Diagnostically Challenging Subtypes of Invasive Lobular Carcinomas: How to Avoid Potential Diagnostic Pitfalls

Abstract

Invasive lobular carcinoma is the most common special breast carcinoma subtype, with unique morphological (discohesive cells, single-cell files, targetoid pattern) and immunohistochemical (loss of E-cadherin and β-catenin staining) features. Moreover, ILC displays a poor response to neoadjuvant therapy, a different metastatic pattern compared to invasive breast carcinoma of no special type, as well as unique molecular characteristics. In addition to the classic variant of invasive lobular carcinoma, several other well-recognized variants exist, including classic, alveolar, tubulolobular, solid, pleomorphic, signet-ring, and mixed. Furthermore, three novel variants of invasive lobular carcinoma, i.e., with extracellular mucin production, papillary features, and tubular elements, have been described during the last decade. We herewith focus on the unique morphological and immunohistochemical characteristics of these novel varieties of invasive lobular carcinoma, as well as differential diagnostic considerations and potential diagnostic pitfalls, especially when dealing with biopsy specimens.

Keywords: differential diagnosis; encapsulated papillary carcinoma; extracellular mucin production; invasive lobular carcinoma; lobular carcinoma with papillary features; lobular carcinoma with tubular elements; mucinous carcinoma; solid papillary carcinoma; tubular carcinoma.

Figure 1

ILC with extracellular mucin production. ((A) 40×): The tumor consists of a mucinous (blue arrows) and a non-mucinous (red arrow) component. ((B,C) 40×): The mucinous component consists of multiple, relatively circumscribed, nodular foci of extracellular mucin. ((D) 100×): On higher power, tumor cells are arranged as single cells, clusters, pseudocribriform structures, or solid nests. ((E,F) 200×): The non-mucinous component shows typical ILC features such as a single-file pattern (blue arrows) and single cells lacking cohesion. ((G) 200×): In both areas without (1(G)) and with extracellular mucin production (1(H)), intracellular mucin and signet-ring cells can be seen. ((I) E-cadherin 200×) On immunohistochemistry, E-cadherin stain was negative; the red arrow points to positive internal control.

Figure 2

ILC with papillary features. ((A,B) 40×): The tumor consists of two components. The first had a solid architectural pattern. ((C) 200×): On high power examination, fibrovascular cores (red arrows) were observed. ((D,E) 40×): The second component shows a typical classic variant ILC morphology, with a single-file pattern and single-cell infiltration. ((F) 200×) On high-power examination, several signet-ring cells were visible. ((G,H) E-cadherin 100×): Immunohistochemically, E-cadherin was negative in both tumor components. Normal ducts and lobules served as an internal control (red arrow). ((I) β-catenin 100×): β-catenin was negative as well.

Figure 3

ILC with tubular elements ((A,B) 100×): Areas of conventional growth pattern consisting of single-cell files. ((C,D) 200×): On higher power examination, tumor cells are characterized by a lack of cohesion. ((E,F) 40×): Adjacent to the single-cell files, several tubular elements can be seen. ((G) E-cadherin 40): On immunohistochemistry, the tubular elements lack E-cadherin staining ((H) β-catenin 40×), but retain β-catenin expression ((I) 40×): This ILC variant may be misdiagnosed as well as differentiated NST or as tubular carcinoma, especially in a biopsy specimen consisting only of tubular structures.