Metastasis to the periocular soft tissue of the orbit is a rare manifestation of metastatic cancer. Infiltrating lobular breast cancer (ILBC) is a special breast cancer subtype, which accounts for 10–15% of all mammary carcinomas and for ~1% of all malignancies. Here, we report on a high frequency of lobular breast cancer in patients with orbital metastases identified in an original series of metastatic tumor specimens and by a systematic literature review. A series of 14 orbital metastases was compiled from formalin‐fixed paraffin‐embedded archival tissues. All cases were subjected to histological re‐review and detailed immunophenotypical characterization. In addition, we performed a meta‐analysis of 68 previously published case reports describing orbital metastases, with special reference to breast cancer subtypes. Based on clinical history, histomorphology, immunophenotype, and/or comparison with matched primary tumors, orbital metastases were derived from breast cancer in 8/14 cases, seven of which were classified as metastatic lobular breast cancer. Other entities included non‐small cell lung cancer (4/14), infiltrating ductal breast cancer (1/14), prostate cancer (1/14) and adenocarcinoma of the esophagus (1/14). In line with this original series of orbital metastases, lobular breast cancer was the most common malignancy in 72 patients with orbital metastases described in 68 independent case reports. In conclusion, lobular breast cancer represents the cancer subtype with the highest prevalence among orbital metastases. The high frequency of ILBC in orbital metastases illustrates the special metastatic behavior of this tumor entity and may have implications for the understanding of the organotropism of metastatic lobular breast cancer.

Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E‐cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)‐positive/HER2‐negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)‐stained sections. In set B (62 cases), participants were provided with HE‐stained sections and E‐cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non‐lobular BC versus mixed BC versus ILC. Pairwise inter‐observer agreement and agreement with a pre‐defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E‐cadherin mutation status. Thirty‐five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter‐observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48–0.66) and substantial in set B (median κ = 0.75, IQR: 0.56–0.86, p < 0.001). Agreement with the reference diagnosis was substantial in set A (median κ = 0.67, IQR: 0.57–0.75) and almost perfect in set B (median κ = 0.86, IQR: 0.73–0.93, p < 0.001). The median frequency of CDH1/E‐cadherin mutations in specimens classified as ILC was 65% in set A (IQR: 56–72%) and 73% in set B (IQR: 65–75%, p < 0.001). Cases with variable subtype calls included E‐cadherin‐positive ILCs harboring CDH1 missense mutations, and E‐cadherin‐negative ILCs with tubular elements and focal P‐cadherin expression. ILCs with trabecular growth pattern were often misclassified as non‐lobular BC in set A but not in set B. In conclusion, subtyping of BC as ILC achieves almost perfect agreement with a pre‐defined reference standard, if assessment is supported by E‐cadherin IHC. CDH1 missense mutations associated with preserved E‐cadherin protein expression, E‐ to P‐cadherin switching in ILC with tubular elements, and trabecular ILC were identified as potential sources of discordant classification.

To date, the AP‐2 family of transcription factors comprises five members. Transcription factor AP‐2beta (TFAP2B)/AP‐2β was first described in 1995. Several studies indicate a critical role of AP‐2β in the development of tissues and organs of ectodermal, neuroectodermal and also mesodermal origin. Germline mutation of TFAP2B is known to cause the Char syndrome, an autosomal dominant disorder characterized by facial dysmorphism, patent ductus arteriosus and anatomical abnormalities of the fifth digit. Furthermore, single‐nucleotide polymorphisms in TFAP2B were linked to obesity and specific personality traits. In neoplasias, AP‐2β was first described in alveolar rhabdomyosarcoma. Immunohistochemical staining of AP‐2β is a recommended ancillary test for the histopathological diagnosis of this uncommon childhood malignancy. In neuroblastoma, AP‐2β supports noradrenergic differentiation. Recently, the function of AP‐2β in breast cancer (BC) has gained interest. AP‐2β is associated with the lobular BC subtype. Moreover, AP‐2β controls BC cell proliferation and has a prognostic impact in patients with BC. This review provides a comprehensive overview of the current knowledge about AP‐2β and its function in organ development, differentiation and tumorigenesis.

Invasive lobular breast cancer (ILC) is a special breast cancer (BC) subtype and is mostly hormone receptor (HR)-positive and ERBB2 non-amplified. Endocrine therapy restrains tumor proliferation and is the mainstay of lobular BC treatment. Mutation of ERBB2 has been associated with recurrent ILC. However, it is unknown whether ERBB2 mutation impacts on the otherwise exquisite responsiveness of early ILC to endocrine therapy. We have recently profiled n = 622 HR-positive early BCs from the ADAPT trial for mutations in candidate genes involved in endocrine resistance, including ERBB2. All patients were treated with short-term preoperative endocrine therapy (pET, tamoxifen or aromatase inhibitors) before tumor resection. Tumor proliferation after endocrine therapy (post-pET Ki67 index) was determined prospectively by standardized central pathology assessment supported by computer-assisted image analysis. Sustained or suppressed proliferation were defined as post-pET Ki67 ≥10% or <10%. Here, we report a subgroup analysis pertaining to ILCs in this cohort. ILCs accounted for 179/622 (28.8%) cases. ILCs were enriched in mutations in CDH1 (124/179, 69.3%, P < 0.0001) and ERBB2 (14/179, 7.8%, P < 0.0001), but showed fewer mutations in TP53 (7/179, 3.9%, P = 0.0048) and GATA3 (11/179, 6.1%, P < 0.0001). Considering all BCs irrespective of subtypes, ERBB2 mutation was not associated with proliferation. In ILCs, however, ERBB2 mutations were 3.5-fold more common in cases with sustained post-pET proliferation compared to cases with suppressed post-pET proliferation (10/75, 13.3% versus 4/104, 3.8%, P = 0.0248). Moreover, ERBB2 mutation was associated with high Oncotype DX recurrence scores (P = 0.0087). In summary, our findings support that ERBB2 mutation influences endocrine responsiveness in early lobular BC.