Breast





Subareolar Abscess


Clinical Features





  • Develops in lactating and nonlactating breasts, usually in nonlactating breasts



  • Found in women of any age, typically during reproductive years



  • Can be seen after reduction mammoplasty



  • May resemble inflammatory carcinoma clinically



  • May present as a painful, erythematous, and edematous breast



  • Organisms associated with abscess formation include bacteria such as Staphylococcus, Proteus, Bacteroides , and Streptococcus species



  • Tuberculosis may be the cause in endemic areas



  • May have a tendency to recur and to form extended fistulas



Gross Pathology





  • Incision and drainage of acute lesion yields purulent drainage



  • Chronic lesion may show development of a fistula from the abscess cavity to the overlying skin



Histopathology





  • Extensive neutrophilic inflammatory infiltrate associated with surrounding breast ducts ( Figure 13.1 )




    Figure 13.1


    Subareolar abscess.

    Dilated ductal structures lined by metaplastic squamous epithelium are noted. The lumens contain keratinous and cellular debris. Mixed inflammatory cells are seen in the background.



  • Involved ducts show extensive squamous metaplasia, with cell debris and keratin plugs in lactiferous ducts



  • Foreign-body giant cell reaction may be seen



Special Stains and Immunohistochemistry





  • Special stains for microorganisms (Gomori methenamine silver [GMS], periodic acid–Schiff [PAS], and acid-fast bacillus [AFB]) are negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Plasma Cell Mastitis





  • Inflammation consists primarily of plasma cells with admixed lymphocytes rather than neutrophils



Granulomatous Lobar Mastitis





  • Granulomatous inflammation in and around breast lobules



Pearls





  • Incision, drainage, and course of antibiotics is first-line treatment



  • May require surgical resection of nipple and major duct system if sinus tract develops or in cases that repeatedly recur





Selected References




  • Dabbs D.J., Weidner N.: Infections of the breast.Dabbs D.J.Breast Pathology.2017.ElsevierPhiladelphia, PA:



  • Ergin A.B., Cristofanilli M., Daw H.: Recurrent granulomatous mastitis mimicking inflammatory breast cancer. BMJ Case Rep 2011; bcr0720103156



  • Li S., Grant C.S., Degnim A., Donohue J.: Surgical management of recurrent subareolar breast abscesses: Mayo Clinic experience. Am J Surg 2006; 192: pp. 528-529.



  • Versluijs-Ossewaarde F.N., Roumen R.M., Goris R.J.: Subareolar breast abscesses: characteristics and results of surgical treatment. Breast J 2005; 11: pp. 179-182.


Plasma Cell Mastitis


Clinical Features





  • Typically found in women in second to fourth decades



  • Usually found several years (average interval, 4 years) after cessation of lactation



  • Presents with acute onset of breast tenderness, redness, and nipple discharge



  • Following acute episode, a hard, palpable mass often remains mimicking carcinoma



  • May be associated with axillary lymphadenopathy



Gross Pathology





  • Large, dilated ducts containing thick, tan-yellow secretion



Histopathology





  • Extensive lymphoplasmacytic infiltrate in and around ducts and lobules ( Figure 13.2 )




    Figure 13.2


    Plasma cell mastitis.

    Dense lymphoplasmacytic infiltrate is noted around a lobular unit. Xanthomatous reaction is also evident.



  • Hyperplasia of ductal epithelium often seen



  • Areas of necrosis may be present



  • Scattered granulomas and histiocytes (xanthomatous reaction) are common



Special Stains and Immunohistochemistry





  • Special stains for microorganisms (GMS, PAS, AFB) are negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Granulomatous Lobar Mastitis





  • Consists primarily of granulomatous inflammation with a minor component of plasma cells



Tuberculous Mastitis





  • Granulomatous inflammation with caseating necrosis



  • May occasionally be positive for AFB



Pearls





  • Clinically mimics carcinoma



  • May be diagnosed by fine-needle aspiration, but hyperplastic ductal epithelium should not be mistaken for carcinoma



  • Excisional biopsy is curative and avoids possible skin ulceration or fistula formation





Selected References




  • Baslaim M.M., Khayat H.A., Al-Amoudi S.A.: Idiopathic granulomatous mastitis: a heterogeneous disease with variable clinical presentation. World J Surg 2007; 31: pp. 1677-1681.



  • Ming J., Meng G., Yuan Q., et. al.: Clinical characteristics and surgical modality of plasma cell mastitis: analysis of 91 cases. Am Surg 2013; 79: pp. 54-60.



  • Tavassoli F.A.: Plasma cell mastitis.Pathology of the Breast.1999.Appleton & LangeStamford, CT:pp. 792-793.


Granulomatous Lobar Mastitis (Granulomatous Mastitis)


Clinical Features





  • Etiology unknown, but has been linked to pregnancy, hormonal therapy, infection with Corynebacterium, and autoimmune disorders



  • Appears after pregnancy



  • Usually presents about 2 years postpartum; may be seen many years later



  • Typically presents as a distinct, hard breast mass



  • Clinically mimics carcinoma



Gross Pathology





  • Firm to hard breast mass, usually located peripherally



  • Mass often has a nodular architecture



  • Measures up to 8 cm; usually 4 to 6 cm



Histopathology





  • Granulomatous inflammation in and around breast lobules (granulomatous lobulitis)



  • Inflammatory reaction in lobules consisting of granulomas, multinucleated giant cells, plasma cells, and eosinophils ( Figure 13.3 )




    Figure 13.3


    Granulomatous mastitis.

    The granulomatous inflammation distorts the lobular unit and shows giant cells.



