Terminal duct lobular unit (TDLU). A, Diagrammatic representation of this structure. ETD = Extralobular terminal duct; ITD = intralobular terminal

Terminal duct lobular unit (TDLU). A, Diagrammatic representation of this structure. ETD = Extralobular terminal duct; ITD = intralobular terminal duct.

Mammary gland

Terminal duct lobular unit (TDLU). B, Photomicrograph of this unit as seen in a normal adult female.

Mammary gland

Immunocytochemical markers of mammary lobule. A, Lactalbumin,, showing positivity in secretory epithelium and intraglandular lumina.

Immunocytochemical markers of mammary lobule. B, Actin,, showing positivity in the outer myoepithelial cell component. Smooth muscle cells present in adjacent vessel walls serve as built-in in controls.

Lactational changes in mammary lobule. There is marked cytoplasmic vacuolization.

Cystic involution of lobule. This is an age-related change of no clinical significance.

A,, Pregnancy-like changes in mammary lobule. These two clinically inconsequential alterations may coexist.

B,, Clear cell changes. These two clinically inconsequential alterations may coexist.

Gross appearance of mammary duct ectasia. Some of the dilated ducts contain a thick dark material.

Post-traumatic traumatic fat necrosis involving breast.

Retraction of skin in a patient with fat necrosis (arrow), as seen in a photograph taken from a well-seasoned paper.

Sclerosing lymphocytic mastitis in a diabetic woman. Some of the lymphocytes infiltrate the gland.

Florid granulomatous reaction to silicone. Foamy macrophages, foreign body-type multinucleated giant cells, and lymphocytes are present.

Gross appearance of fibroadenoma.. The lesion is sharply circumscribed and perfectly round, and it contains numerous slits.

Microscopic appearance of fibroadenoma.. The tumor shown in B has a slightly hypercellular stroma but not to a degree that would justify a diagnosis of phyllodes tumor.

Heavy, coarse calcification in a large breast fibroadenoma as seen in a mammogram.

Fibroadenoma with apocrine metaplasia. A, Hematoxylin eosin eosin section showing a prominent discontinuous layer of plump eosinophilic cells at the base of the gland. These should not be confused with neuroendocrine cells.

Fibroadenoma with apocrine metaplasia. B, Immunostain for GCDFP-15.

Giant fibroadenoma occurring in an adolescent female.

Fibroadenoma with focal involvement by low- grade intraductal carcinoma.

Gross appearance of lactating adenoma. The mass has a distinct lobular configuration, yellowish color, and marked vascularization.

So-called lactating adenoma. The hyperplastic lobules show marked cytoplasmic vacuolization.

Gross appearance of intraductal papilloma.. A polypoid mass is seen protruding within the lumen of a markedly dilated duct.

Intraductal papilloma. A,, Low-power appearance showing complex arborizing architecture.

Intraductal papilloma. B,, High-power view showing dual cell composition, with a well-defined row of myoepithelial cells.

Gross appearance of papilloma presenting as a mural nodule within a cyst.

Papilloma of breast showing entrapment of epithelial structures by fibrohyaline stroma, resulting in a pseudoinvasive appearance.

Typical polypoid shape of nipple adenoma, as seen in a whole mount.

Nipple adenoma. The complex architectural arrangement can lead to overdiagnosis.. The continuity with the squamous epithelium of the skin is a typical feature of this entity.

Sclerosing adenosis. A,, Low-power view. The lobular configuration of the lesion is obvious.

Sclerosing adenosis. B,, Medium-power view. Note the spindle shape of the proliferating cells in the center of the lobule and the fibrillary quality of the cytoplasm, indicative of myoepithelial nature.

Sclerosing adenosis. C, Immunocytochemical stain for actin showing strong immunoreactivity in the myoepithelial cell component.

Sclerosing adenosis. D, Sclerosing adenosis with lobular carcinoma in situ. Note the regularity of the edge and absence of infiltrative features.

Benign perineurial invasion in a breast lesion that had elsewhere the typical features of sclerosing adenosis.

Involvement of the wall of a vessel by sclerosing adenosis,, as highlighted by the Verhoeff van Gieson stain.

Microglandular hyperplasia. A,, Low-power appearance, showing haphazardly scattered small round glands.

Microglandular hyperplasia. B,, On high power, the glands are open and contain a luminal secretion. The myoepithelial cell layer is not discernible.

