The term "classic invasive lobular carcinoma" of the breast defines breast malignancies of vastly different nature.

PURPOSE: To describe in detail the special features of a previously unappreciated "classic invasive lobular carcinoma" which is confined to the terminal ductal lobular units (TDLUs) and differs considerably from the extensive classic invasive lobular carcinoma, and to suggest specific terminology. METHOD: All invasive breast cancer cases without associated microcalcifications diagnosed in our Institution with the histopathologic diagnosis of classic invasive lobular carcinoma during the years 1996-2019 (n = 560) formed the basis of this study. The cases were prospectively classified according to their imaging biomarkers (mammographic features) and followed up to Dec 31, 2021, to determine long-term patient outcome. An additional 2600 invasive breast cancer cases (diagnosed other than invasive lobular carcinoma) without associated microcalcifications served as a reference group. Detailed histopathologic analysis used large format (10x8 cm) thin section technique and staining methods including hematoxylin-eosin (H&E), E-cadherin, cytokeratin CK 5/6, a transmembrane glycoprotein (CD44) and anti-actin or anti-smooth muscle myosin heavy chain. RESULTS: The imaging biomarkers differentiated two separate disease subgroups, having the same histopathologic diagnosis, classic invasive lobular carcinoma. One of these has the imaging biomarker of extensive architectural distortion with no central tumour mass, occupies the extralobular mesenchyme and has a long-term survival of 56%. The other subgroup forms stellate or circular non-calcified tumour masses usually smaller than 20 mm, which appear to arise in the intralobular mesenchyme, and has a significantly better long-term survival of 84%. CONCLUSIONS: There is a striking difference between the subgross histopathology and the mammographic appearance (imaging biomarkers) of two breast malignancies having the same histopathologic diagnosis, "classic invasive lobular carcinoma". The large difference in the long-term outcome of these two tumour types is even more striking. Using the same specific term, "classic invasive lobular carcinoma", to describe these two separate entities can adversely affect management decisions.

The challenging imaging and histopathologic features of diffusely infiltrating breast cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 other breast cancers. Additionally, the immunohistochemical biomarkers are deceptive and unreliable because they indicate a cancer with favourable prognostic features predictive of a good long-term outcome. The low proliferation index is usually indicative of a breast cancer with a good prognosis, but in this subtype the prognosis is poor. If we are to improve the dismal outcome of this malignancy, it will be necessary to clarify its true site of origin, which will be a prerequisite for gaining a better understanding why current management efforts often fail and why the fatality rate is so unfortunately high. Breast radiologists should be watchful for the development of subtle signs of architectural distortion at mammography. Large format histopathologic technique enables adequate correlation of the imaging and histopathologic findings.

Can we improve breast cancer management using an image-guided histopathology workup supported by larger histopathology sections?

PURPOSE: Breast radiologists examine the entire breast in full-size images, while breast pathologists examine small tissue samples at high magnification. The diagnostic information from these complementary imaging approaches can be difficult to integrate for a more clinically relevant evaluation of malignancies spanning several centimetres. We have explored the advantages and disadvantages of imaging guided larger section pathology techniques compared with the standard 2 × 2.5 cm. small section technique. METHODS: We compared the ability of conventional small section histopathology with larger section histopathology techniques to examine surgical resection margins and full disease extent. We evaluated the pre-surgical imaging workup and use of microfocus magnification radiography of sliced surgical specimens in the histopathologic evaluation of disease extent and status of surgical margins. RESULTS: Image assisted large section histopathology of excised breast tissue enables comprehensive examination of an approximately tenfold larger contiguous tissue area than is provided by conventional small section technology. Attempting to cover the full area of each consecutive slice of resected tissue is more labour-intensive and expensive with the small section approach and poses challenges in reconstituting three-dimensional tumour architecture after morcellation and sectioning. Restricting histopathologic examination to a limited number of samples provides an incomplete evaluation of surgical margins. CONCLUSIONS: A considerably improved documentation of breast cancer and a more reliable assessment of tissue margins is provided by using larger sized histopathology samples to correlate with breast imaging findings. These in turn can enable more appropriate treatment planning, improved surgical performance, fewer recurrences, and better patient outcome. Uncertainty of surgical margin evaluation inherent to the standard small section technique can lead to inappropriate decisions in surgical management and adjunctive therapy. Progress in breast diagnosis and treatment will largely depend on whether histopathology terminology and technique will undergo a revolution similar to the one that has already occurred in breast imaging.

Imaging biomarkers of breast cancers originating from the major lactiferous ducts: Ductal adenocarcinoma of the breast, DAB.

