Invasive lobular carcinoma (ILC) is the second most common subtype of breast carcinoma following invasive breast carcinoma of no special type (NST), accounting for 10–15% of breast carcinoma [1]. It has unique clinical, imaging, histological, immunohistochemical, and molecular features.

While usually presenting as a mass-forming lesion, it may remain clinically undetectable.

Mammographic detection may be difficult [2]; ultrasonography is more sensitive but may underestimate tumor size [3]. Magnetic resonance imaging (MRI) may prove more helpful ^[4][5][4,5]. This underestimation of tumor size often results in positive surgical margins, thus requiring additional surgical procedures [6]. Occasionally, ILC may initially manifest as a distant metastatic lesion [7] and thus displays a different metastatic pattern from invasive breast carcinoma of NST [1]. ILC metastasizes less commonly to the lung but more frequently to the peritoneum, gastrointestinal and gynecologic systems ^{[8][9][10][11]}[8,9,10,11].

Histologically, ILC is characterized by distinct morphological features, i.e., small cells lacking cohesion, forming single-cell files or arranged in a concentric pattern around existing ducts and lobular units (targetoid pattern), minimal stromal response, and the presence of a variable number of signet-ring cells [6]. Apart from the classic ILC, first described in 1941 by Foote and Stewart [12], a number of histological variants have so far been described, including alveolar [13], tubulolobular [14], solid [15], trabecular [13], signet-ring [16], pleomorphic ^[17][18][17,18] and mixed [1]. ILC is characterized by deleterious mutations in CDH1 gene mapping in 16q22.1 accompanied by allelic loss of the remaining allele [6] and corresponding to a lack of E-cadherin and aberrant β-catenin immunostaining [19].

ILC usually has a luminal A molecular phenotype and is often estrogen receptor (ER)- and progesterone receptor (PR)-positive and HER−2 neu-negative, therefore being a prime candidate for hormonal therapy. It also shows a poor response to neoadjuvant therapy compared to invasive breast carcinoma of NST.

ILC presents specific molecular characteristics compared to other subtypes of invasive breast carcinoma.

ILC with extracellular mucin production was first described by Rosa et al. in 2009 [20]. A review of the relevant literature has yielded 12 papers describing 39 cases in toto ^{[20][21][22][23][24][25][26][27][28][29][30][31][32]}[20,21,22,23,24,25,26,27,28,29,30,31,32]. In some cases, important clinicopathological data, such as tumor size, lymph node, hormone receptor, Her−2 status, therapy, and follow-up information, are not mentioned.

The age ranged from 31 to 87 years (median 63). Most cases had a palpable or a radiographically detected lesion. The tumor size ranged from 7 to 100 mm (median 40 mm). Multifocality was present in several cases, one being a coexistent invasive breast carcinoma of NST [30]. One patient presented with skin ulceration [20] and another one with skin retraction and thickening, suggestive of inflammatory breast carcinoma [32]. Nodal status was positive in 17 cases.

The mucinous component percentage ranges from 5% to 95% of the total tumor area. In both mucinous and non-mucinous components, the architectural pattern can be of the classical, alveolar, and/or solid variants. Tumor cells are of small or intermediate size, pleomorphic or with apocrine morphology. Moreover, in most cases, a variable number of signet-ring cells can be identified in both areas. In many instances, concurrent lobular intraepithelial neoplasia was identified next to the ILC.

ER and PR were positive in 39/39 and 27/38 (one case does not mention PR status) cases, respectively. Her−2 neu was overexpressed in five tumors. The follow-up time ranged from 2 to 171 months (median 50).

Soong et al. performed molecular analysis interrogating the full coding sequences of 447 genes for mutations and copy number variations and selected introns across for gene rearrangements in 13 cases with adequate material in their series [32]. As expected, alterations of CDH1 at the gene level were present in all but one patient. Notably, concurrent CDH1 mutations and 16q loss were detected in 11 of 13 cases. In the remaining two cases, one harbored 16q loss without detectable CDH1 mutation, and the other harbored CDH1 mutation without loss of a 16q arm. Interestingly, these two cases exhibited signet-ring cell morphology. The most common single-nucleotide variations (SNV) involved CDH1 (10 cases), followed by PIK3CA, POLQ, TP53, ERBB3 (3 cases each), ERBB2, and RUNX1 (two cases each). Other genes with isolated SNV potentially clinically significant included AKT1, FANCD2, GATA3, MAP3K1, MUTYH, PTEN, RB1, and SF3B1 [32].

Furthermore, five cases showed 17p loss, four 18q loss, and five 22q loss. GATA3, FOXA1, CCND1, VEGFA, KAT6A, and POLB recurrent gene amplifications and ERBB2, CDK12, RUNX1, AURKA, ZNF217, ESR1, FGFR1, WHSC1L1, isolated gene-level amplifications were identified. The above genomic analysis argues for the lobular type of this rare breast cancer variant.