  • Fat necrosis and small abscess formation occasionally present



Special Stains and Immunohistochemistry





  • Special stains for microorganisms (GMS, PAS, AFB) are negative



  • Cytokeratin or other epithelial markers can help identify or rule out carcinoma obscured by florid granulomatous reaction



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Plasma Cell Mastitis





  • Marked plasma cell infiltrate in and around lobules



  • Associated ductal epithelial hyperplasia is often seen



Tuberculous Mastitis





  • Granulomatous inflammation with caseating necrosis, possibly AFB positive



Breast Abscess





  • Well-defined aggregates of acute inflammatory cells (abscess formation)



Sarcoidosis





  • Primary sarcoid of the breast is uncommon



  • Noncaseating, sarcoid-type granulomas typically are diffuse and found between breast lobules



Cat Scratch Disease





  • Granulomatous reaction in lymph nodes that may involve intramammary lymph nodes



Pearls





  • Appears after pregnancy



  • Clinically mimics carcinoma



  • Classic histologic picture is an inflammatory reaction in and around lobules with numerous multinucleated giant cells



  • May recur and require many surgical treatments





Selected References




  • Gautier N., Lalonde L., Tran-Thanh D., et. al.: Chronic granulomatous mastitis: imaging, pathology and management. Eur J Radiol 2013; 82: pp. e165-e175.



  • Lacambra M., Thai T.A., Lam C.C., et. al.: Granulomatous mastitis: the histological differentials. J Clin Pathol 2011; 64: pp. 405-411.



  • Marriott D.A., Russell J., Grebosky J., et. al.: Idiopathic granulomatous lobular mastitis masquerading as a breast abscess and breast carcinoma. Am J Clin Oncol 2007; 30: pp. 564-565.



  • Wolfrum A., Kümmel S., Theuerkauf I., et. al.: Granulomatous mastitis: a therapeutic and diagnostic challenge. Breast Care 2018; 13: pp. 413-441.



  • Yau F.M., Macadam S.A., Kuusk U., et. al.: The surgical management of granulomatous mastitis. Ann Plast Surg 2010; 64: pp. 9-16.


Fat Necrosis


Clinical Features





  • May present with a painless palpable breast mass or with breast tenderness



  • May clinically and mammographically mimic carcinoma



  • Believed to be related to trauma, most commonly previous breast surgery; other possibly related etiologic factors include cyst aspiration, radiotherapy, warfarin use, breast infection



Gross Pathology





  • Typically of small size (<2 cm)



  • Single or multiple firm, round or irregular masses



  • Tan-yellow streaks and often areas of dense fibrosis



  • Areas of hemorrhage may be seen



  • Cystic degeneration and calcification may develop



Histopathology





  • Abundant lipid-laden and foamy macrophages surrounding small cystic spaces



  • Foreign-body giant cells and chronic inflammation (lymphoplasmacytic infiltrate) are typical ( Figure 13.4 )




    Figure 13.4


    Fat necrosis.

    Fat vacuoles surrounded by chronic inflammatory cells and giant cells.



  • Fibroblastic proliferation and collagen deposition seen in older lesions



  • Scar formation and peripheral calcification are late manifestations



Special Stains and Immunohistochemistry





  • CD68: histiocytes are positive



  • S-100 protein negative, although it can stain the fat



  • Cytokeratin negative



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Infiltrating Ductal Carcinoma





  • Neoplastic cells show cytologic atypia and increased mitotic activity and lack vacuolated cytoplasm seen in cells of fat necrosis



  • Tumor cells are cytokeratin positive and CD68 negative



Granular Cell Tumor





  • Nests or sheets of polygonal cells with abundant eosinophilic granular cytoplasm



  • Lacks associated giant cells and lymphoplasmacytic infiltrate



  • Granular cells are S-100 protein positive



Pearls





  • History of trauma found in greater than 50% of cases



  • Fat necrosis is almost always found surrounding previous biopsy cavity



  • Skin changes that mimic carcinoma may be seen



  • Mammographically, peripheral calcification, described as eggshell calcifications , may be seen





Selected References




  • Miller J.A., Festa S., Goldstein M.: Benign fat necrosis simulating bilateral breast malignancy after reduction mammoplasty. South Med J 1998; 91: pp. 765-767.



  • Tan P.H., Lai L.M., Carrington E.V., et. al.: Fat necrosis of the breast: a review. Breast 2006; 15: pp. 313-318.



  • Trombetta M., Valakh V., Julian T.B., et. al.: Mammary fat necrosis following radiotherapy in the conservative management of localized breast cancer: does it matter?. Radiother Oncol 2010; 97: pp. 92-94.


Diabetic Mastopathy


Clinical Features





  • Most cases found in females with type 1 diabetes mellitus, with exogenous insulin use



  • Widely reported in premenopausal women, with broad age distribution (teenage years up to fifth or sixth decade)



  • Bilateral in about 50% of cases



  • Presenting complaint is usually a hard, nontender, freely mobile breast mass



  • Mammographic findings are nonspecific



Gross Pathology





  • Hard, homogeneous, white-gray breast tissue



  • Typically no distinct tumor is identified



Histopathology





  • Dense, collagenous stroma (keloid-like) with proliferation of benign-appearing fibroblasts ( Figure 13.5 )




    Figure 13.5


    Diabetic mastopathy.

    Atrophic duct surrounded by dense collagenous stroma.



  • No cytologic atypia



  • Lymphocytic infiltrate around small blood vessels, in and around lobules and ducts



  • Vascular calcifications may be present



Special Stains and Immunohistochemistry





  • Lymphocytes are typically CD20 positive (B-cell lineage)



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Granulomatous Lobar Mastitis





  • Granulomatous inflammation in and around breast lobules



Breast Abscess





  • Prominent neutrophilic inflammatory infiltrate



Fibrocystic Change





  • Shows heterogeneous histologic features that may include cyst formation, apocrine metaplasia, adenosis, and ductal epithelial hyperplasia



Pearls





  • Contributory factor may be alterations in collagen metabolism that exist in diabetic patients



  • Self-limited condition primarily affecting premenopausal women



  • Excisional biopsy is adequate treatment; rare cases have recurred





Selected References




  • Chan C.L., Ho R.S., Shek T.W., et. al.: Diabetic mastopathy. Breast J 2013; 19: pp. 533-538.



