Mammary or breast carcinoma metastatic to lymph nodes.

Breast cancer, third only to prostate and lung cancer in frequency in the United States, is the most common malignant tumor in women. For 2007, approximately 180,000 cases of breast cancer are estimated in the United States, and approximately one-third of patients will die from their disease (1). In the world, over 1,000,000 new cases of breast cancer occur per year, with the highest incidence in the United States and Northern Europe, and the lowest incidence in Asia and Africa (2). Major risk factors for breast cancer include family history, genetic susceptibility (i.e., mutation of the BRCA1 and BRCA2 genes), and conditions that lead to prolonged exposure to estrogen such as long-term hormone replacement therapy, early menarche, late menopause, and having children at a late age or not having children at all (3,4,5). Breast cancer can occur during pregnancy; approximately 1 in 3,000 pregnant women are affected. Breast cancer also rarely occurs in men, representing less than 1% of all cases (1).

Breast carcinomas metastasize to regional lymph nodes, which act as a lymphatic filter for the breast. Two anatomic groups of regional lymph nodes are involved by metastases: axillary and internal mammary. As the former are routinely excised in patients with invasive carcinomas, most of the literature relevant to regional lymph node metastases is focused on the axillary lymph nodes.

Axillary lymph nodes are usually the first anatomic site to be involved by metastases in patients with breast carcinoma (6). Internal mammary lymph nodes are involved less frequently than axillary lymph nodes, and are more often involved when the primary carcinoma arises in the medial half of the breast. The status of the regional lymph nodes is the most important prognostic factor in patients with breast cancer and determines the use of adjuvant therapy after excision of the primary tumor. This importance is recognized by the inclusion of regional lymph nodes in the International Union Against Cancer tumor (T), lymph node (N), metastasis (M) staging system (7). The TNM designation is usually used for clinical staging purposes; pTNM denotes pathologic staging. Any other lymph nodes involved by metastases are coded as distant metastases (M), including those occurring in the supraclavicular and cervical groups, as well as contralateral lymph nodes (7).

Axillary lymph nodes are often first detected by physical examination (palpation), either by the patient or physician. Axillary lymph nodes are palpable in 50% to 60% of patients with clinically detected primary breast carcinomas. The frequency of palpable lymph nodes is much lower in patients in whom the primary breast neoplasms are not detected by physical examination and usually identified by mammography. In general, these primary breast carcinomas are of smaller size. However, it must be remembered that clinical examination of the axilla is not reliable (8). It is common for patients to have histologic evidence of axillary lymph node involvement without obvious lymph node enlargement that can be palpated. Conversely, a subset of patients with clinically palpable lymph nodes, 15% to 20%, do not have histologic evidence of metastatic carcinoma (8).

Risk of lymph node metastases is directly proportional to the size of the primary breast carcinoma. This was shown over 30 years ago in the studies of Haagensen (6). In patients with breast carcinomas smaller than 3 cm in diameter, one in three have axillary lymph node metastases, compared with one in two patients with breast carcinomas larger than 3 cm. Today, despite advances in therapy, size of the primary breast neoplasm remains an important predictor of lymph node metastases and overall prognosis. In a study of 2,233 women with invasive breast carcinoma, for those with equivalent axillary lymph node status, each millimeter (mm) of primary breast tumor diameter correlated with a 1% decrease in survival (9).

Both the number and location of histologically positive lymph nodes has prognostic significance. The importance of the lymph node number involved by metastatic carcinoma is shown in data from the National Surgical Breast Project (10). Patients with breast carcinoma treated with mastectomy who had no lymph node metastases had a 5-year survival rate of 83%. This survival rate dropped with the presence of lymph node metastases: 80% with one lymph node involved, 65% to 70% with two or three lymph nodes involved, 54% with four to six lymph nodes involved, and 28% when more than 12 lymph nodes were involved (10). Patients with axillary lymph node metastases are currently usually stratified into three prognostic categories: 1 to 3, 4 to 9, and 10 or more lymph nodes involved by metastases. In the study of 2,233 women with invasive breast carcinoma mentioned previously, for those in whom the primary breast tumor was of equivalent size, overall survival decreased by 6% for each positive lymph node identified (9).

Location of the axillary lymph node metastases is indicated by the anatomic level (11). Ipsilateral lymph nodes along the axillary vein and its tributaries are divided into three levels as follows:

Using this system, McDivitt and colleagues (12) showed a correlation between anatomic level and 5-year survival. The survival rate was 75% for patients with no involved lymph nodes, 56% for those with metastases at level I, 41% for those
with metastases at level II, and 28% for those with metastases at level III. In another long follow-up study of patients who underwent mastectomy for breast cancer, the 20-year survival rate was 65% for patients with no axillary lymph node metastases, 38% when only level I lymph nodes were involved, 30% when level II nodes were involved, and 12% when level III nodes were involved (13). Skipped levels, also known as skip metastases—that is, involvement of high axillary nodes without apparent involvement of low axillary nodes—are unusual (14,15). In an older study of patients with histologically positive axillary lymph nodes, level III nodes were involved when levels I and II were negative in only 0.4% of patients (14). In a more recent study, the frequency of skip metastases was 10% (15). However, separation of dissected axillary lymph nodes into three levels can only be made reliably when a standard radical mastectomy specimen, including both pectoralis muscles, is available for examination (16). In a modified radical mastectomy (without the pectoralis muscles), lymph nodes can only be identified as low and high axillary groups.

The problem of metastatic carcinoma in axillary lymph nodes without a clinically detectable breast tumor has been discussed by many investigators (17,18,19,20). In a woman, the site of origin is almost always the breast, and mastectomy is recommended even when the primary breast neoplasm cannot be identified despite extensive clinical workup. Careful gross and histologic evaluation of the breast specimen will commonly reveal a small carcinoma, a so-called occult carcinoma, but in some cases a breast primary carcinoma cannot be found. The frequency of occult breast carcinoma is very low. For example, in a series of 6,000 cases of breast carcinoma performed by Haagensen, 0.3% of patients had metastatic adenocarcinoma in axillary lymph nodes with an occult breast carcinoma (6). In other studies, the frequency is similarly low, less than 1% (17,18,19,20). In the event of an apparently occult breast carcinoma, Azzopardi (21) suggested careful investigation of the axillary tail of the breast, where a small primary tumor, sometimes no more than 5 mm in diameter, may be mistaken for a lymph node with metastatic tumor. The distinction in such cases is made by the abundant elastosis in breast tumors but not in the lymph nodes involved by metastasis (21).

Grossly, all lymph nodes within an axillary dissection specimen need to be identified and submitted for histologic examination to identify metastases (7). The total number of lymph nodes is an important prognostic indicator. Gross examination by itself, however, is unreliable for identifying the number of axillary lymph nodes, as their number is usually underestimated. Therefore, the number of lymph nodes in the axilla should not be stated in the gross description until after histologic examination of submitted sections.

In general, invasive breast carcinoma is associated with risk of axillary lymph node metastases. The risk of nodal metastases is low in patients with only in situ breast carcinomas. Theoretically, in situ carcinoma should not be able to spread to lymph nodes, and yet various studies show SLN biopsy specimens involved by metastatic carcinoma in up to 10% of these patients (30,31). Presumably, small foci of invasion have been missed in this subgroup of patients (22). Metastases to lymph nodes arrive via afferent lymphatics and enter sinuses. Therefore, in lymph nodes with partial involvement, the metastases usually have a sinusoidal distribution (Figs. 88.1 and 88.2). With more extensive involvement, the architecture of the lymph nodes becomes progressively replaced (Fig. 88.3).