Pleomorphic Lobular Carcinoma in Situ: A Divergent Entity With Emerging Significance

Many historical evolutions of concepts have emerged regarding lobular neoplasia (LN) since 1865, when Cornil first described this entity as “intraepithelial breast carcinoma in lobules.”[1] Currently, the term “lobular neoplasia” encompasses a spectrum of atypical changes in the lobule that include atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS). According to Page criteria,[2,3] ALH and LCIS differ quantitatively and are composed of small, round, monomorphic, discohesive cells with an increased nuclear/cytoplasmic ratio. The SEER (Surveillance, Epidemiology, and End Results) data have shown that the age-adjusted, age-specific rates of LCIS among women in the United States have increased fourfold in the past 20 years, with a steep rise in LCIS incidence seen in postmenopausal women between the ages of 50 and 70 years.[4] LCIS has been established as a risk factor for subsequent invasive carcinoma, of either the ductal or lobular type. Although the SEER data show that the majority of invasive carcinomas that occur subsequent to lobular neoplasia are ductal, invasive lobular carcinomas comprised up to half of subsequent carcinomas, in comparison to the expected rate of invasive lobular carcinomas (5%–14%) in the general population.[4] Current NCCN (National Comprehensive Cancer Network) guidelines recommend counseling premenopausal patients about risk reduction with tamoxifen, and counseling postmenopausal patients about risk reduction with raloxifene (Evista).[5] LCIS is often multicentric and bilateral, and it is usually diagnosed incidentally following surgical excision of another breast abnormality.[6,7] There are no specific clinical findings (in particular, no palpable lump) associated with these lesions, and the lesion is rarely visible on mammography as a dominant mass.[8,9] When examining pathologic specimens, there are no gross macroscopic features characteristic of LCIS. Multifocality in clinically undetectable lesions makes subsequent management planning difficult. Furthermore, there is no standard of care for treatment when LCIS is the most significant finding on core needle biopsy (CNB). The current management guidelines for LCIS are not adopted uniformly; a follow-up surgical excision is performed when there are features overlapping with DCIS, when there is an association with other high-risk lesions, and when there is an imaging-pathology discordance.[10] The appropriate management when LN is encountered exclusively on CNB specimens has been addressed by some studies and remains controversial. The overall incidence of finding carcinoma on follow-up excision for LN on CNB specimens is reported to be up to 20%.[11,12] The risk of upstaging of CNB specimens is further increased when LN is associated with calcifications or columnar cell alterations.[12] Our study revealed a 13% incidence of upstaging to carcinoma in CNB specimens with LN and columnar cell alterations but only a 9.6% incidence of upstaging in cases with LN alone.[12]

Classical Lobular Carcinoma in Situ (LCIS)

The classical LCIS contains two types of cells. Type A cells are small and relatively uniform in size, have round-to-ovoid nuclei and uniform chromatin with scant cytoplasm, and lack prominent nucleoli. Type B cells are larger, with more abundant and clearer cytoplasm, slightly more pleomorphic nuclei, clumped chromatin, and conspicuous nucleoli. In the current literature, several variants of LCIS are described to include pleomorphic LCIS, pleomorphic apocrine LCIS, LCIS with comedo necrosis, and carcinoma in situ with mixed ductal carcinoma in situ (DCIS)/LCIS. The prognostic value of grading of invasive lobular carcinomas (ILC) was addressed by a few studies. In a large study by Rakha et al,[13] a multivariate analysis showed that histologic grade is an independent predictor of survival and disease-free survival. In the same study, the ILC of intermediate nuclear grade (NG 2) showed higher local/regional recurrence (44% vs 37%) and distant metastasis than the low nuclear grade. The results of this study provide strong evidence for routine assessment and reporting of histologic grading for ILC, and the authors recommended routine reporting of the Nottingham grade for ILC.[13] In contrast, the significance of routine histologic grading of LCIS has not been addressed by many studies, although it is used by many pathologists in practice. Our study exemplifies for the first time the increased upstaging of LCIS of intermediate nuclear grade in a significant number of cases, compared with LCIS of low nuclear grade (0% vs 11%).[11]

