Infiltrating Carcinoma of the Breast Dr. Jane Armes

Case History A 29 year-old woman noted a lump within the right breast whilst breast feeding her three-month old child. She had one other child aged three and a half years. Ultrasound was performed at that time and 'milk cysts' diagnosed. She re-presented five months later, when still breast-feeding, with the lump having approximately doubled in size. Her mother had been diagnosed with breast cancer at age 44 years and now (11 years later) has advanced breast cancer. Her grandmother had died aged 77 years of 'possible breast cancer'. Ultrasound now showed a 25 mm lobulated mass with other smaller areas of possible abnormality within the right breast. An FNA of the largest mass was performed, followed by four separate image-directed core biopsies. All samples were diagnosed as 'adenocarcinoma'. The patient went on to have a right modified radical mastectomy and axillary node dissection. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Macroscopic description The mastectomy specimen measured 175 x 165 x 35 mm with attached skin and nipple. Three cream lesions were noted on sectioning, including two relatively well-defined nodules within the inner upper quadrant and centrally (both 35 mm maximum dimension). The third lesion occurred in the outer lower quadrant and was poorly defined, measuring approximately 10 mm. Microscopic description Three separate areas of invasive carcinoma were identified within the breast. One was a well-circumscribed, 55 mm Grade 3 (tubules 3; nuclei 3; mitoses 3 [21/10 0.5mm hpf]) infiltrating ductal carcinoma, NOS (Figure 1), lying medially within the breast, which was associated with solid DCIS with high cytonuclear grade and necrosis. Lymphovascular space infiltration surrounded this area of carcinoma. Figure 1 - A well-circumscribed infiltrating ductal carcinoma (original magnification x2). Centrally, beneath the nipple, was a 44 mm carcinoma which appeared in part to be a ductal carcinoma, NOS and partly a pleomorphic lobular carcinoma (Grade 3: tubules 3; nuclei 3; mitoses 2 [10 mitoses per 10 0.5mm hpf]). The ductal carcinoma had a more infiltrative growth pattern than the medial tumour. Similar ductal carcinoma in situ was identified in this region (Figure 2). Figure 2 - High grade DCIS and infiltrating ductal carcinoma (original magnification x 4). The third area of carcinoma was present laterally and was seen as multiple foci of Grade 3 pleomorphic lobular carcinoma extending over the majority of the lateral half of the breast (Figure 3). Figure 3 - Pleomorphic lobular carcinoma with a targetoid pattern in the lateral half of the breast (original magnification x 10). Elsewhere the breast showed prominent lactation changes. Fourteen right axillary lymph nodes were identified and nine of these contained metastatic carcinoma (maximum deposit 15 mm). Differential diagnosis Infiltrating carcinoma of the breast. Two separate types of high-grade carcinoma present; Ductal (NOS) and pleomorphic lobular. Further investigations Immunohistochemistry confirmed two distinct carcinomas within the breast, with the invasive ductal carcinoma being e-cadherin positive and all foci of pleomorphic lobular cancer being e-cadherin negative (Figure 4). Figure 4a - E-cadherin staining of central area of breast carcinoma showing e-cadherin positive invasive ductal carcinoma (top right) and DCIS and e-cadherin negative pleomorphic lobular carcinoma (bottom left) (original magnification x 2). Figure 4b - Detail of pleomorphic lobular carcinoma with absent e-cadherin staining in contrast to positive DCIS (original magnification x 10). The invasive ductal carcinoma stained moderately with antibodies to ER in 80% of cells and strongly with antibodies to PR in <5% of cells. In contrast, the pleomorphic lobular carcinoma stained weakly with antibodies to ER in <5% of cells and was entirely negative with antibodies to PR. Both carcinoma types were negative with antibodies to ERBB2. Cyclin D1 staining was present in approximately 20% of tumour nuclei of both pleomorphic lobular and ductal types. The vast majority of the in situ carcinoma stained strongly with antibodies to e-cadherin, confirming in situ ductal carcinoma. After extensive searching, one small area of in situ carcinoma was identified, in the lateral half of the breast, which was e-cadherin negative (Figure 5). This measured 1.5 mm in maximum dimension and was composed of large cells with abundant cytoplasm in small expanded ducts, without associated necrosis or calcification. Figure 5a - In situ neoplasia composed of large cells with abundant eosinophilic cytoplasm (original magnification x 10). Figure 5b - Lack of e-cadherin stain within the in situ neoplasia cells (original magnification x 10). E-cadherin staining was performed on two separate lymph nodes involved by metastatic carcinoma and both metastatic foci were strongly e-cadherin positive. Follow-up The patient was treated with four cycles of Acyclovir and Taxol and is to commence Tamoxifen. She has had no recurrent disease to date (7 months post-diagnosis). Discussion This is an interesting case of a young woman presenting with high-stage breast cancer shortly after full-term birth. It is known that there is a transient risk of breast cancer immediately after full-term birth and that these cancers often present at a high-stage, as in the current case. There is dispute as to whether the late-stage presentation is due to delayed diagnosis or due to accelerated growth of breast cancer cells at this time, due to the effects of pregnancy-related hormones. Whilst delay in diagnosis cannot be excluded in some cases (possibly including the current case), there is overwhelming evidence that pregnancy-related hormones, such as prolactin, contribute to accelerated tumour growth. Both experimental models and epidemiological studies have linked increased prolactin levels to increased breast cancer risk and it has been previously suggested that prolactin is involved in both the initiation and promotion of breast tumourigenesis (summarised in Albrektsen G et al, 2006 [1] ). This case is also unusual in that there appears to be two distinct cancer types within this young woman, one a pleomorphic lobular carcinoma and the other an infiltrating ductal carcinoma, NOS. It is not possible to definitively determine whether the two carcinomas arose independently or whether one evolved from the other. Previous studies have shown that pleomorphic lobular cancers, although high-grade, share the molecular genetic changes of classical lobular carcinomas rather that those of ductal cancers, eg, 16q loss and 1q gain. [2] Further, although the vast majority of in situ neoplasia in this case was high-grade ductal type and e-cadherin positive, one very small focus of e-cadherin negative in situ neoplasia was identified in the lateral part of the breast, possibly a non-invasive precursor of the pleomorphic lobular cancer. Therefore, overall, it is reasonable to postulate that this patient developed two synchronous primary cancers within the single breast. Since, it is likely that two synchronous breast cancers arose within this young woman and given her family history of breast cancer, it is interesting to consider her potential risk of carrying a germline mutation in a breast cancer predisposition gene. The morphology of both of her cancer types is not characteristic of a BRCA1 germline mutation (see case #1). However, we and others [3, 4] have described an increased risk of pleomorphic lobular cancers within young woman with BRCA2 germline mutations, compared with age-matched controls. Other features of BRCA2 cancers, such as their ER and PR positivity rate, their grade (usually Grade 2 or 3) and cyclin D1 expression has not been found to be useful in their differentiation from age-matched non-BRCA1 breast cancers. The BRCA germline mutation status of this patient has not been tested to date. References Albrektsen G et al. Clinical stage of breast cancer by parity, age at birth, and time since birth: a progressive effect of pregnancy hormones? Cancer Epidemiol Biomarkers Prev 2006; 15(1): 65-69. Reis-Filho JS et al. Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. J Pathol 2005; 207(1): 1-13. Armes JE et al. The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study. Cancer 1998; 83(11): 2335-2345. Marcus JN et al. BRCA2 hereditary breast cancer pathophenotype. Br Cancer Res Treat 1997; 44(3): 275-277.