  • Dorokhova O., Fineberg S., Koenigsberg T., et. al.: Diabetic mastopathy, a clinicopathological correlation of 34 cases. Pathol Int 2012; 62: pp. 660-664.



  • Fong D., Lann M.A., Finlayson C., et. al.: Diabetic (lymphocytic) mastopathy with exuberant lymphohistiocytic and granulomatous response: a case report and review of the literature. Am J Surg Pathol 2006; 30: pp. 1330-1336.



  • Hunfeld K.P., Bassler R.: Lymphocytic mastitis and fibrosis of the breast in long-standing insulin-dependent diabetics: a histopathologic study on diabetic mastopathy and report of ten cases. Gen Diagn Pathol 1997; 143: pp. 49-58.


Juvenile or Virginal Hypertrophy


Clinical Features





  • Typically occurs in young girls (<16 years)



  • History of rapid growth of one or both breasts to massive, persistent proportions; overlying skin hyperemia and necrosis can occur



  • Benign findings on mammography



Gross Pathology





  • Diffuse process involving one or both breasts



  • Discrete masses are not seen



Histopathology





  • Characterized by proliferation of connective tissue and ductal structures ( Figure 13.6 )




    Figure 13.6


    Juvenile hypertrophy.

    Ductal structures surrounded by loose proliferating connective tissue.



  • Lacks normal lobular development



  • May be histologically identical to gynecomastia



Special Stains and Immunohistochemistry





  • Noncontributory



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Juvenile Fibroadenoma





  • Discrete nodules measuring an average of 2 to 3 cm in diameter that are able to be “shelled out” from surrounding breast tissue



  • Hypercellular collagenous stroma with proliferation of slitlike, branching ducts



Pearls





  • Cases in which each breast weighed more than 17 pounds have been reported



  • Histologically resembles gynecomastia of the male breast



  • May be related to hypersensitivity of mammary tissue to estrogen stimulation that occurs during puberty



  • Usually sporadic, but familial cases have been described; PTEN gene mutation has been linked to virginal hypertrophy with increased risk for malignant transformation





Selected References




  • Govrin-Yehudain J., Kogan L., Cohen H.I., et. al.: Familial juvenile hypertrophy of the breast. J Adolesc Health 2004; 35: pp. 151-155.



  • Koves I.H., Zacharin M.: Virginal breast hypertrophy of an 11 year old girl. J Pediatr Child Health 2007; 43: pp. 315-317.



  • Netscher D., Mosharrafa A.M., Laucirica R.: Massive asymmetric virginal breast hypertrophy. South Med J 1996; 89: pp. 434-437.


Granular Cell Tumor


Clinical Features





  • Typically found in premenopausal women



  • Presents as a firm, painless, solitary mass more frequently in the upper inner quadrant



  • Mimics carcinoma on mammography



Gross Pathology





  • Firm, hard mass with well-circumscribed or occasionally infiltrative borders



  • Typically measures less than 5 cm



  • Gray-white or tan cut surface



  • May grossly mimic infiltrating carcinoma



Histopathology





  • Composed of nests or sheets of polygonal cells with abundant eosinophilic cytoplasmic granules



  • Cells have uniform, round nuclei with open chromatin and prominent nucleoli



  • Occasional mitotic figures may be seen



  • Infiltrative growth pattern; often surrounds nerves and infiltrates adipose tissue ( Figure 13.7 )




    Figure 13.7


    Granular cell tumor.

    Microscopically, the tumor cells infiltrate the breast parenchyma in small nests separated by delicate fibrous bands.



  • Surface epithelium may show pseudoepitheliomatous hyperplasia



Special Stains and Immunohistochemistry





  • S-100 protein: highlights cytoplasmic granularity with strong cytoplasmic and nuclear staining



  • CD68 is positive



  • Carcinoembryonic antigen (CEA): diffuse immunoreactivity



  • Calretinin, inhibin, nestin, SOX10, NSE, CD56 positive



  • Cytokeratin and epithelial membrane antigen (EMA) negative



  • Actin, myoglobin, desmin negative



Other Techniques for Diagnosis





  • Electron microscopy demonstrates myelin figures and numerous lysosomes



Differential Diagnosis


Histiocytic Lesions, Including Fat Necrosis and Mammary Duct Ectasia





  • Granular cell tumor is usually not immunoreactive with histiocyte-associated antigens, such as α 1 -antitrypsin and α 1 -antichymotrypsin, but reactivity for CD68 is seen



Apocrine Carcinoma





  • Tumor cells are large, with pleomorphic nuclei and prominent nucleoli



  • Typically shows an associated intraductal component



  • Positive for cytokeratin



Metastatic Neoplasms, Including Oncocytic Renal Cell Carcinoma, Melanoma, and Alveolar Soft Part Sarcoma





  • Malignant histologic features, along with panel of immunohistochemical stains, including cytokeratin, EMA (positive in renal cancer), MART-1, HMB-45 (positive in melanoma), and myoglobin (positive in alveolar sarcoma), help in the differential diagnosis



Pearls





  • Virtually always benign; only rare reports of metastasis



  • Eosinophilic cytoplasmic granules are due to abundant lysosomes



  • Treated by wide local excision; may recur if not completely resected





Selected References




  • Gavriilidis P., Michalopoulou I., Baliaka A., et. al.: Granular cell breast tumour mimicking infiltrating carcinoma. BMJ Case Rep 2013; bcr2012008178



  • Lara M.C., Herera A.M., Cardoso R.T., et. al.: Granular cell tumor in breast. Breast Cancer 2017; 9: pp. 245-248.