PURPOSE: As we have previously demonstrated, breast cancers originating in the major lactiferous ducts and propagating through the process of neoductgenesis are a distinct subtype of invasive breast cancers, although by current practice they are placed within the group termed ductal carcinoma in situ (DCIS) and are consequently underdiagnosed and undertreated. Imaging biomarkers provide a reliable indication of the site of origin of this breast cancer subtype (Ductal Adenocarcinoma of the breast, DAB) and have excellent concordance with long-term patient outcome. In the present paper, the imaging biomarkers of DAB are described in detail to encourage and facilitate its recognition as a distinct, invasive breast cancer subtype. METHODS: Correlation of breast imaging biomarkers with the corresponding histopathological findings using large format technology, with additional evidence from subgross, thick section histopathology to demonstrate the complex three-dimensional structure of the newly formed duct-like structures, neoducts. RESULTS: There are six imaging biomarkers (mammographic tumour features) of DAB. Four subgroups have characteristic malignant-type calcifications on the mammogram. Two of these are characterized by intraluminal necrosis producing fragmented or dotted casting type calcifications on the mammogram; another two subgroups are characterized by intraductal fluid production which may eventually calcify, producing skipping stone-like or string of pearl-like calcifications. A fifth DAB subgroup presents with bloody or serous nipple discharge and is usually occult on mammography but is detectable with galactography and magnetic resonance imaging (MRI). The sixth subgroup presents as architectural distortion on the mammogram without associated calcifications. CONCLUSIONS: Radiologists can use these well-defined imaging biomarkers to readily detect Ductal Adenocarcinoma of the Breast, DAB. Immunochemical biomarkers are generally not determined from the DAB itself, due to the erroneous assumption that DAB is non-invasive. MRI plays a crucial role in determining disease extent and guiding surgical management. The accumulating evidence that this disease subtype is, in fact, an invasive cancer, necessitates an urgent re-evaluation of the diagnostic and management criteria for this poorly understood malignancy.

Breast cancers originating from the major lactiferous ducts and the process of neoductgenesis: Ductal Adenocarcinoma of the Breast, DAB.

PURPOSE: To call attention to a highly fatal breast cancer subtype arising from the major lactiferous ducts that is currently underdiagnosed as ductal carcinoma in situ (DCIS) with or without microinvasion. METHOD: All breast cancers diagnosed at the Department of Mammography, Falun Central Hospital, Sweden, since 1977 have been classified according to their mammographic tumour features (imaging biomarkers) and followed up at regular intervals for the past four decades. The imaging biomarkers characteristic of breast cancers apparently arising from the major lactiferous ducts have been correlated with large format thin and thick section histopathology and long-term patient outcome. RESULTS: Breast cancers arising within the major lactiferous ducts propagate intraductally and produce continuously branching neoducts through epithelial-mesenchymal transformation (EMT), an invasive process termed neoductgenesis, which eventually forms a massive tumour burden. The high fatality of this breast cancer subtype indicates its truly invasive nature, although it is conventionally termed ductal carcinoma in situ, DCIS, terminology which is at odds with its poor long-term patient outcome. The neoducts are filled with multiple layers of malignant cells, have no attached lobules, and propagate by forming multiple invasive side branches. These newly formed duct-like structures are surrounded by a desmoplastic reaction (cancer associated fibroblasts, CAFs) and periductal lymphocytic infiltration. The neoducts are tightly packed together in irregular formations bearing no resemblance to the paniculate branching structure of normal lactiferous ducts. Cancers originating from the major ducts have six imaging biomarkers which can be easily recognized at breast imaging. These are described in detail in an accompanying article. CONCLUSIONS: Neoductgenesis in the breast, DAB, is similar in appearance and prognosis to ductal adenocarcinoma of the prostate, DAP. We propose the term ductal adenocarcinoma of the breast, DAB, to facilitate its recognition as a distinct invasive breast cancer subtype. The high fatality rates associated with neoductgenesis reflect the failure of current histopathologic diagnostic criteria to effectively guide therapeutic practice. When the neoducts are associated with small stellate/spiculated or spherical/oval-shaped invasive cancers arising from the terminal ductal lobular units (TDLUs), the prognosis and management are erroneously estimated according to the smaller invasive tumour(s), giving a false sense of security often resulting in undertreatment. Recognition that neoductgenesis is an invasive malignancy is a prerequisite for preventing treatment failure.

A new approach to breast cancer terminology based on the anatomic site of tumour origin: The importance of radiologic imaging biomarkers.

PURPOSE: To use mammographic tumour features (imaging biomarkers) to classify breast cancer according to its apparent anatomic site of origin in the new era where tumours are found at their nonpalpable, earliest detectable phase. METHOD: Large format, subgross, three-dimensional histopathologic images of breast cancer subtypes and their corresponding imaging biomarkers were correlated with large format thin section histopathology and long-term patient outcome. RESULTS: This systematic correlation indicates that breast cancers arise from three separate fibroglandular tissue components: the terminal ductal lobular units (TDLUs), the major lactiferous ducts, and in the stem cells of the mesenchyme. The resulting three cancer subgroups have distinctly different clinical, histopathological and mammographic presentations and different long-term outcomes. The relative frequency of these three breast cancer subgroups is approximately 75%, 20% and 5%, respectively. Classification of breast cancers according to their anatomic site of origin, as demonstrated with breast imaging and confirmed by subgross histopathology, correlates closely with the long-term patient outcome. CONCLUSIONS: Classification of breast cancers according to their site of origin helps overcome the inconsistencies in the current histopathologic terminology with its ductal-lobular dichotomy. The ability of the imaging biomarkers to determine the site of tumour origin and serve as a prognostic indicator emphasizes the increasingly crucial role of breast imaging in the management of breast cancer. Basing breast cancer management upon anatomically relevant terminology challenges the conventional mindset. Our proposals are based on research results from an unprecedented number of prospectively collected nonpalpable breast cancers diagnosed at their earliest detectable phases and followed up for several decades. This article is a general introduction to a series of forthcoming articles describing in detail the breast malignancies originating from the three sites of origin.