—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 4 - Pleomorphic Apocrine Lobular Carcinoma in Situ (PALCIS)

Stuart J. Schnitt
Beth Israel Deaconess Medical Center
Boston, MA


Click on each slide thumbnail image for an enlarged view
Clinical History
A 75 year old woman was found to have suspicious microcalcifications on a screening mammogram. A wire-localized excisional biopsy was performed. Diagnosis: Pleomorphic apocrine lobular carcinoma in situ (PALCIS)


Case 4 - Figure 1 - Pleomorphic apocrine lobular carcinoma in situ (PALCIS). Low power view demonstrating ductal spaces filled with and distended by a solid pattern proliferation of epithelial cells, with focal comedo necrosis and calcifications.
Case 4 - Figure 2 - Pleomorphic apocrine lobular carcinoma in situ (PALCIS). Medium power view showing comedo necrosis and calcification in one of the involved spaces.



Case 4 - Figure 3 - Pleomorphic apocrine lobular carcinoma in situ (PALCIS). At higher power, the abundant eosinophilic cytoplasm of the neoplastic cells is evident as is the cellular dyshesion.
Case 4 - Figure 4 - Pleomorphic apocrine lobular carcinoma in situ (PALCIS). Nuclear pleomorphism and "apocrine" cytoplasmic features are evident in this high power view.

Discussion It is now generally accepted that term "ductal carcinoma in situ" (DCIS) encompasses a heterogenous group of lesions that differ with regard to their presentation, histologic features, immunophenotype, genetic alterations, and clinical behavior [1, 2] . In contrast, lobular carcinoma in situ (LCIS) is still viewed by many as a homogeneous entity. When considering LCIS, many pathologists envision primarily, if not exclusively, the classical form of LCIS as initially described by Foote and Stewart more than 60 years ago [3], a lesion composed of loosely cohesive small cells with small, uniform nuclei that involve the lobules in a solid growth pattern. Clinical follow-up studies have indicated that women with LCIS as described by Foote and Stewart [3] are at a substantially increased risk for developing invasive breast cancer, that the risk is approximately equally distributed in both breasts (at least in studies with long-term follow-up), and that the subsequent invasive cancers may be either ductal or lobular in type (although invasive lobular carcinomas develop much more frequently in women with LCIS than in the general population) [4]. The results of these follow-up studies have led to the view that LCIS represents a marker or risk indicator for subsequent invasive breast cancer rather than a precursor lesion. However recent immunophenotypic and genetic data support the notion that at least some examples of LCIS, like DCIS, do in fact represent direct precursors of invasive carcinoma, albeit non-obligate precursors [5].

The results of recent histopathologic and immunophenotypic studies (the latter primarily using antibodies to e-cadherin and, to a lesser extent, high molecular weight cytokeratins) [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16] have challenged the long-held view that LCIS represents a single, stereotypical entity by demonstrating that some LCIS lesions exhibit cytologic and/or architectural features beyond those traditionally thought of as being associated with LCIS. For example, some LCIS lesions may show modest variation in nuclear size and shape (Haagensen type B cells) [17] or even marked nuclear pleomorphism (pleomorphic LCIS, PLCIS) [18, 19, 20, 21] , apocrine differentiation [22], myoid and clear cell cytoplasmic change [12], prominent signet ring cell forms [12], and comedo-type necrosis [14, 15] . Moreover, immunophenotypic studies have demonstrated that there are important differences between classical forms of LCIS and PLCIS, with the latter more likely to show a moderate to high proliferative rate and immunostaining for p53 protein [20]. Taken together, the results of these studies suggest that LCIS, much like DCIS, represents a spectrum of lesions rather than a homogenous entity. In recognition of this concept, it has been proposed that LCIS should be stratified into three grades in a manner analgous to the three-tiered grading systems in common use for DCIS [16, 20] .