  • Mátrai Z., Langmár Z., Szabó E., et. al.: Granular cell tumour of the breast: case series and review of the literature. Eur J Gynaecol Oncol 2010; 31: pp. 636-640.


Fibrocystic Changes


Clinical Features





  • Most common condition involving the female breast



  • Affects primarily premenopausal women (third to fifth decades)



  • Bilateral and multifocal



  • Irregular, firm, and nodular breast tissue with discrete lumps



  • Breasts often tender



  • Breast nodularity typically fluctuates with the menstrual cycle



Gross Pathology





  • Irregular, rubbery, fibrotic breast tissue



  • Macroscopic cysts containing clear or turbid fluid often seen



  • Blue-domed cysts may be present



Histopathology


See Figures 13.8 to 13.10 .




Figure 13.8


Fibrocystic changes characterized by cyst formation, stromal fibrosis, and sclerosing adenosis.



Figure 13.9


Fibrocystic changes with columnar cell lesions.

A, Dilated acini showing columnar cell change are lined by two cell layers with occasional apical snouts, luminal secretions, and no atypia. Distended acini showing ( B ) columnar cell change and ( C ) columnar cell hyperplasia with cytologic atypia (flat epithelial atypia) are lined by more than two layers, with occasional papillary formation and cell atypia.



Figure 13.10


A, Apocrine metaplasia. Dilated ducts lined by metaplastic apocrine cells. The cells are columnar and have granular pink cytoplasm. B, Ductal hyperplasia without atypia. The ductal spaces are distended by a solid proliferation of hyperplastic ductal cells. Notice prominent fenestrations with variable size of the secondary lumens.


Cyst Formation





  • Variably sized cysts lined by flattened or cuboidal epithelial cells



Stromal Fibrosis





  • Dense periductal and perilobular fibrosis



Apocrine Metaplasia





  • Cysts lined by large, polygonal cells with abundant granular, eosinophilic cytoplasm and small, hyperchromatic nuclei



Sclerosing Adenosis





  • Multiple well-defined foci are usually present



  • Proliferation of attenuated ductules with preservation of the lobular configuration



  • Increased stromal and myoepithelial cells



  • Microcalcifications are often seen in ducts or stroma



Epithelial Hyperplasia without Atypia (Usual Ductal Hyperplasia)





  • Proliferation of ductal cells forming duct lumens filled with a heterogeneous population of round to oval cells



  • The nuclei of these cells grow, creating a streaming pattern



  • Irregular, slitlike fenestrations are often seen at the periphery of the ducts



  • Cells can grow as bands that cross the lumen of the duct



Columnar Cell Lesions





  • Enlarged acini of terminal ductal lobular units (TDLUs) lined by columnar cells with occasional luminal secretions and calcification




    • Columnar cell change (CCC)



    • Columnar cell hyperplasia (CCH)



    • Flat epithelial atypia (CCC and CCH with cytologic atypia)




      • Distended acini with undulating borders; up to two epithelial layers; ovoid nuclei oriented perpendicular to basement membrane and inconspicuous nucleoli; infrequent mitosis; apical snouts may be seen with occasional luminal secretions and calcification



      • No nuclear atypia is seen



      • More than two cell layers with papillary formation; apical snouts, secretions, and calcifications are common



      • Acini with rigid contours, round nuclei with nucleoli not oriented perpendicular to basement membrane, occasional mitosis; epithelial cells in three to five layers with cytologic atypia





Special Stains and Immunohistochemistry





  • ER, PR, BCL-2, low molecular weight keratin (CK8, 18, 19 positive in columnar cell lesions [CCL])



  • Negative for p53, C-erb-B2 (HER-2-neu), and high molecular weight keratin (CK5/6, CK14, 34beta E12)



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Fibromatosis





  • Greater cellularity composed of elongated spindle cells



  • Lacks cyst formation and other features that characterize fibrocystic changes



Atypical Ductal Hyperplasia or Ductal Carcinoma in Situ





  • Shows greater cytologic atypia and complex architectural changes than CCLs with atypia (flat epithelial atypia)



Pearls





  • May clinically mimic carcinoma



  • Most common diagnosis made after lumpectomy (>50% of all surgical procedures involving the breast)



  • Typically displays several features, including cyst formation, apocrine metaplasia, fibrosis, chronic inflammation, and epithelial hyperplasia without atypia



  • CCLs show 16q loss; may represent early lesion of low-grade ductal carcinoma in situ (DCIS)



  • Believed to be related to hormonal imbalance involving estrogen and progesterone; oral contraceptives decrease risk for fibrocystic changes



  • Sclerosing adenosis is associated with a slight (1.5 to 2 times) increased risk for carcinoma



  • No increased risk for carcinoma associated with apocrine metaplasia, stromal fibrosis, or mild ductal epithelial hyperplasia without atypia; florid ductal hyperplasia without atypia increases risk for carcinoma slightly (1.5 to 2 times)





Selected References




  • Aulmann S., Braun L., Mietzsch F., et. al.: Transitions between flat epithelial atypia and low-grade ductal carcinoma in situ of the breast. Am J Surg Pathol 2012; 36: pp. 1247-1252.



  • Biggar M.A., Kerr K.M., Erzetich L.M., et. al.: Columnar cell change with atypia (flat epithelial atypia) on breast core biopsy-outcomes following open excision. Breast J 2012; 18: pp. 578-581.



  • Ellis I.O.: Intraductal proliferative lesions of the breast: morphology, associated risk and molecular biology. Mod Pathol 2010; 23: pp. S1-S7.



