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Chapter 11

comedo type) tends to be a well-defined, tan tumor with white to pale yellow flecks composed of necrotic DCIS (­comedos) that extrude from the cut surface when the lesion is com- pressed. Abundant calcification in the lesion can impart a gritty sensation upon cutting. Although these findings are suggestive of this type of carcinoma, a similar gross appear- ance is found in some instances of duct ectasia and mastitis. Most classifications of DCIS have been based on histo- pathologic features of the lesions, but some investigators have drawn attention to the distinction between grossly apparent and microscopic lesions. Gump et al. 96 studied 70 consecutive patients treated in one institution for lesions classified as DCIS on an initial biopsy. Fifty-four (77%) had carcinomas classified as “gross” because the patient pre- sented with a palpable tumor, nipple discharge, or Paget dis- ease. The majority of these patients (48 of 54 or 89%) had a mass. Microscopic DCIS in 16 (23%) was nonpalpable, and it was detected by mammographic calcifications or it was an incidental finding. Invasive carcinoma was found in six (12%) surgical specimens subsequent to an initial biopsy that revealed gross DCIS, but not in the patients who had microscopic DCIS. Axillary lymph node (ALN) metastases were found in only one patient with a gross lesion, and not in any patient with microscopic DCIS. A slightly more complex classification based on anatomic distribution was proposed by Andersen et al. 97 They identi- fied three types of growth patterns, which occurred individ- ually or in combinations. “Microfocal” lesions involved “one or a few lobules and/or ducts” measuring up to 5 mm. “Dif- fuse” DCIS involved a region of 5 to 10 mm or an entire seg- ment of the breast, and the “tumor-forming” type consisted of closely connected glandular structures that occupied an area of 60 to 70 mm, resulting in a palpable mass. Microfo- cal and diffuse types of DCIS were typically not palpable. A population-based review of cases revealed that 18 of 35 pa- tients (51%) with DCIS had microfocal lesions, 13 (37%) had the diffuse type, and 4 (11%) had tumor-forming DCIS. 21 No ALN metastases were found in any of the patients who had an axillary dissection. The microanatomic site of origin of many DCIS appears to be in the terminal duct lobular unit (TDLU). The most con- vincing evidence for this conclusion comes from the sub- gross microdissection studies of Wellings et al. 98 Expanded TDLUs sometimes resemble primary or secondary segmen- tal ducts, but their lobular origin is suggested by an excessive number of duct structures within a low-power microscopic field and by the accompanying stroma. Recently character- ized columnar cell lesions lend support to this conclusion. Exceptions can be found to the concept of the TDLU ori- gin of DCIS. For example, it does not readily describe DCIS limited to major central lactiferous ducts, sometimes asso- ciated with Paget disease or nipple discharge. Occasionally, Microscopic Pathology General Histologic Features

random sections disclose foci of DCIS in sections of one or more segmental ducts with no apparent lobular connection even when the lesion is traced with serial sections. The rela- tive frequency of origin from the TDLU or from larger duct structures, and the clinical significance of this distinction remain to be determined. The microscopic classification of DCIS became the sub- ject of heightened interest after the widespread introduction of breast conservation therapy. Interest in factors associated with the success or failure of this therapy directed attention not only to variants described on the basis of growth pattern, but also to finer cytologic details. The spectrum of histologic patterns of DCIS in men does not differ appreciably from the appearance of the disease in women. There is a higher proportion of papillary DCIS in men, and comedo DCIS is less frequent than in women. In standard histologic sections, DCIS is confined within the lumens of ducts and lobules involved in the process. When studied by immunohistochemistry (IHC) for laminin or type IV collagen, basement membranes in DCIS appear intact or focally discontinuous. 99–101 The presence or absence of mitotic figures is not a definitive feature in the diagnosis of DCIS, because mitoses may also be found rarely in normal and hyperplastic epithelium. However, the finding of one or more mitoses per 10 high-power fields (HPFs) suggests DCIS. Myoepithelium in DCIS Myoepithelial cells are often retained but attenuated inDCIS, and they are occasionally hyperplastic at the periphery of the duct (Fig. 11.4). Myoepithelial cells do not generally accom- pany the neoplastic epithelial proliferation within the duct lumen in DCIS except for certain types of carcinoma arising in a papilloma or in solid papillary DCIS. Experimental evidence suggests that myoepithelial cells may have a paracrine tumor suppressor effect on DCIS, act- ing to inhibit invasion. 102 Tumor suppression capabilities of myoepithelial cells include inhibition of invasion 103 and of angiogenesis. 104 In vitro , myoepithelial cells have been shown to have the capacity to inhibit breast carcinoma cell growth and to induce apoptosis. 105 These tumor-inhibiting properties have been attributed in part to the expression of maspin, a pro- tease inhibitor, by myoepithelial cells. 106 Other tumor suppres- sor genes expressed by myoepithelial cells include cytokeratin 5 (CK5), smooth muscle actin (SMA), and caveolin-1. 107 The functional activity of myoepithelial cells in in situ carcinoma is significantly changed compared with normal epithelium. These alterations include overexpression of che- mokines CXCL12 and CXCL14, which bind to and enhance the invasiveness of carcinoma cells. 108 In particular, CXCL12 and its receptor CXCR4 appear to promote breast carcinoma cell growth and metastases. 109,110 Cell Types in DCIS The range of subtle differences in cell type found inDCIS usu- ally engenders little comment, but certain distinct variants have been identified and described by specific names. Signet