1. b. The lesion depicted in the image is mammary duct ectasia. The history is classic. The lesion is characterized by a dilatation of ducts, inspissation of breast secretions, and a marked periductal and interstitial chronic granulomatous inflammatory reaction. Smoking is associated with periductal mastitis. The infiltrate associated with periductal mastitis consists of lymphocytes and macrophages. Intraductal papillomas do not present with thick secretions. Duct ectasia is of clinical significance because it can be confused with carcinoma by palpation and on mammographic examination.

2. d. The histologic findings in fibrocystic breast changes are cyst formation, often with apocrine metaplasia, fibrosis, usually secondary to cyst rupture, and adenosis. These are all forms of nonproliferative breast changes. Atypical ductal hyperplasia is a form of proliferative breast disease and is not a component of fibrocystic changes.

3. c. Changes of the breast in proliferative disease without atypia include moderate to florid hyperplasia, sclerosing adenosis, papilloma, complex sclerosing lesion or radial scar, and fibroadenoma with complex features. Nonproliferative (fibrocystic) breast changes include duct ectasia, apocrine metaplasia, cysts, adenosis, and fibroadenoma without complex features, as well as fibroadenomatoid change. Changes of the breast in proliferative disease with atypia include atypical ductal and lobular hyperplasia.

4. e. The most common risk factors for the development of breast carcinoma as identified by epidemiologic studies include age, age at menarche, age at first live birth, first-degree relatives with breast cancer, history of breast biopsies, and race. A history of second-degree relatives with breast cancer is not identified as a risk factor. Additional recognized risk factors include estrogen exposure, radiation exposure, carcinoma of the contralateral breast or endometrium, geographic influence, diet, obesity, exercise, breastfeeding, and environmental toxins.

5. d. The BRCA1 is located on chromosome 17q21. It is a tumor suppressor gene, not an antiapoptotic factor. Patients tend to have an early onset of breast carcinoma, often in their 40s and 50s. There is a risk of other carcinomas in the ovary, colon, and pancreas. These patients have a greater incidence of medullary carcinoma of the breast, poorly differentiated carcinomas, ER and PR negativity, and Her-2/neu negativity.

6. b. The lesion depicted here is comedocarcinoma. It is characterized by solid sheets of pleomorphic cells with high-grade nuclei and central necrosis. The necrotic cell membranes do indeed calcify and are detected on mammography as clusters or linear and branching microcalcifications. Periductal concentric fibrosis and chronic inflammation are common. Extensive lesions may be palpable as a vague nodule. It is one of the subtypes of ductal carcinoma in situ (DCIS).

7. a. Most invasive lobular carcinomas show a loss of chromosome 16q22.1 that includes a cluster of at least eight genes responsible for cell-cell adhesion, including E-cadherin and β-catenin. Well to moderately differ – entiated tumors are diploid with increased hormone receptor expression and decreased HER-2/neu expression. Poorly differentiated tumors tend to be aneuploid with decreased hormone receptor expression and increased HER-2/neu expression. The E-cadherin on the opposite chromosome (i.e., the one that does not show loss) is inactivated by mutations, not upregulated.

8. c. Fibroadenomas are the most common benign breast neoplasm in women from ages 20 to 35. The variant giant fibroadenoma shows a racial predilection for black females in the adolescent years. The stroma of fibroadenomas includes CD34 positive fibroblasts and Factor XIIIa positive dendrophages. While these lesions are seen to increase in size during pregnancy, they decrease in size as the patient ages, leading to increased hyalinization and decreased stromal elements. Fifteen percent of fibroadenomas show apocrine metaplasia, and the metaplastic cells stain positively for GCDFP-15.

9. c. While ductal carcinoma in situ (DCIS) is accepted as a precursor lesion to invasive ductal carcinoma, progression to an invasive type does not occur in all cases. In most cases, the process of transformation may take years to decades, but in some patients, the interval to transformation is much shorter. There is a definite relation between the microscopic type of DCIS and the invasive component seen later. The risk of transformation in comedocarcinoma is much higher than in cases of noncomedo DCIS.

10. d. The lesion depicted in this figure is invasive lobular carcinoma, which is highlighted by tumor cells in a single-file pattern and a minimally desmoplastic stroma in many cases. Cytokeratin AE1/AE3, EMA, GCDFP-15, and lactalbumin are common to many lesions of the breast. E-cadherin distinguishes lobular carcinoma from other processes in the breast because of its negative staining pattern. Most cases of lobular carcinoma show a loss of chromosome 16q22.1, resulting in a loss of the E-cadherin gene.

11. b. Inflammatory carcinoma of the breast was originally a clinical diagnosis (i.e., the entire breast was reddened and warm with edema). Histologic studies of some of the cases revealed an undifferentiated carcinoma invading the dermal lymphatics of the breast. It was found that some cases showed dermal lymphatic invasion without overt clinical symptoms. Calcifications may be seen, but do not contribute to the pathologic diagnosis. Large clear cells in the epidermis are a finding in Paget disease of the breast, as are eczematous type changes of the nipple.

12. c. In Paget disease of the breast, one may see intracytoplasmic melanin granules in the cytoplasm of the tumor cells. The granules have most likely been transferred from neighboring melanocytes by the process of cytocrinia, in which the tumor cells have imbibed melanin. In this case, and to avoid an erroneous diagnosis of melanoma, the HMB-45 immunostain is most useful, as it will be positive in melanoma and negative in Paget disease of the breast.