  • Logullo A., Nimir C.: Columnar cell lesions of the breast: a practical review for the pathologist. Surg Exp Pathol 2019; 2:



  • Sudarshan M., Meguerditchian A.N., Mesurolle B., et. al.: Flat epithelial atypia of the breast: characteristics and behaviors. Am J Surg 2011; 201: pp. 245-250.


Adenosis


Clinical Features





  • Primarily affects premenopausal women (third and fourth decades)



  • Typically found in association with fibrocystic changes but may form solitary firm masses mimicking cancer



  • May be found in biopsy material removed for suspicious or indeterminate microcalcifications



Gross Pathology





  • Findings are often those of fibrocystic changes with areas of fibrosis and cyst formation



  • Florid adenosis tumors are well circumscribed; sclerotic tumors tend to be less well defined at borders



  • Lesions with abundant microcalcifications have a gritty cut surface



Histopathology


See Figure. 13.11 .




  • Usually consists of a circumscribed, benign proliferation of ductal structures



  • Ducts have an oval or elongated contour



  • Well-defined epithelial and myoepithelial layers



  • Microcalcifications are often seen



  • Increase in cell size, but no evidence of nuclear pleomorphism, normal mitoses, focal necrosis, or infarction can be seen in florid adenosis, especially during pregnancy and lactation



  • Sclerosing adenosis can involve nerves



  • Several patterns and variants of adenosis exist




    • Sclerosing adenosis (most common variant)



    • Apocrine adenosis



    • Microglandular adenosis (rare variant)




      • Multiple well-defined foci are usually present



      • Proliferation of attenuated ductules with preservation of the lobular configuration



      • Increased stromal and myoepithelial cells



      • Dense stroma surrounding ducts



      • Microcalcifications are often seen



      • Ductule proliferation with extensive apocrine metaplasia



      • Cells with large nucleolus



      • Haphazard arrangement of small, round ductules lacking lobular architecture that simulate an infiltrative pattern



      • Background shows hypocellular, collagenous stroma



      • Proliferating ducts often extend around normal breast ducts and lobules and may extend into adjacent adipose tissue



      • Duct lumens contain a colloid-like eosinophilic, secretory material (PAS positive)



      • Bland cytologic features with cells typically showing clear or vacuolated cytoplasm and rare mitotic figures



      • Atypical microglandular adenosis has foci of both typical adenosis and areas of more complex structure and cytologic atypia



      • Myoepithelial layer is absent (negative for S-100 protein, smooth muscle actin [SMA], smooth muscle myosin heavy-chain, and p63)



      • Positive for collagen IV



      • Usually negative for EMA and estrogen receptor (ER)





  • Adenosis tumor: grossly recognized mass formed by numerous adjacent foci of adenosis




Figure 13.11


A, Sclerosing adenosis. Well-circumscribed area of closely packed ducts retaining a lobular configuration. B, Sclerosing adenosis showing dense collagenous stroma between the proliferating tubules. Notice multiple microcalcifications in the tubules. C, Microglandular adenosis. Proliferation of tubules lacking lobular architecture in a dense collagenous background.


Special Stains and Immunohistochemistry





  • Cytokeratin, S-100, and cathepsin D highlight epithelial cells of microglandular adenosis



  • SMA, S-100, smooth muscle myosin heavy chain, and p63 highlight myoepithelial cell layer



  • PAS, laminin, and collagen IV highlight basement membrane of sclerosing adenosis



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Infiltrating Tubular Carcinoma





  • Haphazardly arranged ducts with angulated, open lumens and bridges of epithelial cells



  • Absent myoepithelial layer (also absent in microglandular adenosis)



  • Lumens lack eosinophilic secretions



  • Lining cells have eosinophilic cytoplasm and often show apical snouts



  • Reactive, fibroblastic stroma with desmoplasia often seen



  • Often associated with an intraductal carcinoma component



  • Usually positive for EMA and ER



Infiltrating Lobular Carcinoma





  • Classically shows small, uniform, rounded cells infiltrating in single-file lines or alveolar pattern



  • Lacks lobular configuration and myoepithelial cell layer (similar to microglandular adenosis)



Pearls





  • Classically sclerosing adenosis is a ductule proliferation that maintains a lobular architecture



  • Myoepithelial cell proliferation in sclerosing adenosis is helpful to distinguish from carcinoma



  • Microglandular adenosis is often difficult to distinguish from tubular carcinoma; best distinguishing features include the shape of the ductules and the stromal characteristics



  • Adenosis has been shown to be associated with a slight increased risk for carcinoma (1.5 to 2 times)





Selected References




  • Foschini M., Eusebi V.: Microglandular adenosis of the breast: a deceptive and still mysterious benign lesion. Hum Pathol 2018; 82: pp. 1-9.



  • Salarieh A., Sneige N.: Breast carcinoma arising in microglandular adenosis: a review of the literature. Arch Pathol Lab Med 2007; 131: pp. 1397-1399.



  • Seidman J.D., Ashton M., Lefkowitz M.: Atypical apocrine adenosis of the breast: a clinicopathologic study of 37 patients with 8.7 year follow up. Cancer 1996; 77: pp. 2529-2537.



  • Shin S.J., Simpson P.T., Da Silva L., et. al.: Molecular evidence for progression of microglandular adenosis (MGA) to invasive carcinoma. Am J Surg Pathol 2009; 33: pp. 496-504.



  • Wen Y.H., Weigelt B., Reis-Filho J.S.: Microglandular adenosis: a non-obligate precursor of triple-negative breast cancer?. Histol Histopathol 2013; 28: pp. 1099-1108.