During a review of problematic in situ breast carcinomas, we recently identified a subgroup of 10 cases that appear to represent yet another variant of LCIS which we have termed pleomorphic apocrine LCIS (PALCIS) [23]. All 10 cases presented with mammographic microcalcifications that raised the suspicion of DCIS. Nine of these 10 lesions occurred in post-menopausal women (median age 57.5 years). Histologically the lesions were all characterized by distension of involved spaces by a proliferation of large epithelial cells with apocrine cytology, including abundant eosinophilic cytoplasm and generally round nuclei. The nuclei showed moderate to marked pleomorphism. All lesions showed foci of necrosis, most often of the comedo type, and all lesions exhibited calcifications within involved spaces. In view of this constellation of features, a diagnosis of DCIS was entertained in all cases. However, in all of these cases, areas of the in situ carcinoma exhibited cellular dyshesion, and intracytoplasmic vacuoles were present in at least some of the neoplastic cells, features more commonly seen in LCIS than in DCIS. In some instances these vacuoles were large enough to produce signet ring cell forms. These lesions were similar in appearance to at least some of the lesions described by Sneige, et al as "pleomorphic lobular (ductal lobular) carcinoma in situ (PL/DLCIS)" [20].

Biomarker analysis revealed that all 10 cases were negative for e-cadherin expression, supporting a lobular rather than ductal phenotype. All 10 cases also showed variable cytoplasmic staining for gross cystic disease fluid protein (GCDFP)-15, consistent with the apocrine differentiation seen on hematoxylin-eosin stained sections. Fifty percent of the cases were estrogen receptor positive, 45% were progesterone receptor positive and 40% showed HER2 protein overexpression by immunohistochemistry. Seven of nine cases studied (78%) had a Ki67 proliferation rate >10% and seven of 9 cases showed at least focal cytoplasmic expression of cytokeratin 5/6. Based upon the histologic features and immunophenotype, we considered these lesions to represent variants of LCIS rather than DCIS.

To futher define the nature of PALCIS, we are currently performing an analysis of these lesions using array-based comparative genomic hybridization (aCGH). To date, aCGH has been performed on two of our PALCIS cases. Both of these cases showed loss of the entire arm of chromosome 16q and gain of 1q, genetic alterations characteristic of classical types of LCIS. These results provide further evidence that PALCIS represents a variant of LCIS.

The major differential diagnostic consideration for PALCIS is DCIS of intermediate or high nuclear grade. The key histologic clues to correctly classifying these lesions as lobular rather than ductal, even in the presence of prominent comedo necrosis and calcifications, are the presence in PALCIS of cellular dyshesion and intracytoplasmic vacuoles. Immunostains for e-cadherin can be a useful adjunct in this differential diagnosis, since all PALCIS cases studied to date have been e-cadherin-negative, whereas virtually all DCIS cases are e-cadherin-positive, regardless of nuclear grade or architectural pattern [6, 7, 8, 11, 15, 24, 25, 26, 27, 28] . PALCIS lesions are distinguished from PLCIS by the presence of prominent apocrine features on hematoxylin and eosin-stained sections. However, this distinction may be more of academic than practical value and it is reasonable to consider PALCIS a variant of PLCIS in which apocrine features are particularly prominent.

The appropriate management of patients with PALCIS is uncertain. Although these lesions appear to represent variants of LCIS, it should be emphasized that our current understanding of the clinical behavior of LCIS is based upon follow-up studies of patients with the classical form of the disease. The natural history of variant forms LCIS, particularly those characterized by marked nuclear pleomorphism and/or comedo-type necrosis (including PALCIS) is at this time unknown. It could be argued that in the absence of data to suggest otherwise, it is most prudent to treat such patients in manner similar to patients with DCIS, with complete excision of the lesion with tumor-free margins with or without radiation therapy(20). In fact, some pathologists prefer to categorize such lesions in their pathology reports as "in situ carcinomas with ductal and lobular features" rather than as variants of LCIS, both to emphasize the ambiguous histologic features and to ensure that patients with these lesions will be treated in a manner similar to that of patients with DCIS. On the other hand, it could be argued that in the absence of data suggesting that these lesions have a natural history that differs from that of classical forms of LCIS, treating such patients as if they had DCIS may be overly aggressive. Given that the biomarker profile of PALCIS and PLCIS is in some ways more similar to that of high grade DCIS than to classical LCIS, and given retrospective data suggesting that lesions categorized as lobular intraepithelial neoplasia (LIN) 3 (a category that includes the pleomorphic forms of LCIS) appear to be more highly associated with the presence of invasive lobular carcinoma than other forms of lobular neoplasia(16), at the present time we subscribe to the view that these lesions are probably most appropriately treated in a manner similar to DCIS.

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