Case 3 -

Collision or Intimacy of LCIS and DCIS Ian O. Ellis Nottingham University Hospital, U.K.

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Clinical History Woman aged 36, Presented with a lump in her left breast. First noticed 2 years previously. Clinically a suspicious 30mm mass. Mammography and ultrasound showed a malignant appearing 28mm speculate mass. Core biopsy showed invasive carcinoma. FNA of axillary node showed malignant cells. Right breast asymptomatic and no abnormality on clinical examination. Mammography showed 38mm of suspicious calcification. Core biopsy showed LCIS with ADH. Initial treatment left mastectomy and right wide local excision. Case material from the right breast specimen. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Case 3 - Figure 2 Case 3 - Figure 3 Case 3 - Figure 4 Low and high magnification views of a duct space showing effacement of the normal epithelium by a population of atypical cells arranged in a micropapillary configuration. The features are typical of low to intermediate grade DCIS. Case 3 - Figure 5 Low and high magnification views of a duct spaces an admixture of DCIS with islands of paler cells with the morphology of lobular neoplasia (LCIS). Case 3 - Figure 6 Low and high magnification views of a duct spaces an admixture of DCIS with islands of paler cells with the morphology of lobular neoplasia (LCIS). Case 3 - Figure 7 An expanded lobule adjacent to the tissue illustrated in figure 1-6 showing features typical of lobular carcinoma in situ. Case 3 - Figure 8 More examples of intimately admixed DCIS and LCIS. Case 3 - Figure 9 More examples of intimately admixed DCIS and LCIS. Case 3 - Figure 10 E-Cadherin immunocytochemistry staining shows strong membrane positive reactivity in the DCIS component and negativity in the LCIS component in the pure and admixed areas. Case 3 - Figure 11 E-Cadherin immunocytochemistry staining shows strong membrane positive reactivity in the DCIS component and negativity in the LCIS component in the pure and admixed areas. Case 3 - Figure 12 E-Cadherin immunocytochemistry staining shows strong membrane positive reactivity in the DCIS component and negativity in the LCIS component in the pure and admixed areas. Diagnosis: Collision or Intimacy of LCIS and DCIS; a chance finding or manifestations of the same disease? Discussion Are Lobular Carcinoma in situ and low grade DCIS more closely related than we have previously believed? Recent molecular profiling studies have shown the existence at least five different BC subtypes, each with different clinical outcomes. These include luminal (A and B), basal, HER2 and normal like sub types. The luminal subtype 'A' have higher levels of oestrogen receptor alpha and a better survival outcome compared with luminal subtypes 'B' [1, 2]. The basal and HER2 subtypes are generally of higher grade that the luminal subtypes. Furthermore, there is convincing genetic evidence to suggest that low grade (LGBC) and high grade DCIS and invasive breast cancers evolve through distinct evolutionary pathways [3, 4]. LGBCs are usually diploid/near-diploid and harbour recurrent loss of chromosome 16q and gains of chromosome 1q. In contrast, high grade breast cancers are usually aneuploid with complex genetic profiles and infrequent deletion of 16q [5, 6]. In high grade breast cancers, even when loss of 16q is present, the underlying genetic mechanism appears to be distinct from that seen in LGBCs [7]. Taken together, these findings suggest that progression from LGBC to high grade breast cancers is an unlikely biological phenomenon [4, 7, 8] and that LGBC's are a distinct class of breast cancer. How do more traditional histological system relate to these emerging classes? Which histological types of breast cancer are found in the luminal subtype of breast cancer? It has recently been recognised that there is a high frequency of co-existence of columnar cell lesions (CCLs), flat epithelial atypia (FEA),lobular neoplasia, including atypical lobular hyperplasia and lobular carcinoma in situ (LN) and atypical ductal hyperplasia/low grade ductal carcinoma in situ (ADH/low grade DCIS) with invasive tubular carcinoma (TC), tubulolobular carcinoma (TLC) and classic invasive lobular carcinoma (ILC) and we have recently [9] proposed the concept of a family of related low nuclear grade precursor, in situ and invasive neoplastic lesions (LNGBN) of the breast which include these lesions as members. This observation is further supported by the identification that FEA, ADH/low grade DCIS, LN and invasive low grade breast cancers have remarkably similar immunophenotypes and molecular genetic characterisitics and that this phenotype and genotype is distinct from that seen in high grade breast cancers. Given that the morphological and immunohistochemical features of FEA cells are almost identical to those seen in ADH/ low grade DCIS and LN, and that the molecular genetic changes of FEA are similar to those found in matched low grade breast cancers [10], our findings suggest that FEA is a common non-obligate precursor of LGBC and ILC. Taken together, these lesions may represent a family of precursor, in situ and invasive neoplastic lesions belonging to the luminal 'A' subclass of breast cancer. If this hypothesis is correct, why do we see such morphological diversity between some family members, for example low grade DCIS versus LCIS and invasive tubular carcinoma versus classical invasive lobular carcinoma? Presently, cancer is perceived as a clonal disease that depends on multiple genetic mutations in division-competent stem and progenitor cells [11]. After transformation, these cells can become neoplastic due to deregulation of self-renewal, differentiation, membrane transport activity, telomerase activity and anti-apoptotic pathways, resulting in the ability to migrate and metastasise [11]. Subsequently, the heterogeneity of BCs may derive from inherent differences in the underlying originator cell population and/or result from stochastic genetic and epigenetic events causing different combinations of oncogene activation and loss of tumour suppressor gene (TSG) function in normal breast stem or committed progenitor cells [11, 12]. E-cadherin (CDH1) is a TSG localised on chromosome 16q21 and is frequently lost in ILC. It is recognised that CCLs, ADH/low grade DCIS, TC, ICC, low grade IDC, and TLC are positive for E-cadherin, and in contrast LN and ILC lack expression of this tumour suppressor gene and adhesion molecule. We speculate that loss of normal CDH1 gene expression, which is associated with the development of lobular differentiation [3, 4, 8], is a secondary event which confers particular morphological and behavioural characteristics to these members of the LNGBN family. Take Home Messages Breast cancer is now recognised to include up to five distinct molecular genetic sub types; Luminal (A and B), Basal, HER2 and Normal like The luminal A class is characterised by high expression of estrogen and progesterone receptors, and luminal epithelial cell characteristics These characteristics are shared by many so called traditional special types of breast cancer including both classical lobular carcinoma, and tubular carcinoma and their known precursors Co localisation of lobular neoplasia (ALH and LCIS) with columnar cell lesions, and ADH and low grade DCIS has been described with or without coexisting low grade or lobular invasive breast cancer The concept of a low grade (luminal A type) family of invasive, insitu and their precursors is emerging which includes columnar cell lesions, classical lobular carcinoma and tubular carcinoma Flat epithelial atypia (FEA) appears to represent a non obligate precursor of this low grade familty of insitu and invasive breast cancers. 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