Radial Sclerosing Lesion and Radial Scar


Clinical Features





  • Uncommon before 30 years of age



  • Typically small and therefore usually nonpalpable but may form palpable masses



  • Usually an incidental finding; associated with adenosis and fibrocystic changes



  • Mammographically shows a dense central radiolucent zone with thin, linear densities radiating outward; microcalcifications may be seen



  • Can mimic carcinoma on mammography



  • In many patients, this lesion is multifocal or bilateral; clustering of scars may occur



Gross Pathology





  • Typically of small size, rarely larger than 1 cm ( radial scar refers to lesions <1 cm; complex sclerosing lesion describes lesions >1 cm)



  • Shows irregular, stellate, dense fibrotic tissue; may grossly mimic carcinoma



Histopathology





  • Pseudoinfiltrative lesions



  • Central collagenous scar showing fibrosis and elastosis, with entrapped ducts showing dual epithelial and myoepithelial layer; basement membrane intact ( Figure 13.12 )




    Figure 13.12


    Radial scar.

    Central collagenous scar surrounded by proliferating ducts in a radial pattern resembling sclerosing adenosis.



  • Epithelial proliferation with stellate or radial arrangement of ductules resembling sclerosing adenosis



  • Commonly seen fibrocystic changes, including ductal hyperplasia, duct ectasia, adenosis, and papillomatosis surrounding fibrotic zone



  • Ducts may show squamous metaplasia



  • Perineural infiltration by benign ducts may be seen



  • Necrosis is rare, but small areas can be present



  • Ducts should not infiltrate into adjacent adipose tissue



Special Stains and Immunohistochemistry





  • p63, CD10, SMA, and S100 highlight myoepithelial layer



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Tubular Carcinoma





  • Ducts do not have a myoepithelial cell layer



  • Often infiltrates into surrounding fatty tissue



Pearls





  • Most commonly seen in association with adenosis



  • Can grossly and histologically mimic carcinoma



  • Presence of a myoepithelial layer and lack of infiltration are the best distinguishing characteristics



  • Carcinoma has been seen to arise in a background of a radial scar



  • Believed to be benign but associated with atypia and malignancy; radial scar may be an independent risk factor for the development of carcinoma





Selected References




  • Andacoglu O., Kanbour-Shakir A., Teh Y.C., et. al.: Rationale of excisional biopsy after the diagnosis of benign radial scar on core biopsy: a single institutional outcome analysis. Am J Clin Oncol 2013; 36: pp. 7-11.



  • Eusebi V., Millis R.R.: Epitheliosis, infiltrating epitheliosis, and radial scar. Semin Diagn Pathol 2010; 27: pp. 5-12.



  • Ha S., Cha J.H., Shin H., et. al.: Radial scars/complex sclerosing lesions of the breast: radiologic and clinicopathologic correlation. BMC Med Imaging 2018; 18: pp. 39.



  • Sanders M.E., Page D.L., Simpson J.F., et. al.: Interdependence of radial scar and proliferative disease with respect to invasive breast carcinoma risk in patients with benign breast biopsies. Cancer 2006; 1: pp. 1453-1461.



  • Tóth D., Sebő É., Sarkadi L., et. al.: Role of core needle biopsy in the treatment of radial scar. Breast 2012; 21: pp. 761-763.


Intraductal Papilloma (Solitary and Multiple)


Lesions characterized by an overgrowth of epithelial and myoepithelial cells that surround fibrovascular stalks


Clinical Features


Solitary Papilloma





  • Typically arises from lactiferous ducts in central breast tissue (beneath the areola) and often presents with serous or bloody nipple discharge



  • Usually found in women in their fifth or sixth decade



Multiple Papillomas





  • Multiple papillary masses typically located in peripheral breast tissue in contiguous branches of the ductal system



  • Occurs in younger women (40s and early 50s)



  • Occurs far less frequently than solitary papillomas



Gross Pathology





  • Large papillomas may be visible in the lumen of a dilated or cystic duct



  • Palpable lesions typically measure 2 to 3 cm, but cystic lesions can be larger than 10 cm



Histopathology





  • Organized papillary proliferation of ductal epithelium on a frond-forming fibrovascular core or stroma ( Figure 13.13A and B )




    Figure 13.13


    Intraductal papilloma.

    A, Dilated duct showing papillary proliferation on a sclerotic fibrovascular core. B, Distended duct showing a papillary lesion with a delicate fibrovascular core. C, Multiple intraductal papillomas. Distended ducts showing multiple papillary lesions.



  • Any degree of epithelial hyperplasia of the usual type may be seen



  • Fusion of papillae often results in glandlike spaces or solid areas



  • Presence of a myoepithelial cell layer in papillae and around glandular spaces, although it can be focally absent



  • Papillomas may show apocrine, squamous, mucinous, clear cell, or sebaceous metaplasia



  • Sclerosis of the cores with entrapment of ductal epithelium may occur and may be mistaken for invasive carcinoma



  • Infarction associated with torsion of the cores may happen, hindering evaluation of atypia and malignancy




    • Solitary papilloma




      • Papillae with single layer of cuboidal to columnar epithelium; focal epithelial hyperplasia may be seen



      • Typically shows minimal cellular atypia and rare mitotic activity



      • May show extreme distortion and fusion of papillary fronds (solid intraductal papilloma) or marked sclerosis (sclerosing papilloma)




    • Multiple papillomas




      • Multiple papillomas with involvement of more than one duct system or multiple foci within a single duct system (see Figure 13.13C )



      • Arise in terminal duct lobular units and may extend into terminal



      • May show prominent epithelial hyperplasia



      • Atypia may develop with papillae lined by pseudostratified, elongated epithelial cells




    • Atypical papilloma (papilloma with atypia, papilloma with atypical ductal hyperplasia [ADH]) and papilloma with DCIS




      • Papillomas with foci of epithelial proliferation with full architectural and cytologic criteria for the diagnosis of ADH or DCIS



