The challenging imaging and histopathologic features of diffusely infiltrating breast cancer

•Architectural distortion is the imaging biomarker of this breast cancer subtype.•The features of this cancer deviate from those of other breast cancer subtypes.•The immunohistochemical biomarkers are deceptive and unreliable.•Long-term survival is poor despite screening and advancement in therapy.•Large format histopathology is necessary to determine the true disease extent. Clinical, imaging and outcome observations indicate that diffusely infiltrating breast cancer, presenting as a large region of architectural distortion on the mammogram and conventionally termed classic infiltrating lobular carcinoma of diffuse type, represents a very unusual breast malignancy. This article aims to draw attention to the complex clinical, imaging, and large format thin and thick section histopathologic features of this malignancy, which challenges our current diagnostic and therapeutic management practices. Prospectively collected data from the randomized controlled trial (1977–85) and from the subsequent, ongoing population-based mammography service screening (1985–2019) with more than four decades of follow up in Dalarna County, Sweden provided the database for investigating this breast cancer subtype. Large format thick (subgross) and thin section histopathologic images of breast cancers diagnosed as “diffusely infiltrating lobular carcinoma of the breast” were correlated with their mammographic tumour features (imaging biomarkers) and the long-term patient outcome. This malignancy does not have a distinct tumour mass or focal skin retraction at clinical breast examination; instead, it causes an indistinct “thickening” and eventually shrinks the entire breast. A dominant feature is extensive architectural distortion on the mammograms caused by an excessive amount of cancer-associated connective tissue. Unlike other invasive breast malignancies, this subtype forms concave contours with the surrounding adipose connective tissue, a feature that makes it difficult to detect on mammograms. Women with this diffusely infiltrating breast malignancy have a 60% long-term survival. Its long-term patient outcome is surprisingly poor compared to that expected from its relatively favourable immunohistochemical biomarkers, including a low proliferation index and remains unaffected by adjuvant therapy. The unusual clinical, histopathologic and imaging features of this diffusely infiltrating breast cancer subtype are consistent with a site of origin quite different from that of othe