breast_book_cover.gif (5551 bytes)    MEDULLARY CARCINOMA
Medullary carcinomas account for fewer than 5% to 7% of all invasive breast cancers. Some studies have indicated that this type of breast cancer has a favorable prognosis, despite its aggressive histologic appearance.However, considerable controversy exists regarding the appropriate histologic definition of medullary carcinoma, as well as the reproducibility of this diagnosis among pathologists. As a result, the prognostic implications of this diagnosis are uncertain.

Clinical Presentation

Patients with medullary carcinoma usually present at a relatively younger age than patients with other breast cancers; the mean age at presentation is in the late fifth and early sixth decades, with a wide age range reported.The majority of patients with medullary carcinoma present with a palpable mass, usually in the upper outer quadrant. Of interest, some patients with this tumor type exhibit axillary lymphadenopathy at the time of presentation, suggesting the presence of metastatic disease. Histologic examination of the lymph nodes in such cases, however, typically reveals benign reactive changes. Rare examples of medullary carcinoma have been reported in men.

To some degree, the mammographic features of medullary carcinoma reflect the pathologic features, although they are not specific. Most lesions are associated with a moderately well defined mass unassociated with calcifications.However, a significant proportion of cases of medullary carcinoma show an ill-defined margin. Moreover, the majority of mammographically well-circumscribed cancers are infiltrating ductal carcinomas rather than medullary carcinomas.On ultrasonographic examination, medullary carcinomas are generally well circumscribed, frequently lobulated, and hypoechoic.

Gross Pathology

The mean size of medullary carcinomas is similar to that of breast cancers of no special type. In gross appearance, these lesions are well-circumscribed, soft, tan-brown to grey tumors that bulge above the cut surface of the specimen. A multinodular appearance may be appreciated in some cases. Areas of hemorrhage, necrosis, or cystic degeneration may be present in tumors of any size, but prominent necrosis is usually seen in larger tumors.
Histopathology

Three similar but distinct classification systems for the histologic diagnosis of medullary carcinomas have been proposed by Ridolfi et al., Wargotz and Silverberg, and Pedersen et al.All three classification schemes recognize the following attributes of medullary carcinomas, but the relative importance and the mandatory nature of each are stressed to different degrees: (a) syncytial growth pattern of the tumor cells in more than 75% of the tumor, (b) admixed lymphoplasmacytic infiltrate, (c) microscopic circumscription, (d) grade 2 or grade 3 nuclei, and (e) absence of glandular differentiation  Tumors that lack a variable number of these characteristics (depending on the system used) are classified either as atypical medullary carcinoma or invasive ductal carcinoma. The Ridolfi system has the most stringent and the Pedersen system1 the least stringent criteria. Regardless of the classification system used, however, medullary carcinoma is frequently overdiagnosed. Studies assessing the reproducibility and prognostic implications of the various classification systems have yielded conflicting results and are summarized below.

In addition to the histologic features listed earlier, medullary carcinomas may be associated with a DCIS component (usually comprised of cells that are morphologically similar to the invasive component), hemorrhage, tumor necrosis, cystic degeneration, and various types of metaplasia of the tumor cells, most often squamous metaplasia.Patients with medullary carcinoma do not appear to have an increased incidence of multicentricity or contralateral cancers.

The expression of various biological markers in medullary carcinomas is more reflective of the aggressive histologic features of these tumors than of the favorable prognosis reported by some investigators. Estrogen-receptor positivity has been reported in 0% to 33% of medullary carcinomas and progesterone-receptor positivity in 0% to 36%. DNA studies performed in conjunction with various NSABP protocols demonstrated that 85% of medullary carcinomas are aneuploid. A review of the karyotypic analysis of 14 examples of medullary carcinoma revealed complex chromosomal alterations in 9 (64%), which was a significantly greater proportion than that seen in tubular and mucinous carcinomas.128 In addition, medullary carcinomas are associated with p53 protein accumulation in the majority of cases,131 and HER-2/neu overexpression has been reported in 0% to 14% of lesions.

Clinical Course and Prognosis

Although studies have differed in the histologic criteria used, most studies indicate that the incidence of axillary lymph node metastases is lower in patients with medullary carcinomas (19% to 46%) than in those with atypical medullary carcinomas (30% to 52%) or invasive ductal carcinomas (29% to 65%).

