The breasts may be secondarily exposed to radiation during diagnostic procedures such as mammography and fluoroscopy (1), or in the course of irradiation administered to another organ such as mediastinal radiotherapy for Hodgkin lymphoma (2,3,4,5). The radiation exposure in these situations has been associated with an increased risk for the development of breast carcinoma (2,6,7,8,9). Wendland et al. (10) reported that the standard incidence ratio (SIR) for breast carcinoma among Hodgkin lymphoma patients who received radiotherapy was 3.17 when compared to the general population, and Schaapveld et al. (11) recorded an SIR of 4.7. The SIR for breast carcinoma in irradiated Hodgkin lymphoma patients was 1.90 when compared to nonirradiated patients, and the SIR in nonirradiated Hodgkin lymphoma patients was 1.67 when compared to the general population. These findings indicate that women treated for Hodgkin lymphoma have an elevated risk for breast carcinoma compared to the general population and that irradiation further increases this risk. Girls irradiated between the ages of 9 and 16 years face an especially high likelihood of developing breast carcinoma (9,12,13). This risk declines gradually during later adolescence and early adulthood. These results suggest greater susceptibility to breast carcinoma when radiation exposure is near puberty. The cumulative probability of developing breast carcinoma by 40 years of age has been reported to be 30% to 35% (3,13).

Most studies report breast carcinoma after irradiation for Hodgkin lymphoma in women, but in rare instances breast carcinoma may also occur in men (14). Data from several studies (15,16,17) include 189 patients who developed 214 breast carcinomas after radiotherapy for Hodgkin lymphoma. The median age at the time of diagnosis of Hodgkin lymphoma was 25 years. The median age at the time of diagnosis of breast carcinoma was 42 years, and the median interval was 18.6 years. The frequency of bilaterality was 13.2%; most contralateral tumors were metachronous. Axillary lymph node metastases occurred in 32% of the invasive carcinomas for which axillary lymph nodes were examined.

Patients who received supradiaphragmatic radiotherapy for the treatment of Hodgkin lymphoma are candidates for radiologic surveillance. In the absence of randomized controlled clinical trials, the efficacy of various imaging techniques has not been established for this situation. Mammography is reported to have high sensitivity for detecting carcinomas in the breast of women irradiated for Hodgkin lymphoma, especially when calcifications are present (18,19,20,21). Ultrasonography may be employed as an adjunct to mammography, but one cannot rely on this technique as a primary screening modality because of a relatively high frequency of false-positive findings (22). Magnetic resonance imaging (MRI) is effective for detecting tumor-forming, largely invasive carcinomas in women with genetic and other high-risk predispositions to breast carcinoma, but it has less sensitivity than mammography for detecting ductal carcinoma in situ (DCIS) (23).

Macroscopic examination of the irradiated breast does not disclose distinctive alterations, and the carcinomas arising in such breasts do not display distinctive macroscopic features. Microscopic study does not reveal structural changes attributable to irradiation in the underlying mammary tissue. Approximately 15% of the carcinomas detected in this setting are DCIS. Invasive carcinomas tend to be poorly differentiated; otherwise, they do not differ significantly in their morphologic characteristics from tumors in women without prior irradiation (5,24). Nearly all carcinomas have been ductal carcinomas of the NOS variety; however, special types of ductal carcinoma such as mucinous carcinoma have been encountered rarely, and so have invasive lobular carcinomas (14,16,17). The carcinomas are more likely to be bilateral and to occur in the medial regions of the breasts (20,25). Both synchronous and metachronous bilateral carcinomas have been reported (17,20,25). Carcinomas arising after irradiation for Hodgkin lymphoma display the “triple-negative” receptor panel more frequently than do sporadic breast carcinomas (26).

Mastectomy represents the most common primary surgical treatment of patients in this setting. Deutsch et al. (27) described 12 patients successfully treated with lumpectomy and radiation with “good to excellent cosmetic results” and “no significant acute adverse reactions and no late sequelae” after a median follow-up of 46 months.

