Surgical Pathology Review: easing the transitions

Atypical ductal hyperplasia (ADH)

Context

• Nonobligate precursor lesion, clonally related to low-grade DCIS.

Clinical findings

• ADH presents most often as clustered microcalcifications.

Prototypical morphology

• ADH is an intraductal proliferation (Figure 5-9) in which the qualitative morphologic features of low-grade DCIS are present focally.
• Ducts are mildly expanded, and there is architectural complexity with punched-out cribriform spaces, micropapillae, or rigid arched bridges.
• The cells are low grade and monomorphic with round nuclei, condensed chromatin and inconspicuous nucleoli (intermediate or high nuclear grade, regardless of quantitative extent, are characteristics of DCIS).
• The atypical proliferation involves less than 2 mm extent or less than two contiguous ducts (greater than 2 mm or two contiguous ducts characterized as DCIS).

Special studies

• CK5/6 is negative in the intraductal population (unlike mosaic positivity in UDH).
• ER positivity is strong and diffuse (unlike variable positivity in UDH).

Treatment and prognosis

• Excision is recommended to rule out DCIS or invasive carcinoma.
• ADH confers 4–5× increase in relative risk for subsequent breast cancer.

 

Atypical lobular hyperplasia (ALH)

Context

• Nonobligate precursor lesion associated with bilateral increased risk of breast cancer.
• ALH is cytologically similar to lobular carcinoma in situ but is limited in extent.
• Together, ALH and lobular carcinoma in situ (LCIS) are referred to as lobular neoplasia.
• Lobular neoplasia tends to be multicentric and bilateral.

Clinical findings

• These are asymptomatic, incidental lesions.

Prototypical morphology

• Distended lobules (Figure 5-10) are seen filled with loosely cohesive, monomorphic cells with low-grade nuclei.
• ALH involves less than 50% of acini in a terminal ductal lobular unit (more than this constitutes LCIS).

Special studies

• Absence of membranous E-cadherin staining (in contrast to ductal proliferations).
• Absence of nuclear beta catenin (in contrast to ductal proliferations).
• Cytoplasmic p120 staining (as opposed to membranous staining in ductal lesions).

Treatment and prognosis

• Treatment options include surveillance, chemoprevention with tamoxifen, and excision.
• ALH confers 4–5× increase in relative risk for subsequent breast cancer (including both ductal and lobular types).

Lobular carcinoma in situ (LCIS)

Context

• LCIS, together with ALH, is considered part of the lobular neoplasia spectrum.
• There is poor reproducibility in the distinction of ALH and LCIS.
• LCIS is frequently associated with flat epithelial atypia.
• LCIS is the most common in situ lesion in fibroadenoma.
• LCIS is multicentric and/or bilateral in 50% of cases.

Clinical findings

• Usually an incidental finding, although up to 15% of cases associated with microcalcifications.
• Pleomorphic/florid LCIS may present as a mass and is more likely to have calcifications.

Prototypical morphology

• The lobule is expanded (Figure 5-11), and acini are filled with small, loosely cohesive monomorphic cells (classic type), by definition in greater than 50% of a terminal duct lobular unit.
• When involving ducts, the neoplastic cells proliferate between basement membrane and luminal epithelial cells in a clover leaf-like pattern.
• Pleomorphic LCIS shows increased nuclear pleomorphism and atypia, sometimes with central necrosis and calcification, closely resembling DCIS.
• Florid LCIS shows classic nuclear features but fills and distends ducts in a DCIS-like pattern, often with comedonecrosis.

Special studies

• Negative for membranous E-cadherin staining (in contrast to ductal lesions).
• Negative for nuclear beta catenin (in contrast to ductal lesions).
• Cytoplasmic p120 staining (membranous staining in ductal lesions).

Treatment and prognosis

• LCIS confers 8 –10× risk of malignancy for bilateral breasts.
• Management may include follow-up, tamoxifen, or excision.
• Excision with margin clearance is recommended for pleomorphic LCIS.