In 2016, Rakha et al. described three cases of ILC mimicking papillary carcinoma [33]; this was followed by four more single case reports ^{[34][35][36][37]}[34,35,36,37]. This variant of ILC has been described under different terms such as “ILC mimicking papillary carcinoma” [33], “lobular breast cancer with solid growth pattern mimicking a solid-papillary carcinoma” [34], “ILC with papillary features” [35], “ILC with solid and encapsulated papillary carcinoma growth pattern” [36], “ILC mimicking encapsulated papillary carcinoma” [37].

Important clinicopathological data, including tumor size, lymph node, hormone receptor, Her−2 status, therapy, and follow-up information, are lacking in some of the aforementioned papers. In cases with available information, the age ranged from 61 to 86 years (median 73). All patients presented with a palpable lesion. Imaging findings (mammography and ultrasound) showed a well-circumscribed nodular mass in three cases ^[35][36][37][35,36,37] and a hypoechoic, highly vascularized mass in one case [34]. The tumor size ranged from 1.2 to 5.5 cm (median 2.8). There was no metastatic lymph node involvement in cases with available information.

Histologically, ILC with papillary features has, in most cases, two distinct components; the first consists of a nodular at least partially encapsulated tumor with a solid papillary growth pattern, fibrovascular cores, and focal hemosiderin deposition. In all but one case, a second component with the morphology of a classic variant ILC was found in close relation with the nodular neoplasm. The single case lacking a classic ILC component showed LCIS around the main tumor [36].

Immunohistochemically, all cases lack E-cadherin expression and are associated with loss of β-catenin ^[33][34][33,34] or aberrant (cytoplasmic) p120 ^[36][37][36,37] expression. GATA3 positivity supported a primary breast tumor ^[35][37][35,37]. Immunostains for various myoepithelial cell markers, such as p63, CK5/6, CK14, calponin, smooth muscle actin, and smooth muscle myosin heavy chain, were negative either within or in the periphery of the nodules. Immunostains for neuroendocrine differentiation markers (Chromogranin A, Synaptophysin, and CD56) were also negative where performed ^{[33][35][36][37]}[33,35,36,37]. ER and PR showed intense staining, while HER−2 neu was uniformly negative.

The three cases reported by Rakha et al. did not show local recurrence or metastasis within a median follow-up of 13 months [33]. Two additional cases mentioned that patients were alive with no evidence of disease after a follow-up of 8 and 10 months, respectively ^[36][37][36,37].

Christgen et al. examined the molecular profile of a case of ILC encompassing solid-papillary and classic variant ILC patterns [34], classified as luminal type B and luminal type A, respectively. Both variants shared common copy number profiles, including the loss of 6q, 11q, 13q, and 16q harboring CDH1 and the gain of chromosome 1q, suggesting a common origin. Interestingly, sequencing analysis revealed a unique CDH1 mutation resulting in a truncated E-cadherin protein in both components, further arguing for a clonal origin. Li et al. performed next-generation sequencing that revealed a frameshift mutation in exon 7 of CDH1 [36].

This ILC variant displays tubular elements with P-cadherin expression. So far, there is only one manuscript (2020) describing 13 cases [38].

Clinically, the age ranged from 42 to 79 years (median 59). Clinical information concerning the imaging characteristics and tumor size was not mentioned. Five cases had lymph node involvement, two being micrometastases. Some cases were bifocal, multifocal, or bilateral. One case was ovarian metastasis.

Histologically, ILC with tubular elements is characterized by tumor cells arranged in several different architectural patterns seen in ILC (classic, trabecular, solid, and dispersed) admixed with tubular elements of variable shape and size (longitudinal, teardrop shaped, small round tubules with narrow lumina). Tubular elements represent a variable amount of total tumor area. Nuclear atypia is low or intermediate overall. In some cases, concurrent lobular carcinoma in situ can be identified.

Immunohistochemically, E-cadherin expression was strongly reduced in one and completely absent in 12 cases in both components, i.e., ILC and tubular. Despite this E-cadherin loss, most cases retained focal β-catenin expression. P-cadherin was expressed in 12 cases, with stronger staining in tubular elements and weaker or absent staining in the conventional ILC areas. All tumors were ER-positive, and Her−2 neu-negative; PR was positive in eleven cases. The tubular elements had a lower proliferative activity, as measured by Ki67 immunostaining. No information about follow-up time was available.

All tumors underwent molecular analysis. Eleven cases harbored CHD1 mutations, while two lacked detectable CDH1 mutations. Four patients exhibited bifocal, multifocal, and bilateral lesions with tubular elements present in a single focus. Molecular analysis in these cases showed almost always identical CDH1 mutations in all foci, suggesting clonal relatedness of ILC with tubular elements and adjacent ILC with a conventional growth pattern.

Chromosomal analysis revealed gains on 1q, 8q, 11q13, and 16p and losses on chromosomes 8p, 11q, 16q, and 22q [38]. Notably, all cases examined exhibited either a copy number loss and loss of heterozygosity (LOH) or a copy number neutral LOH of 16q22.1 harboring CDH1 gene [38]. In the same study, P-cadherin mRNA expression was assessed by quantitative real-time RT-PCR in two different regions, one with conventional morphology and the second consisting almost exclusively of tubules. The region with tubular morphology showed increased P-cadherin mRNA expression.