Irradiation of the breast most commonly occurs as a component breast-conservation therapy for breast carcinoma. A small percentage of patients treated with breast-conserving therapy develop carcinoma in the treated breast. Recurrences most often occur 2 to 6 years after the completion of breast-conserving treatment and typically sit near the site of prior mass, whereas new primary carcinomas tend to develop more than 10 years
following treatment and most often involve tissue distant from the excision site (28). Imaging studies often disclose parenchymal distortion, scarring, fat necrosis, and scattered coarse calcifications in the treated breast. Cases exhibiting a new mass, a suspicious area of enhancement on MRI, a change in the features of a postoperative scar, or the appearance of new, pleomorphic calcifications warrant a biopsy to investigate the possibility of recurrent carcinoma.

The histologic alterations associated with irradiation of underlying mammary tissue appear most obvious in terminal duct-lobular units (29,30,31) (Figs. 23.1, 23.2, 23.3). The changes include collagenization of intralobular stroma, thickening of
periacinar and periductular basement membranes, atrophy of acinar and ductular epithelium, cytologic atypia of epithelial cells, and relative prominence of acinar myoepithelial cells, which seem to be preserved to a greater extent than the epithelial cells (32). Generally, the effects in larger ducts appear less pronounced than those in terminal duct-lobular units. Apocrine epithelium is susceptible to developing severe cytologic atypia after therapeutic radiotherapy, especially in hyperplastic foci. When evaluating a posttreatment biopsy, it is useful to examine the pretreatment specimen for evidence of apocrine metaplasia. Atypical fibroblasts can be found in a minority of specimens (Fig. 23.4).

In any one patient, most of the glandular tissue responds in a relatively uniform fashion if the entire breast has been irradiated; however, one can observe substantial variation in the severity of changes from one patient to another. The changes occasionally may be so slight as to be virtually indistinguishable from physiologic atrophy. In one study, differences in radiation effects among individual patients did not correlate with the radiation dose, patient age, posttreatment interval, or the use of adjuvant chemotherapy (29). Once established, the effects of irradiation do not seem to regress. After studying 120 breast specimens obtained at intervals ranging from less than 1 year to more than 6 years after radiotherapy, Moore et al. (31) did not observe significant variation in the appearance of the radiation-related alterations.

When a radioactive implant or an external “boost” has been used, histologic changes in the adjacent area may be more severe than those in the distant regions of the breast. Epithelial atypia may occur in larger ducts and it may be superimposed on existing hyperplasia or apocrine metaplasia (Fig. 23.5). Fat necrosis and atypia of stromal fibroblasts are more common in proximity to such areas (30,33,34). Radiation-induced vascular changes, which are not ordinarily seen after external beam radiotherapy, may be seen in this setting. Small- and medium-sized arteries may show sclerosis, fragmentation of elastica, endothelial atypia, and myointimal proliferation leading to narrowing of the vascular lumina. Prominent, cytologically atypical endothelial cells are also apparent in capillaries.

In situ lobular and ductal carcinomas persisting after radiation therapy are largely intact; consequently, the affected lobules and ducts appear filled and, often, expanded by the neoplastic population. Frequently, little or no microscopic change
attributable to treatment is evident when pre- and postirradiation samples of in situ carcinoma are compared (Figs. 23.6 and 23.7). Greater cytologic atypia after treatment is encountered in a minority of cases (Fig. 23.8). In one study (35), the grade of the pretreatment DCIS matched that of the recurrent DCIS in 95 (84%) of 113 cases. Recurrent invasive carcinomas also resemble their pretreatment counterparts in their histologic type, grade, and receptor expression (Fig. 23.9), whereas the histologic characteristics of the new primary carcinomas tend to differ from those of the pretreatment carcinomas (36). Irradiated invasive carcinoma cells occasionally contain multiple hyperchromatic nuclei or display focal necrosis not evident in the pretreatment tissue. These findings suggest that the cells represent residual carcinoma showing radiation effects.