Adenomyoepithelial adenosis.. The glands are relatively large, with a wide, open lumen and apocrine metaplasia. The cellular component in between is composed of myoepithelial cells. B,, S-100 S Protein stain highlights the prominent myoepithelial component.

Fibrocystic changes, including cystic dilatation, apocrine metaplasia,, florid ductal hyperplasia, and fibrosis.

Photomicrograph demonstrating florid ductal hyperplasia. There is no evidence of necrosis, and individual cells are well supported by their stroma.. A prominent cleft has formed between a solid intraluminal proliferation and an outer epithelial row. This feature is usually indicative of a benign condition.

Florid ductal hyperplasia. Note the oval shape of the nuclei and the parallel arrangement, resulting in a streaming effect.

Structure resembling a renal glomerulus in florid ductal hyperplasia.

Ductal hyperplasia showing irregularly shaped ridges connecting opposite portions of the wall. Note the fact that the oval nuclei are arranged parallel to the long axis of the ridge.

Collagenous spherulosis.. The cylinders have a round shape and a homogeneous pink staining quality, consistent with basement membrane material.

Gross appearance of radial scar.

Typical stellate shape of radial scar as seen on low power.

Abundant deposition of elastic tissue in the central portion of a radial scar, as highlighted by the Verhoeff van Gieson stain.

A,, Benign ductular structures entrapped in radial scar. Note their regular contour and the hypocellular hyaline quality of the stroma.

B,, Tubular carcinoma shown for comparison. Note the angulated shape of the glands and the desmoplastic stroma.

Radial scar with associated low-grade intraductal carcinoma.

Two different breast lesions diagnosed as atypical lobular hyperplasia by four experts in breast pathology. There is lobular enlargement and proliferation, but some lumina are preserved, and there is only minimal distention of individual units.

Two different breast lesions diagnosed as atypical ductal hyperplasia by two experts in breast pathology. There is marked epithelial proliferation in structures of ductal type associated with atypia,, but they were felt not to fulfill criteria for carcinoma in situ.

Proliferative ductal lesion diagnosed as atypical ductal hyperplasia on account of the cytoarchitectural features and small size.

Flat epithelial atypia.. The spaces are dilated and lined by columnar epithelium showing scanty atypia.

Low-power area of calcification

High-power views of the corresponding microscopic specimen.

Specimen from a fine needle aspiration (FNA) biopsy. This was diagnosed as breast carcinoma and followed by the performance of a mastectomy, which confirmed the cytologic interpretation.

Cytologic features of various types of breast lesions as seen in FNA specimens: A, fibroadenoma.

Cytologic features of various types of breast lesions as seen in FNA specimens: B, apocrine metaplasia.

Cytologic features of various types of breast lesions as seen in FNA specimens: C,, invasive ductal carcinoma.

Cytologic features of various types of breast lesions as seen in FNA specimens: D,, invasive ductal carcinoma.

Cytologic features of various types of breast lesions as seen in FNA specimens: E, medullary carcinoma.

Cytologic features of various types of breast lesions as seen in FNA specimens: F, mucinous carcinoma.

Cytologic features of various types of breast lesions as seen in FNA specimens: G,, invasive lobular carcinoma.

Biopsy-induced induced artifactual changes: A,, tumor cells along needle tract.

Biopsy-induced induced artifactual changes: B,, tumor cells in lumen of lymph vessel.

Biopsy-induced induced artifactual changes: C,, tumor cells in lumen of artery.

In situ ductal carcinoma with comedo-type necrosis.

Preservation of a myoepithelial cell layer in high- grade intraductal carcinoma. (Smooth muscle actin immunostain)

Invasive ductal carcinoma associated with extensive intraductal carcinoma component.

Intracystic carcinoma of the breast. The papillary configuration of the tumor is already grossly evident.

High-power view of an in situ papillary carcinoma. Note the layering of cells, loss of nuclear polarity, marked hyperchromasia,, and lack of a myoepithelial cell layer.

In situ papillary carcinoma. The arborizing nature of this tumor and the stout fibrovascular core are not too different from those of a benign papilloma.

Papillary carcinoma with so-called globoid or clear cells. These cells, which are immunoreactive for GCDFP-15, should not be confused with myoepithelial cells. B,, Negative immunostain for smooth muscle actin.

Solid type of in situ ductal carcinoma. There is no necrosis.

Low-grade in situ ductal carcinoma of cribriform type.