Pleomorphic Lobular Neoplasia

Pleomorphic lobular carcinoma (PLC) is defined as lobular carcinoma cells with an infiltrating pattern similar to classic ILC, but with pleomorphic nuclei. In earlier studies, this variant was categorized under ‘‘mixed group''; it has now been established as a distinct entity of ILC and has gained recognition through subsequent studies. PLC tumors have a characteristic apocrine cytoplasm which is strongly and diffusely positive for gross cystic disease fluid protein 15 (GCDFP-15), an apocrine marker. In comparison to classic ILC, these tumors tend to be less ER and PR positive, and more HER2/neu positive.[14] A study that compared the recurrence-free survival and overall survival in patients with classic ILC and PLC show that the latter patients tend to have a shorter relapse-free survival and higher recurrence rates.[14,15] These invasive carcinomas characteristically are associated with an in situ component that is histologically similar to the invasive component, described initially by Frost et al.[16] Pleomorphic lobular carcinoma in situ (PLCIS), a rare, distinct variant of lobular carcinoma in situ (LCIS), is composed of large, pleomorphic, discohesive cells with eccentric nuclei and eosinophilic cytoplasm. Comedo necrosis is common and makes it difficult to distinguish from high-grade ductal carcinoma in situ (DCIS).[15,17] The natural history of pure PLCIS on core needle biopsies (CNB), on the other hand, is still poorly understood. There is a dearth of reports and long-term follow-up studies addressing the issue. In our study addressing the significance of pure PLCIS on CNB, we found upstaging to a significant lesion in approximately 25% of cases (3 of 12) in the follow-up resections. The histology of the invasive carcinomas encountered were classic type, mixed (pleomorphic and classic), and pleomorphic types. Residual PLCIS was found on follow-up excisional procedures in 83% of cases (10 of 12), and only classic LCIS was observed in the remaining 17% (2 of 12 cases),[18] similar to the case described in this issue of ONCOLOGY by Kounalakis et al.

Both PLC and PLCIS harbor the hallmark molecular genetic features of lobular carcinomas that show additional molecular genetic changes and more complex karyotypes than LCIS/ILC, demonstrating that PLCIS may be a direct precursor of invasive PLC. The majority of PLCIS and classic LCIS cases demonstrated loss of 16q and gain of 1q. Changes on chromosomes 1, 11, 14, 16, and 8 are frequently observed in both PLC and PLCIS. Deletions in chromosome 16q and amplification of regions of 1q are associated with loss of e-cadherin and beta-catenin expression and are the characteristic genetic abnormalities seen in classic lobular carcinoma. The characteristic 8q23.1, 14q23.3, and 12p12.2 reported in high-grade DCIS were seen in our cases of PLCIS as well. PLCIS exhibits features that overlap with both classic lobular neoplasia and high-grade DCIS.[19,20]

Conclusions

In conclusion, Kounalakis et al have comprehensively discussed the significance of PLCIS, a divergent entity with emerging significance. PLCIS coexists with PLC or may exist as an isolated lesion and display characteristic cytomorphologic features that allow it to be identified. Similar to its high-grade ductal counterparts, PLCIS shares a high proliferation rate and HER2/neu overexpression, despite an immunoprofile similar to that of classic lobular neoplasia. In recent years, e-cadherin and P120 immunostains have contributed enormously to our ability to distinguish these variants of lobular neoplasia from their ductal counterparts. Although recent studies have contributed to developments in the management of these lesions, a larger number of cases in clinical studies is needed so that we can better understand the biology of these lesions and establish appropriate clinical management strategies. Targeted therapy focusing on ER/PR expression (eg, with endocrine therapy) may be of great value. Use of trastuzumab (Herceptin) in cases of HER2-overexpressing PLC is a possibility that can be evaluated in the near future.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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