13. c. Phyllodes tumors and fibroadenomas are both fibroepithelial lesions of the breast. Fibroadenomas are more common before the age of 30, whereas phyllodes occur in the 40s. The stroma is extremely important when trying to decide between a phyllodes tumor and a fibroadenoma. Phyllodes tumors are distinguished from fibroadenomas on the basis of cellularity, mitoses, stromal overgrowth, nuclear pleomorphism, and infiltrative borders. Malignant phyllodes tumors show a dense stromal cellularity with mitoses, while it is more common to see a loose connective tissue stroma without mitotic activity in fibroadenomas. phyllodes tumors are often diagnosed at smaller sizes because of increased awareness of breast disease, much like fibroadenomas.

14. c. The lesion in the figure represents mucinous carcinoma. It is characterized histologically by small clusters of tumor cells floating in large pools of mucin as seen here. Foci of hemorrhage within these tumors are frequently seen. The tumor has strong cytoplasmic reactivity for MUC2 and decreased reactivity for MUC1 when compared with ductal carcinoma NOS. One quarter to one half of these tumors show endocrine differentiation consisting of argyrophilia, neuron specific enolase positivity, and dense core granules on electron microscopy. The mucin in the tumor is almost entirely extracellular and it may be of acid or neutral type. Grossly, these lesions tend to have sharply defined borders.

15. a. The tumor in this image is an example of tubular carcinoma. The angulated shape of the glands and apical snouts are characteristic features of this lesion. Calcifications were noted elsewhere in the lesion. Mitotic figures are absent in these lesions and nuclear pleomorphism is scant. Because of the marked degree of cellular differentiation in these lesions, it is not at all unusual for them to be underdiagnosed as benign. Metastases to the axillary lymph nodes occur in only 10% of cases and the prognosis is excellent. Because of the well-differentiated nature of this lesion, radial scar and microglandular adenosis are important differential diagnostic considerations and are sometimes difficult to differentiate from tubular carcinoma. The diagnosis is relatively uncommon, accounting for a frequency of 1% to 3% in clinical practice.

16. a. HER2/neu is an oncogene that encodes a transmembrane glycoprotein with tyrosine kinase activity known as p185, which belongs to the family of epidermal growth factor receptors. Its overexpression can be measured by immunohistochemistry and FISH. The performance of FISH is recommended for immunoreactivity graded 1+ and 2+. Overexpression (or positivity) of HER2/neu is seen in more aggressive tumors is an indication to treat patients with trastuzumab (Herceptin), which specifically targets HER2 receptors. Several centers have reported improvement in patient response when HER-2/neu therapy is combined with conventional chemotherapy.

17. d. Blunt duct adenosis is a histologic diagnosis and a clinically evident mass is not usually associated. Sarcoidosis, coccidiomycosis, breast abscess, and silicone reaction can all cause single or multiple breast masses in patients.

18. b. The histology represented here is that of collagenous spherulosis. It is characterized by the presence of intraluminal clusters of generally eosinophilic but sometimes basophilic collagen-rich spherules that seem to arise within the spaces between the epithelial and myoepithelial cells. The lesion can be seen in association with intraductal papilloma and sclerosing adenosis. Exceptionally, foci of lobular carcinoma in situ can involve this lesion. Collagen is seen ultrastructurally in association with basement membrane material and mineral deposition. Collagenous spherulosis can be seen in association with salivary gland tumors. Because this lesion does not contain any type of mucin, it would not be positive for Alcian blue.

19. b. A group convened by the College of American Pathologists recommended grouping patients with fibrocystic lesions in the following categories:

I. No or mild hyperplasia: no increased risk for subsequent invasive carcinoma.

II. Moderate or florid hyperplasia: 1.5 to 2 times the risk.

III. Atypical ductal or lobular hyperplasia: 5 times the risk.

IV. Ductal or lobular carcinoma in situ: 8 to 10 times the risk. (This fourth category, although not fibrocystic breast disease, was added by the group for the sake of completeness.)

20. c. Histiocytoid carcinoma is a cytologic variant of invasive lobular carcinoma and therefore does not belong to the invasive ductal carcinoma subgroup. Tubular, mucinous, metaplastic, and cribriform carcinomas are all distinct subtypes of invasive ductal carcinoma.

21. b. This is an example of pleomorphic lobular carcinoma. It has the pattern of growth of a classical invasive lobular carcinoma complete with the single cell file pattern of growth but exhibits a marked degree of nuclear pleomorphism and abundant cytoplasm. It frequently shows apocrine metaplasia and focal signet ring morphology. Expression of p53 and HER2/neu is very high. Lack of E-cadherin staining is in keeping with the lobular nature of the tumor.

22. d. Angiosarcoma can occur secondary to lymphedema following axillary dissection. Microscopically, the diagnostic areas are characterized by freely anastomosing vascular channels lined with atypical cells. The tumor is thought to arise from blood vessels, not lymph vessels. The differential diagnosis includes metaplastic carcinoma, the acantholytic variant of squamous cell carcinoma, and pseudoangiomatous stromal hyperplasia. Radiation-induced angiosarcomas are actually more common than de novo angiosarcomas and can occur anywhere from 2.5 to 10 years after radiation is given.