Contemporary Evaluation of Breast Lymph Nodes in Anatomic Pathology

Beth T. Harrison, MD; Jane E. Brock, MBBS, PhD


Am J Clin Pathol. 2018;150(1):4-17. 

In This Article

Histopathologic Evaluation of the SLNs: Common Diagnostic Pitfalls

Various findings may be confused for metastatic carcinoma involving lymph nodes. A false-positive diagnosis, whether issued at the time of intraoperative consultation or final review, may result in unnecessary ALND, although the likelihood is decreasing with current trends in practice. False-positive results in the evaluation of axillary lymph nodes have been reported in up to 3.7% of cases.[23]

Benign inclusions are the most common cause of false-positive diagnoses. Nevus cell rests are small clusters of spindle-shaped melanocytic cells present in up to 6.2% of axillary lymph node dissections, typically in the capsule of lymph nodes Image 1G. Capsular nevi are usually morphologically distinct from breast carcinoma and S100 positive and keratin negative by IHC.[24] Benign glandular inclusions include ectopic breast tissue and endosalpingiosis. Ectopic breast tissue within axillary lymph nodes is uncommon but well documented and consists of bland-appearing cysts and tubules with or without associated stroma. The epithelium may be involved by apocrine metaplasia, squamous metaplasia, or epithelial hyperplasia.[25] Immunohistochemical confirmation of a myoepithelial cell layer aids in the diagnosis. Endosalpingiosis in supradiaphragmatic lymph nodes is quite rare and usually restricted to the mediastinum; however, rare involvement of axillary lymph nodes has been documented Image 1C, Image 1D, and Image 1E.[23] Benign breast epithelium may also be found in axillary lymph nodes as a result of iatrogenic displacement and mechanical transport. Epithelial displacement is most frequently observed following core biopsy of papillary lesions, both benign and malignant.[26] When any of the above types of benign inclusions are encountered, they are best distinguished from metastatic carcinoma by morphologic comparison to the primary breast tumor.

Undesired cytokeratin immunoreactivity in nonneoplastic cells is present in up to 10% of axillary SLNs and may raise concern for metastatic carcinoma Image 1F. More specifically, plasma cells and fibroblastic reticulum cells have been shown to react with antibodies against cytokeratin (CK) 8 and 18, including CAM5.2 (primarily recognizes CK8) and pan-CK (recognizes CK5, CK6, CK8, and CK18) cocktails. In contrast to CAM5.2 and pan-CK, CK AE1/AE3 antibody (recognizing 11 cytokeratin peptides, including CK8) is associated with little undesired immunoreactivity and should be the antibody of choice in the examination of SLNs.[27]

Finally, not all tumors found in axillary tissue are lymph node metastases. It is important to consider that a tumor deposit in the axilla may actually be the primary site. Even a biopsy that appears to be a nodal metastasis can actually be a triple-negative primary with a dense lymphoplasmacytic infiltrate Image 2A and Image 2B. This is more likely if no parenchymal breast lesion is seen on imaging. Findings that would suggest a primary include a lack of lymph node capsule and sinus at the edge of the lesion, the presence of in situ carcinoma as confirmed by myoepithelial markers, and the presence of normal breast epithelium in the surrounding tissue Image 2C and Image 2D. This can be a very challenging diagnosis on core needle biopsy. Another rare possibility is an adnexal primary tumor, which would be located in skin/subcutis and typically has an identical immunophenotype and morphology to breast carcinoma. In the absence of a skin adnexal gland in situ component, this is a diagnosis of exclusion and based on location of the tumor. There is harm done to the patient by calling an axillary primary a metastasis in error: adequate margin evaluation may not be given to the excision specimen, and the patient may get a mastectomy or be offered whole-breast radiation therapy based on the incorrect assumption that there is an occult primary lurking in the breast.

Image 2.

Axillary primary. Tumor nodules in axillary adipose tissue are counted as completely replaced lymph nodes; however, one should consider the possibility of an axillary primary, particularly if the tumor is circumscribed and triple-negative and lymph node architecture is not well visualized. Although the dense lymphocytic infiltrate and circumscribed margin mimics a lymph node in this example (A, H&E, x2; B, H&E, ×10), in situ carcinoma (arrowhead) and normal breast tissue (arrow) adjacent to the mass, both highlighted by the retained myoepithelial cell layer on a p63 immunostain (C and D, ×20; arrows), support interpretation as a primary. Clinical correlation is always required on biopsy sampling of axillary masses.