      • Papillomas with non-high-grade DCIS when lesion is larger than 3 mm



      • Papillomas with ADH (atypical papillomas) when lesion is smaller than or equal to 3 mm



      • DCIS most often of low or intermediate nuclear grade with solid, cribriform, or micropapillary patterns; small necrotic foci may be present



      • Focal loss or reduction of myoepithelial cells in the ADH and DCIS foci



      • Presence of large atypical or higher-grade lesion foci or necrosis should prompt designation of carcinoma in situ arising within a papilloma





Special Stains and Immunohistochemistry





  • SMA, calponin, S-100 protein, smooth muscle myosin heavy chain, and p63 highlight myoepithelial cells



  • ER stains a variable minority of epithelial cells in papillomas without atypia, with diffuse positivity in ADH and low-grade DCIS foci



  • High-molecular-weight cytokeratins (HMWCKs), such as 5/6, 14, and 34βE12, stain epithelial cells in papillomas without atypia, whereas ADH and low-grade DCIS foci are negative



  • Combination of ER positivity and HMWCK negativity is a useful indicator of neoplastic population in an intraductal papillary proliferation



  • CD34/factor VIII demonstrate vascular endothelial cells within fibrovascular cores (helps distinguish between endothelial and myoepithelial cells)



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Papillary Ductal Carcinoma in Situ





  • Prominent neoplastic proliferation of epithelial cells showing papillary architecture and features of intraductal carcinoma characterized by unequivocal comedo, cribriform, solid, or micropapillary architecture; no apocrine metaplasia; necrosis often seen



Encapsulated (Intracystic) Papillary Carcinoma and Noninvasive Papillary Carcinoma





  • Papillary proliferation growing within dilated ducts and consisting entirely of papillae lacking a myoepithelial cell layer; studies failed to demonstrate myoepithelial cells at the periphery of tumor nodules



Pearls





  • Papillomas, solitary and multiple, without atypia have been shown to be associated with an increased risk for malignancy, the risk being greater with multiple lesions



  • Women with multiple papillomas with atypia have a particularly high breast cancer risk



  • Clinical significance of atypical papillary lesions is uncertain, and complete excision is recommended with careful follow-up



  • Deferring the diagnosis of carcinoma to paraffin sections is recommended when diagnosis of an intraductal papilloma is made on frozen section



  • Loss of heterozygosity (LOH) at loci 16p13 is identified in papillomas with florid hyperplasia



  • Frozen sections are not recommended on papillary lesions



  • Most important feature for distinguishing between a benign papilloma and a papillary carcinoma is the presence of a uniform myoepithelial layer in the proliferating papillary intraluminal component



  • Presence of apocrine metaplasia within the lesion favors a benign diagnosis





Selected References




  • Collins L.C., Schnitt S.J.: Papillary lesions of the breast: selected diagnostic and management issues. Histopathology 2008; 52: pp. 20-29.



  • Jakate K., De Brot M., Goldberg F., et. al.: Papillary lesions of the breast: impact of breast pathology subspecialization on core biopsy and excision diagnoses. Am J Surg Pathol 2012; 36: pp. 544-551.



  • Jorns J.: Papillary lesions of the breast: a practical approach to diagnosis. Arch Pathol Lab Med 2016; 140: pp. 1052-1059.



  • Richter-Ehrenstein C., Tombokan F., Fallenberg E.M., et. al.: Intraductal papillomas of the breast: diagnosis and management of 151 patients. Breast 2011; 20: pp. 501-504.



  • Shamonki J., Chung A., Huynh K.T., et. al.: Management of papillary lesions of the breast: can larger core needle biopsy samples identify patients who may avoid surgical excision?. Ann Surg Oncol 2013; 20: pp. 4137-4144.



  • Tse G.: Papillary lesions of the breast. Diagn Pathol 2018; 24: pp. 64-70.


Florid Papillomatosis of the Nipple


Clinical Features





  • May be seen at any age, typically in middle-aged women (fourth and fifth decades)



  • Rarely reported in men



  • Frequently presents with serous or bloody nipple discharge



  • Pain or itching may be experienced



  • Palpable mass is present in most cases



  • May resemble Paget disease clinically



Gross Pathology





  • Generally forms a discrete mass



  • Nipple frequently shows ulceration, erythema, and scaling



Histopathology





  • Characteristic feature is florid ductal hyperplasia with lesions grouped into four subtypes according to their growth pattern: sclerosing papillomatosis, papilloma, adenosis, and mixed proliferative patterns ( Figure 13.14A and B )




    Figure 13.14


    Florid papillomatosis.

    A, Distended ducts filled with hyperplastic ductal cells are extending into the upper dermis. B, Tubular arrangement with focal ductal hyperplasia and fibrous stroma.



  • Myoepithelial cell hyperplasia is common, but in sclerosing lesions may be inconspicuous or absent



  • Foci of necrosis and normal mitosis may be present



  • Areas of ADH, DCIS, or invasive carcinoma within papillomatosis may be seen



Special Stains and Immunohistochemistry





  • SMA, calponin, S-100 protein, smooth muscle myosin heavy chain, and p63 highlight myoepithelial cells



  • Keratin 34betaE12 highlights epithelial cells



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Paget Disease





  • Identification of neoplastic tumor cells within epidermis of nipple that stain for Her-2 neu



Ductal Carcinoma in Situ or Invasive Carcinoma





  • Often present when florid papillomatosis is found



  • May be associated with or be present away from area of papillomatosis



  • Intraductal carcinoma should show a cribriform, comedo, solid, or micropapillary architecture and may show necrosis



Pearls





  • Benign epithelial tumor arising in the large ducts of the nipple



  • Treatment involves complete excision, usually with removal of the nipple



  • Associated with concomitant or subsequent carcinoma in 10% of cases; carcinoma may be found anywhere in the breast





Selected References




  • Brownstein M.H., Phelps R.G., Magnin P.H.: Papillary adenoma of the nipple: analysis of fifteen new cases. J Am Acad Dermatol 1985; 12: pp. 707-715.



