Genetic and phenotypic characteristics of pleomorphic lobular carcinoma in situ of the breast

Abstract

The clinical, pathologic, and molecular features of pleomorphic lobular carcinoma in situ (PLCIS) and the relationship of PLCIS to classic LCIS (CLCIS) are poorly defined. In this study, we analyzed 31 cases of PLCIS (13 apocrine and 18 nonapocrine subtypes) and compared the clinical, pathologic, immunophenotypic, and genetic characteristics of these cases with those of 24 cases of CLCIS. Biomarker expression was examined using immunostaining for E-cadherin, gross cystic disease fluid protein-15, estrogen, progesterone, androgen receptor, human epidermal growth factor receptor2, CK5/6, and Ki67. Array-based comparative genomic hybridization to assess the genomic alterations was performed using microdissected formalin-fixed paraffin-embedded samples. Patients with PLCIS presented with mammographic abnormalities. Histologically, the tumor cells were dyshesive and showed pleomorphic nuclei, and there was often associated necrosis and microcalcifications. All lesions were E-cadherin negative. Compared with CLCIS, PLCIS showed significantly higher Ki67 index, lower estrogen receptor and progesterone receptor expression, and higher incidence of HER2 gene amplification. The majority of PLCIS and CLCIS demonstrated loss of 16q and gain of 1q. Apocrine PLCIS had significantly more genomic alterations than CLCIS and nonapocrine PLCIS. Although lack of E-cadherin expression and the 16q loss and 1q gain-array-based comparative genomic hybridization pattern support a relationship to CLCIS, PLCIS has clinical, mammographic, histologic, immunophenotypic, and genetic features that distinguish it from CLCIS. The histologic features, biomarker profile, and genomic instability observed in PLCIS suggest a more aggressive phenotype than CLCIS. However, clinical follow-up studies will be required to define the natural history and most appropriate management of these lesions.

Figure 1

Pathologic features of pleomorphic lobular carcinoma in situ (PLCIS). A. Low power photomicrograph showing massive expansion of ducts and lobules by neoplastic cells, with associated comedo necrosis and calcifications (Original magnification 40×); B. High power view of PLCIS with apocrine cytology showing dyshesive cells with nuclear pleomorphism and abundant eosinophilic cytoplasm (400×); C. High power view of PLCIS with non-apocrine cytology (400×).

Figure 2

Immunophenotype of pleomorphic lobular carcinoma in situ. (Original magnification 400X). A. Absence of staining for E-cadherin (note the positive membranous staining in the adjacent normal ducts); B. Strong cytoplasmic staining demonstrated for GCDFP-15; C. Strong expression of androgen receptor; D. Lack of ER expression (note focal nuclear staining in adjacent normal duct); E. HER2 protein overexpression. F. High Ki-67 labeling index.

Figure 3

The genomic profile of an apocrine subtype of pleomorphic lobular carcinoma in situ by high-resolution array-based comparative genomic hybridization. In this example, the lesion shows gains of 1q and 16p, losses of 11q, 13q, 16q, and 18, and amplification of 11q13.3 (the region containing cyclin D1 gene).

Figure 4

Frequency plots of genomic copy number gains and losses in pleomorphic lobular carcinoma in situ (PLCIS) and classic LICS (CLCIS). The proportion of LCIS lesions in which each BAC clone is gained (green) or lost (red) is plotted on the y axis according to its genomic location on the×axis. Vertical dotted lines represent chromosome centromeres. A: CLCIS (N=20); B: PLCIS (N=21); C: Non-apocrine PLCIS (N=13); D: Apocrine PLCIS (N=8).

Figure 5

Unsupervised hierarchical clustering of genome copy number profiles measured for 21 pleomorphic lobular carcinoma in situ (PLCIS) and 20 classic LICS (CLCIS). Green indicates increased genome copy number, red indicates decreased copy number, and yellow indicates amplified copy number. The bar to the left indicates chromosome location with chromosome 1pter at the top and 22qter and X at the bottom. The top color bars indicate types of LCIS. In the upper bar, apocrine PLCIS is blue and non apocrine PLCIS is green. In the lower bar, CLCIS is green, and PLCIS is blue. Four clusters emerge: Clusters 1 and 4 are enriched with CLCIS, while cluster 2 with nonapocrine PLCIS and cluster 3 with apocrine PLCIS. Note that cluster 3 is characterized by genome amplification and shows the highest genome instability.

Figure 6

Hypothesized pathway for lobular neoplasia along a multistep model of breast cancer progression. Solid arrows indicate the predominant pathway, while dashed arrows indicate a potential pathway. TDLUs, terminal duct lobular units; +, gain; −, loss; E-cad, E-cadherin; ALH, atypical lobular hyperplasia; LCIS, lobular carcinoma in situ; ILC, invasive lobular carcinoma; ↓, decreased expression; PLCIS, pleomorphic LCIS.