diagn Cytopathol 2003;28:325)
Micro images: amyloid occurs in lobule (lower left) and as separate stromal nodule (upper right, AFIP); amyloid with osseous metaplasia; hyaline material and chronic inflammation; amyloidosis (bilateral breast masses) - fig 1: 1.7-cm, ill-defined mass containing coarse calcifications, fig 2: H&E, fig 3: Congo Red, fig 4: polarized light; various images
Cytology images: dense hyaline material and giant cells
Positive stains: Congo red (red-orange with apple green birefringence under polarized light), metachromatic with crystal violet
EM: straight, nonbranching, haphazard amyloid fibrils, 5-10 mm, mixed with collagen fibers
Definition: nodule composed of mature adipocytes, thin walled vessels and fibrin thrombi
May be cellular; adipose tissue component may be minimal
Usually subcutaneous nodules on extremities and trunks of young adults, rare in breast
Usually NO pain, unlike these tumors elsewhere
Case reports: 70 year old woman with breast mass (Radiology 2003;227:773), cellular angiolipoma (Breast J 2002;8:47, Mod Path 1993;6:497), multiple bilateral tumors (Aust NZ J Surg 1982;52:614)
Treatment: simple excision
Gross: encapsulated yellow nodule(s) up to 2 cm
Micro: well circumscribed lesion of mature adipose tissue and capillary sized vessels; hyaline thrombi in vessels; usually non-infiltrative; no necrosis, no atypia, no hemorrhage, no mitotic figures
Cytology: hypocellular, mature adipose tissue in hemorrhagic background; rare benign appearing spindled endothelial cells in clusters or strands resembling capillaries (Cancer 1999;87:359)
Micro images: mature adipose tissue and capillaries in fibrous stroma; anastomosing capillaries lined by inconspicuous endothelial cells (AFIP)
site unknown - mature adipose tissue and capillaries; capillary proliferation between adipocytes; soft tissue - mature adipose tissue and prominent vasculature (AFIP); prominent vascular thrombi (AFIP) #1; #2; #3
Definition: rare adenoma that is (a) composed exclusively of benign apocrine cells (homogeneous), (b) sharply demarcated from surrounding breast tissue; (c) contains only epithelial proliferative elements; and (d) has minimal supportive stroma
Case reports: simultaneous occurrence with invasive ductal carcinoma (Pathol Res Pract 2007;203:809), 45 year old man with 3 mm tumor (Archives 2003;127:1498), 47 year old woman (W V Med J 2008;104:16)
Micro: benign glands with abundant granular, eosinophilic cytoplasm, apical luminal blebs and decapitation secretion; may contain calcifications (Pathology 2001;33:149)
Micro images: apocrine adenoma #1; #2; fig 1: 3 mm subareolar density; fig 2: well circumscribed nodule of small eosinophilic glands; fig 3: uniform eosinophilic cells with apocrine snouts, consistent with decapitation secretion
DD: prominent apocrine changes as a part of fibrocystic changes, well differentiated apocrine carcinoma
References: Stanford University
Atypical or benign vascular proliferations post-radiation of breast
Develops after external radiotherapy for breast carcinoma, within field of radiation (AJCP 1994;102:757)
Mean age 61 years, develops 1-12 years (mean 6 years) after therapy in radiation field
May recur within radiation field (Cancer 2007;109:1584); may progress to angiosarcoma, particularly vascular type (see below, AJSP 2008;32:943)
May have lymphatic origin (Histopathology 1999;35:319)
Treatment: complete excision with careful followup for recurrence
Gross: one or more circumscribed papules, small vesicles or erythematous plaques, usually in irradiated field, median 0.5 cm; frequently multiple synchronous lesions with discoloration
Micro: relatively well circumscribed, anastomosing growth pattern of irregular slit-like vascular spaces dissecting dermal collagen but not extending into subcutis; lined by single layer of endothelial cells without atypia; often micropapillary tufts; no necrosis, no mitotic figures, no blood lakes; resembles benign lymphangioendothelioma or patch-stage Kaposi's sarcoma
Lymphatic type: predominantly thin walled, variably anastomosing lymphatics primarily in superficial dermis
Vascular type: predominantly small, irregularly dispersed, capillary type vessels, invested by pericytes, often blood filled, in superficial or deep dermis; associated with extravasated red blood cells or hemosiderin, minor lymphatic type component
Positive stains: CD31, D2-40 (lymphatic marker), variable CD34
DD: well differentiated angiosarcoma (may be part of morphologic continuum with atypical vascular lesions, J Am Acad Dermatol 2007;57:126), hobnail hemangioma, benign lymphangioendothelioma
References: AJSP 2002;26:328, AJSP 2005;29:983
Autosomal dominant syndrome of myxomas / myxoid lesions in skin, subcutis and breast (AJSP 1991;15:713), spotty pigmentation present from birth, endocrine overactivity, psammomatous melanotic schwannomas, and intraductal breast adenoma composed of long, straight, narrow, roughly parallel tubules with distinct epithelial and myoepithelial cells (AJSP 1991;15:722)
Linked to PRKARIA gene at 17q23-24 (found in 46% of Carney’s syndrome cases) and CNC2 gene at 2p16 (J Med Genet 2003;40:268)
References: eMedicine, Atlas of Genetics and Cytogenetics
Rare
See also Soft Tissue Chapter-chondroid lipoma
Case reports: 66 year old woman (Archives 1977;101:149), detected by mammography (Archives 1989;113:369)
Gross: well demarcated, islands of cartilage project from cut surface, resembles fibroadenoma (Breast 2006;15:425)
Micro: mature fibrous stroma, adipose tissue, breast ducts, mature cartilage
Micro images - s