Data regarding survival rates in patients with medullary carcinoma must be interpreted with an understanding of the histologic criteria used for diagnosis. Most pathologists currently use the histologic criteria set forth by Ridolfi et al.,who reported a significantly better 10-year survival rate for 57 patients with medullary carcinoma (84%) than for 79 patients with atypical medullary carcinomas (74%) and 56 patients with nonmedullary carcinomas (63%). A later study by Wargotz and Silverberg, using slightly modified criteria, reported 5-year survival rates of 95% for 24 patients with medullary carcinoma, 80% for 16 patients with atypical medullary carcinoma, and 70% for 10 patients with breast cancers of no special type. A subsequent study using the Ridolfi criteria confirmed these findings and reported 10-year survival rates of 92% for 26 patients with medullary carcinoma, 53% for 23 patients with atypical medullary carcinoma, and 51% for 46 patients with breast cancers other than medullary carcinoma.Several other reports have called these earlier findings into question, however. Pedersen  examined the prognostic implications of each of the criteria put forth by Ridolfi and found many to be poorly reproducible or to lack prognostic significance. Furthermore, the authors could not demonstrate a survival advantage in patients with medullary carcinoma as defined using these criteria. These authors proposed their own classification and suggested that it yielded superior prognostic information. Similarly, using Ridolfi's criteria, Ellis et al. could not demonstrate a significant difference in the 10-year survival rate for patients with medullary carcinoma (51%) compared with patients with atypical medullary carcinoma (55%) and patients with carcinoma of no special type (47%); patients with medullary carcinoma did demonstrate a more favorable survival rate than did patients with grade 3 tumors of no special type.6 Moreover, in a review of the NSABP experience, Fisher analyzed survival data for 198 patients with medullary carcinomas and 149 patients with atypical medullary carcinomas enrolled in multiple trials and reported that node-negative patients with medullary carcinoma and node-positive patients with medullary carcinoma treated with chemotherapy (melphalan and 5-fluorouracil) experienced modestly improved survival rates compared with control patients with breast cancers of no special type. This improved survival was not observed, however, in untreated node-positive patients, although the sample sizes in this group were small. The authors concluded that “the prognosis of typical medullary cancer is not as ‘good' as previously perceived.”

In addition to the clinical follow-up studies that question a favorable prognosis for medullary carcinoma, several studies have also questioned the practical applicability of the diagnostic criteria. Specifically, several studies have been published in which a number of pathologists (including those with expertise in breast pathology) failed to attain acceptable consensus in diagnosing medullary carcinomas using the criteria of Ridolfi.In one of these studies,a direct comparison was made between the criteria advocated by Ridolfi Wargotz and Silverberg,and Pedersen. In that study, the criteria of Pedersen were the most reproducible. None of the three classification systems, however, was related to axillary lymph node status or overall survival. In contrast, a clinical follow-up study examining a relatively small number of patients with medullary carcinoma suggested that the Ridolfi classification system is superior to the Pedersen classification system in predicting improved survival.

In summary, although some patients with medullary carcinoma may have improved survival compared with patients with breast cancers of no special type, the ability of pathologists to reliably and reproducibly identify this subset of patients is suboptimal. Clinicians must be aware of these limitations when confronted with a pathology report suggesting the diagnosis of medullary carcinoma. Given the difficulty in diagnosing these lesions, one could argue that treatment decisions, particularly those related to the use of adjuvant chemotherapy, should not rest solely on assumptions regarding the prognostic implications of medullary carcinoma.

The results of the use of breast-conserving therapy in patients with medullary carcinoma have been reported in three studies with a total of 72 patients.The local recurrence rates in the two studies with a median follow-up of approximately 5 years were 4% and 7%. In one study with a 10-year median follow-up, however, local recurrences were observed in 5 of 17 patients (29%). In all three studies, no significant differences were seen in local recurrence rates among patients with medullary carcinoma and patients with invasive ductal carcinoma. Thus, the available limited data suggest that conservative surgery and radiation therapy are an appropriate local treatment for patients with medullary carcinoma.