Trabecular bars in intraductal carcinoma. Note the perpendicular arrangement of the nuclei in relation to the long axis of the bars.

Micropapillary carcinoma of breast. Some of the papillae lack a central fibrovascular core.

Ductal carcinoma in situ of so-called clinging type. One or two layers of atypical cells line dilated glandular structures containing granular intraluminal material in which ghosts of tumor cells are identified.

So-called lobular cancerization. The lobule is markedly expanded and composed of relatively large tumor cells with the appearance of ductal-type type carcinoma. Typical ductal carcinoma was present elsewhere in the specimen.

Apocrine variant of in situ ductal carcinoma.

Endocrine-type ductal carcinoma in situ: A, hematoxylin eosin. eosin.

Endocrine-type ductal carcinoma in situ: B, chromogranin.

Typical pattern of involvement of terminal duct lobular unit by lobular carcinoma in situ.

Marked expansion of a lobular unit by lobular carcinoma in situ. A few small spaces are still present in the smaller focus.

Involvement of duct by lobular carcinoma in situ. In the presence of such change, a thorough search for typical areas of lobular involvement should be undertaken.

Typical gross appearance of invasive ductal carcinoma. Note the irregular (crab-like) shape of the tumor, white fibrous appearance, and chalky streaks. Retraction of the overlying skin is obvious in the specimen shown in B.

A,, Gross appearance of typical invasive ductal carcinoma. Chalky streaks can be seen throughout the tumor. A central space can be identified in some of them (arrows).

B,, Elastic tissue stain of the lesion illustrated in A showing that chalky streaks correspond to a markedly thickened elastic layer in the wall of non-neoplastic neoplastic ducts crossing the tumor. (B,( Verhoeff van Gieson)

Prototypical invasive ductal carcinoma.

Vascular invasion by breast carcinoma demonstrated by positivity of endothelial cells for Ulex europaeus lectin I.

Tubular carcinoma of breast. The angulated shape of the glands and the cellular stroma are characteristic of this lesion.

Invasive cribriform carcinoma. Some of the nodules have a predominantly solid appearance.

Typical gelatinous gross appearance of pure mucinous carcinoma. Note the sharply circumscribed quality of the tumor.

Mucinous carcinoma of the breast. Clusters of well-differentiated tumor cells are seen floating in a sea of mucin.

Argyrophilic cells present in another case of mucinous carcinoma of the breast, indicative of neuroendocrine differentiation. (Sevier Munger stain)

Early form of mucin-producing low-grade carcinoma showing the mechanism of formation of the epithelial strips typically seen floating in the mucin.

Gross appearance of medullary carcinoma. Note the well-circumscribed character and fleshy appearance.

Medullary carcinoma. The large tumor cells grow in a syncytial fashion and are sharply separated from the surrounding stroma, which is heavily infiltrated by lymphocytes and plasma cells.

Gross appearance of secretory carcinoma. The tumor is well circumscribed and shows a variegated cut surface.

Secretory carcinoma. The small uniform glands are filled by a secretory material.

Breast carcinoma with neuroendocrine differentiation (so-called carcinoid tumor of breast ).

Strong reactivity for chromogranin in breast carcinoma with neuroendocrine differentiation.

Gross appearance of metaplastic carcinoma. A large, fleshy mass is seen protruding inside a cavity. Microscopically, this tumor showed an admixture of squamous and spindle elements.

Metaplastic carcinoma. The tumor shown in A exhibits a blending of the carcinomatous and sarcoma-like components, whereas that depicted in B has a biphasic ( carcinosarcomatous ) appearance.

Large tumor embolus in a dermal lymph vessel in a case with the clinical appearance of inflammatory carcinoma.

Eczema-like hyperemic and eroded clinical appearance of Paget s disease.

Low-power views of Paget s disease. The cleftlike separation between the tumor cells and the overlying squamous epithelium is characteristic.

High-power views of Paget s disease. The cleftlike separation between the tumor cells and the overlying squamous epithelium is characteristic.

Melanin colonization in breast carcinoma as seen with argentaffin stain.

Immunohistochemical demonstration of malignant intraepithelial cells in Paget s disease: A, EMA immunostain.

Immunohistochemical demonstration of malignant intraepithelial cells in Paget s disease: B, HER2/neu immunostain.

Biopsy of nipple showing scattered clear cells in the basal layer ( Toker s cells ). These cells show a mild degree of nuclear atypia and were immunohistochemically similar to the cells of Paget s disease.

