Ductal Proliferations of the Breast: The Good, the Bad, and the Ugly

Transcription

1 Ductal Proliferations of the Breast: The Good, the Bad, and the Ugly Melinda F. Lerwill, MD CRITERIA FOR DISTINGUISHING LOW-GRADE DUCTAL CARCINOMA IN SITU FROM USUAL DUCTAL HYPERPLASIA CYTOLOGY Low-grade atypia Usual ductal hyperplasia Cell population Monomorphic Polymorphic Nuclear shape Round or oval Oval, elongated to tapered Nuclear contours Smooth Grooves and notches Chromatin Homogeneous, fine, hyperchromatic Granular, slightly open, euchromatic Nucleoli Often inconspicuous Small nucleoli present Nuclear pseudoinclusions Absent Often present Cytoplasm - amount Increased Modest Cytoplasm - staining quality Eosinophilic, amphophilic, or Eosinophilic clear Cell borders Often conspicuous Inconspicuous Cellular maturation* Absent Present ARCHITECTURE Atypical Usual ductal hyperplasia Cell distribution Uniformly spaced nuclei Jumbled, overlapping nuclei Cells around spaces show Polarization Lack of polarization Architectural patterns Cribriform spaces, Roman arches, trabecular bars, micropapillae, solid growth with regular nuclear spacing Fenestrations, solid growth with overlapping nuclei, uncommonly micropapillae SECONDARY FEATURES Ductal carcinoma in-situ Usual ductal hyperplasia Necrosis Common Rare Pagetoid spread Sometimes present Absent Intermixed benign apocrine cells Absent Occasionally present Calcifications Frequent Infrequent CAUTION! No single criterion listed above can reliably distinguish an atypical from a nonatypical process. All features must be considered TOGETHER. *Cellular maturation: Usual ductal hyperplasia occasionally demonstrates maturation. In this phenomenon, the central cells appear smaller and darker than the peripheral cells. The mature cells are more closely packed, have smaller and darker nuclei, and contain less cytoplasm than the peripheral cells. Two caveats apply: 1) Maturation is not evident in many cases of usual ductal

2 hyperplasia, so its absence does not exclude a benign process, and 2) some ductal carcinomas in-situ may demonstrate pseudo-maturation where the central cells contain slightly smaller and darker nuclei than the peripheral cells. However, unlike the maturation of usual ductal hyperplasia, pseudo-maturation does not show a tight overlapping cell arrangement, and the cells are not as small as those seen in hyperplastic maturation. Polarization: In neoplastic ductal proliferations, the atypical cells demonstrate polarization. This means they have a basally located nucleus and an apical cytoplasmic compartment. When these polarized neoplastic cells form secondary spaces, they radially array themselves with their apical cytoplasmic compartments pointing towards the space. This is how cribriform spaces are formed. Trabecular bars, Roman arches, and carcinomatous micropapillae are also polarized structures; they are formed by cells radially oriented to the adjacent luminal space. Polarization is not a feature of benign hyperplastic proliferations, whose cells do not radially orient themselves around a luminal space, instead often longitudinally streaming along the border. Necrosis: The presence of necrosis is strongly suggestive of carcinoma but may occur in three benign lesions: radial scar, nipple adenoma, and juvenile papillomatosis. Micropapillary Proliferations Micropapillary DCIS Extensive Micropapillary UDH Focal in a background of conventional UDH Distribution of micropapillary changes Size of involved ducts Markedly distended Slightly distended Contents of ducts Dirty cellular debris Clean Configuration of micropapillae Variable size and shape Uniform size and shape Cytologic atypia Present Absent Maturation Absent Present A good rule of thumb: An extensive micropapillary proliferation in a woman is most likely micropapillary DCIS; in a man, it is most likely gynecomastia. INTERMEDIATE-GRADE DUCTAL CARCINOMA IN SITU A diagnosis of intermediate-grade ductal carcinoma in situ can be rendered when the carcinoma demonstrates either: 1) a low nuclear grade with comedonecrosis, or 2) an intermediate nuclear grade. Intermediate-grade nuclei are moderately enlarged (~2X the size of an RBC or normal duct epithelial cell nucleus) and usually have slightly coarser chromatin and more conspicuous nucleoli than low-grade nuclei. Some features of intermediate-grade nuclei can superficially overlap with those of hyperplastic nuclei. These features include the presence of nuclear membrane irregularities, open chromatin, and nucleoli. The nuclei of intermediate-grade DCIS are uniformly enlarged, however, unlike in benign hyperplasia where only the peripheral cells near the basement membrane show notable nuclear enlargement. Other features that, when present, point towards intermediate-

3 grade DCIS rather than benign hyperplasia include clumped and cleared chromatin, hyperchromasia, deep and highly irregular nuclear clefts, and red nucleoli. Intermediate-grade DCIS lacks evidence of maturation. The presence of architectural atypia is suggestive of a neoplastic rather than benign hyperplastic process. ATYPICAL DUCTAL HYPERPLASIA The dividing line between atypical ductal hyperplasia and low-grade ductal carcinoma is arbitrary and subjective. The two diagnostic entities are not truly distinct biologic entities, being merely different points along the continuum of low-grade ductal neoplasia in the breast. The presence of low-grade cytologic atypia, as detailed above, is required for either diagnosis. The difference between a diagnosis of atypical ductal hyperplasia and one of ductal carcinoma in situ lies in the degree of proliferation of the atypical cells. Most pathologists would agree that alterations classified as atypical ductal hyperplasia demonstrate a lesser degree of proliferation than ductal carcinoma in situ. The problem lies in how lesser degree of proliferation is defined, or whether it is definable. Some pathologists require complete involvement of at least 2 glandular spaces/duct profiles for a diagnosis of ductal carcinoma in-situ and would classify lesions not meeting this threshold as atypical ductal hyperplasia. Others require a minimum 2 mm aggregate diameter before rendering a diagnosis of ductal carcinoma in-situ. There is established precedent for using these types of quantitative criteria. One should remember, however, that they represent artificial measures of proliferation and are limited by the fact that they are 2-D assessments of complex 3-D structures, and they do not necessarily - in fact, likely do not - reflect biology. At our institution, we do not use strict quantitative criteria to differentiate between atypical ductal hyperplasia and low-grade ductal carcinoma in situ. Rather, we evaluate the degree of proliferation of the atypical cells (typically reflected in the degree of architectural atypia and degree of glandular expansion) and the extent of involvement within the breast tissue. Lesions with low-grade cytologic atypia and limited architectural atypia (limited proliferation) are classified as atypical ductal hyperplasia, whereas those with low-grade cytologic atypia and well-developed architectural atypia are classified as low-grade ductal carcinoma in situ. It is, admittedly, a subjective approach, and most cases do fall within the general bounds of the 2 duct profile or 2 mm rules. However, we prefer to make our assessment based on histologic characteristics rather than on numeric ones, and therefore do not rely on quantitative factors alone to distinguish the two entities.

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