Ductal carcinoma in situ (DCIS)

Context

• Clonal proliferation of epithelial cells surrounded by myoepithelial cell layer and confined within the basement membrane.
• High-grade DCIS and low-grade DCIS appear to be distinct processes at the molecular level, with intermediate-grade DCIS representing a mixture of these two types.

Clinical findings

• High-grade DCIS can be mass forming, and some cases present as nipple discharge, but over 90% of cases are detected by mammography.
• Radiographically, DCIS usually presents as microcalcifications. Those associated with low-grade DCIS are often described as clustered, fine, and crystalline, while in high-grade DCIS, they are described as large, amorphous, linear, and branching.

Prototypical morphology

• Grossly, most cases demonstrate no apparent lesion. There may be cheesy material identified within dilated spaces in comedo-type DCIS, and in other cases there may be an indurated lesion.
• DCIS can be low, intermediate, or high grade (Figure 5-12). Grading is based largely upon nuclear features, but some grading systems take necrosis into account.
• Architectural patterns include solid, cribriform (with rigid punched-out spaces), comedo, papillary, micropapillary, clinging, etc, but these are often mixed, and reproducibility is poor.
• Necrosis must be distinguished from luminal secretion, which lacks evidence of cell death and instead consists solely of acellular eosinophilic granular material. Sometimes necrosis occurs in the center of a duct involved by solid-type DCIS, and this is called comedonecrosis. In other cases, central necrosis is present with cribriform or other patterns, while in still other cases necrosis may involve random individual cells (“punctate” necrosis).
• Low-grade DCIS is by definition greater than 2 mm or involves more than two contiguous ducts, while there is not a quantitative criterion attached to high-grade DCIS.
• Extensive high-grade DCIS may be associated with foci of microinvasion.

Special studies

• Low-grade DCIS usually shows strong and diffuse ER expression. CK5/6, human epidermal growth factor receptor 2 (HER2), and p53 are negative.
• High-grade DCIS can show variable ER and CK5/6 expression and often overexpresses HER2 and p53.

Treatment and prognosis

• High-grade DCIS more likely to recur and to progress than low-grade DCIS.
• For all grades, local excision is recommended, with partial or total mastectomy.
• Sentinel lymph node biopsy may be considered for extensive high-grade DCIS, and in such cases lymph node metastases are occasionally encountered.
• Margin status is the strongest predictor of local recurrence. It is known that the risk of recurrence is lower with greater distance from nearest margin, but there is not a universally accepted threshold distance.
• Tamoxifen therapy is known to reduce the risk of local recurrence.
• DCIS confers 8 –10× risk of malignancy in ipsilateral breast.

Paget disease of nipple

Context

• Paget disease is the presence of breast carcinoma within the nipple epidermis.
• The majority of lesions are associated with underlying DCIS or invasive carcinoma.

Clinical findings

• The cutaneous changes resemble eczema: crusted erythematous lesions with scale.

Prototypical morphology

• Large cells with abundant pale cytoplasm are present within the epidermis, arranged singly (“buckshot”) or in small groups (Figure 5-13).
• The cells have atypical nuclear features and intracytoplasmic mucin.
• A lichenoid dermal infiltrate may be seen.

Special studies

• Paget cells are consistently positive for CK7 and mucin stains.
• They are variably positive for carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), GCDFP, and GATA3.
• HER2 is overexpressed in most cases, and ER/PR are usually negative.
• Paget cells are negative for high-molecular-weight keratins, p63, and melanocytic markers.
• The immunophenotype of Paget cells may be indistinguishable from benign Toker cells; they are distinguished based on cytologic atypia.

Treatment and prognosis

• Prognosis and treatment depend on presence of underlying invasive carcinoma.
• Pure Paget disease, without underlying malignant breast lesion, has excellent overall survival, with lymph node metastases being rare.