Invasive lobular carcinoma. The tumor cells are small and uniform with round nuclei and grow in an Indian file fashion.

Typical target-like growth of tumor cells around an uninvolved duct in invasive lobular carcinoma.

Indian file pattern of growth of invasive lobular carcinoma.

Pleomorphic variant of invasive lobular carcinoma.

Cytoplasmic vacuolization with nuclear displacement in breast carcinoma due to lipid accumulation.

Signet ring carcinoma of the breast, this is regarded as a variant of lobular carcinoma. B, Alcian blue PAS stain.

Immunocytochemical stain for estrogen receptors in invasive breast carcinoma. The strong nuclear positivity in tumor cells is shown against a negative cytoplasmic and stromal background.

Strong (3+) membrane immunoreactivity for HER2/neu in high-grade breast carcinoma.

Breast carcinoma metastatic to vertebra. The normal bone marrow has been flushed out by placing a thin slice of tissue under a strong jet of water.

Metastasis of mammary lobular carcinoma to lamina propria of large bowel mucosa. B, Keratin 7 immunostain.

Cluster of metastatic cells in sentinel lymph node highlighted with keratin stain.

Breast implant (left) surrounded by a thick fibrous wall that has undergone heavy calcification (right).

Striking vacuolization of breast carcinoma cells induced by chemotherapy. The appearance simulates that of histiocytes. The tumor cells shown in B are located within a blood vessel.

Benign mixed tumor of breast. A prominent myxochondroid stroma is interspersed among the glandular structures.

Adenoid cystic carcinoma of breast. The appearance is similar to that of its more common homolog in salivary glands.

Adenomyoepithelioma. In some areas there is a clear relationship between the secretory and the myoepithelial component (similar to that seen in adenomyoepitheliosis), but in others the spindle myoepithelial cells become the exclusive neoplastic element.

Gross appearance of phylloides tumor. The tumor shown in A exhibits the typical appearance of the cut surface. The tumor illustrated in B has undergone extensive hemorrhagic infarct.

Two views of low-grade phylloides tumor, showing cleft-like spaces and concentration of tumor cells beneath the epithelium.

Phylloides tumor with adipose tissue differentiation of the neoplastic stromal component.

Typical hemorrhagic gross appearance of angiosarcoma of breast.

Extremely well-differentiated angiosarcoma of breast.

Complex anastomosing vascular pattern in angiosarcoma of breast.

Benign hemangioendothelioma of breast in a child. The appearance is identical to that of the homologous tumor seen more commonly in skin or salivary gland.

Epithelioid (histiocytoid) hemangioma located within the breast substance.

Sarcoma of breast. The entrapped epithelial tissue lacks the features of a phylloides tumor.

MALT-type malignant lymphoma of breast. Some of the neoplastic lymphocytes infiltrate the glandular structures.

Granulocytic sarcoma of breast. It is easy to misdiagnose this lesion as a large cell lymphoma.

Gross appearance of so-called hamartoma of breast. There is a combination of cystic dilatation of ducts, fibrosis, and entrapment of adipose tissue. This lesion is more distinctive and impressive grossly than microscopically.

Glandular epithelium and fibrous stroma with distorted arrangement in hamartoma of breast.

So-called myoid hamartoma of breast.

Gross appearance of fibromatosis involving breast. The mass is solid and ill defined.

Pseudoangiomatous stromal hyperplasia. Thin channels lined by spindle cells are seen scattered within a hyalinized stroma.

Bizarre multinucleated cells in mammary stroma. This neoplastic change is analogous to that more often seen in the stroma of the upper aerodigestive tract and in the genital tract.

So-called virginal hypertrophy of breast, showing proliferative changes in epithelium and stroma.

Juvenile papillomatosis (Swiss cheese disease). The gross appearance is that of clustered cystic formations.

Juvenile papillomatosis (Swiss cheese disease). Wholemount view showing variously sized cystic formations, alternating with solid epithelial proliferations.

Epithelial proliferation surrounded by a hypocellular myxoid halo in gynecomastia.

Myofibroblastoma of male breast. The microscopic appearance is very reminiscent of solitary fibrous tumor.

Carcinoma of the male breast composed of welldifferentiated tumor cells with abundant granular cytoplasm having oncocytic features.

Grading of the immunohistochemical staining for HER2/neu overexpression