  • Rosen P.P., Caicco J.A.: Florid papillomatosis of the nipple: a study of 51 patients, including nine with mammary carcinoma. Am J Surg Pathol 1986; 10: pp. 87-101.



  • Rosen P.P., Oberman H.A.: Atlas of Tumor Pathology: Tumors of the Mammary Gland. 3rd Series, Fascicle 7.1993.Armed Forces Institute of PathologyWashington, DC


Pseudoangiomatous Stromal Hyperplasia


Clinical Features





  • Found in women of childbearing age but can also affect men with gynecomastia



  • Presents as a firm, palpable, nontender, solitary breast mass or area of thickening



  • Can be found as an incidental finding in patients undergoing biopsies for other reasons



Gross Pathology





  • Well-circumscribed and typically encapsulated



  • Variable size (typically 3 to 4 cm)



  • Cut section demonstrates a fibrous, tan-white, homogeneous tumor



Histopathology





  • Characterized by complex, anastomosing, empty slitlike spaces (pseudoangiomas) in a dense collagenous stroma ( Figure 13.15 )




    Figure 13.15


    Pseudoangiomatous stromal hyperplasia.

    Complex anastomosing slitlike spaces in a dense collagenous background.



  • Empty spaces lined by monomorphic myofibroblastic spindle cells resembling endothelial cells



  • Can form solid foci of prominent spindle cells



Special Stains and Immunohistochemistry





  • Vimentin positive in spindle cells lining pseudoangiomatous spaces



  • CD34 positive in most lesions



  • CD31 mostly negative



  • SMA variably reactive



  • Cytokeratin, factor VIII negative



Other Techniques for Diagnosis





  • Electron microscopy: pseudoangiomatous spaces lined by cells showing fibroblastic differentiation



Differential Diagnosis


Hemangioma





  • Slitlike spaces are vascular channels and often contain blood



  • Lining cells are endothelial and show cytokeratin, CD31, factor VIII, and Ulex europaeus positivity



Low-Grade Angiosarcoma





  • Intercommunicating vascular spaces lined by atypical endothelial cells with hyperchromatic nuclei



  • Infiltrative architecture typically extending into adjacent breast tissue



Pearls





  • Pseudoangiomatous stromal hyperplasia (PASH) is a benign lesion that must be distinguished from low-grade angiosarcoma



  • Treatment is wide local excision; clear margins are necessary to avoid recurrences



  • Development may be related to hormonal factors



  • Positivity for CD34 supports the diagnosis





Selected References




  • Bowman E., Oprea G., Okoli J., et. al.: Pseudoangiomatous stromal hyperplasia (PASH) of the breast: a series of 24 patients. Breast J 2012; 18: pp. 242-247.



  • Drinka E.K., Bargaje A., Erşahin Ç.H., et. al.: Pseudoangiomatous stromal hyperplasia (PASH) of the breast: a clinicopathological study of 79 cases. Int J Surg Pathol 2012; 20: pp. 54-58.



  • Ferreira M., Albarracin C.T., Resetkova E.: Pseudoangiomatous stromal hyperplasia tumor: a clinical, radiologic and pathologic study of 26 cases. Mod Pathol 2008; 21: pp. 201-207.



  • Gresik C.M., Godellas C., Aranha G.V., et. al.: Pseudoangiomatous stromal hyperplasia of the breast: a contemporary approach to its clinical and radiologic features and ideal management. Surgery 2010; 148: pp. 752-757.


Adenoma


Clinical Features





  • Some may represent unusual types of fibroadenomas



  • All present as breast masses



  • Lactating adenoma is often recognized during pregnancy or while lactating



Gross Pathology





  • Well-defined, circumscribed, tan-yellow tumors



  • Typically less than 5 cm in greatest diameter



  • Lactating adenomas may be multiple



Histopathology


Tubular Adenoma





  • Proliferation of benign glands of uniform size and shape ( Figure 13.16A )




    Figure 13.16


    A, Tubular adenoma. Densely packed ductal structures lined by epithelial and myoepithelial cells. B, Lactating adenoma. The ducts are lined by vacuolated secretory cells. The lumens contain secretory material.



  • Lined by a single layer of epithelial cells showing bland nuclear features



  • Myoepithelial cells surround each gland



Lactating Adenoma





  • Proliferation of benign ducts with preservation of a lobular architecture; typically sharply delineated from the surrounding breast tissue



  • Ducts lined by benign-appearing epithelial cells with vacuolated cytoplasm; may show hobnail appearance (see Figure 13.16B )



  • Duct lumens contain eosinophilic secretions



  • Typically shows increased secretion if removed postpartum, less secretion if removed during pregnancy



  • Prone to infarction during pregnancy



Apocrine Adenoma





  • Extremely rare lesions



  • Discrete mass, homogeneous throughout, sharply demarcated from surrounding breast tissue and composed of benign breast ducts with apocrine epithelium and minimal supportive stromal component



  • Often shows papillary and cystic architecture



Special Stains and Immunohistochemistry





  • SMA, S-100, and p63 highlight myoepithelial cell layer



  • PAS highlights luminal secretion in lactating adenoma



Other Techniques for Diagnosis





  • Noncontributory



Differential Diagnosis


Tubular Carcinoma





  • Composed of small angulated ducts with infiltrative growth pattern



  • Lacks myoepithelial cell layer



  • Shows reactive, desmoplastic stroma surrounding proliferating ducts


Mar 11, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Breast
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