Cribriform lesions of the breast



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CRIBRIFORM LESIONS OF THE BREAST
Yunn-Yi Chen, M.D., Ph.D.

Department of Pathology, University of California San Francisco

Cribriform originates from the Latin cribrum which means sieve. In pathology, cribriform refers to a sieve-like histologic pattern in which sheets of epithelial cells are punctuated by, usually rounded, gland-like spaces. Four breast epithelial lesions are characterized by a uniform cribriform architecture, including cribriform ductal carcinoma in situ (DCIS), invasive cribriform carcinoma, collagenous spherulosis and adenoid cystic carcinoma (ACC). Correct categorization of these cribriform epithelial proliferations is often challenging as they appear deceptively similar and can be easily confused with one another, especially in core needle biopsy specimens. However, they are biologically distinct entities ranging from innocuous histologic findings to in situ process and invasive carcinoma, dictating divergent clinical behaviors and management plans.


This presentation focuses on a practical diagnostic algorithm for cribriform breast lesions based on combined distinguishing morphologic features and immunohistochemical characteristics. The helpful morphologic features to evaluate include: 1) growth pattern, whether the lesion is lobulocentric or diffuse; 2) constituent epithelial cell population, whether it consists of single or dual populations; and 3) type(s) of lumen and luminal content. Myoepithelial markers are useful diagnostic adjunct, which may be complemented by estrogen receptor (ER) and/or cytokeratin (CK) stains in some cases.

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Cribriform Ductal Carcinoma in Situ

Cribriform DCIS comprises most of the cribriform breast lesions encountered at the routine practice. At low power scanning, the normal lobular and ductal architecture is preserved and the associated stroma is usually not altered. However, when cribriform DCIS involves an underlying radial scar/complex sclerosing lesion, it may reveal a worrisome diffuse or infiltrative growth pattern and the stroma may be myxoid or slightly cellular suggesting a desmoplastic response. The glands in cribriform DCIS are round with a smooth contour. The neoplastic cells feature a single population of luminal type epithelial cells which usually display a moderate amount of eosinophilic cytoplasm and low to intermediate grade nuclei. Calcifications are often noted within the cribriform spaces. In problematic cases, immunostains with myoepithelial markers (p63, SMM, calponin) are very helpful in highlighting the intact myoepithelial cell layer to confirm the in situ process. It should be noted that focal decrease or even loss of expression for myoepithelial markers may be observed in DCIS especially when involving a radial sclerosing lesion. The epithelial cells demonstrate luminal phenotype with diffuse expression for ER and low molecular weight (LMW) CK (such as CAM5.2) and lack of reactivity for CK5/6.


Collagenous Spherulosis

Collagenous spherulosis is a rare benign lesion characterized by aggregates of acellular, eosinophilic, fibrillar spherules or myxoid material accompanied by proliferation of both epithelial and myoepithelial cells that are arranged in a distinctive cribriform architecture. Typically, collagenous spherulosis is encountered as an incidental microscopic finding arising in a background of benign proliferative processes, including intraductal papilloma, radial sclerosing lesion and sclerosing adenosis. Occasionally, the lesion is associated with calcifications and may be detected by mammography and targeted for biopsy. Very rarely, collagenous spherulosis can present as a palpable mass. Currently, there is no evidence to indicate that collagenous spherulosis is associated with increased risk of subsequent cancer.


Microscopically, the lesion is lobulocentric in distribution, usually limited to a few lobules or arising within a microscopic intraductal papilloma. The proliferating cells consist of biphasic myoepithelial and epithelial cells, both with bland cytologic features. The cribriform spaces are composed predominantly of myoepithelial-lined pseudolumens admixed with epithelial-lined true glandular lumens. The characteristic hyaline or myxoid basement membrane-like material is found within the pseudolumens. On closer inspection, a thin ring of eosinophilic, hyaline or “cuticle-like” material separates the compressed myoepithelial cells from the psuedolummen. Compared to the myoepithelial cells, the epithelial cells have more cytoplasm and may exhibit apical cytoplasmic snouts. Eosinophilic secretion may be observed in the true glandular spaces. The dual cell populations can be confirmed with epithelial (CAM5.2 and EMA) and myoepithelial markers (p63, SMM, calponin and SMA). In addition, both the hyaline and myxoid deposits are decorated by immunostains to laminin and type IV collagen, supporting these as basement membrane materials.

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Invasive Cribriform Carcinoma

Invasive cribriform carcinoma is a distinct subtype of breast cancer that is composed of cribriform glands and associated with a favorable clinical course. Pure invasive cribriform carcinoma is uncommon. Tumors displaying cribriform growth pattern are often admixed with various proportion of invasive carcinoma of other type, most commonly ductal carcinoma of no special type. There is also a tendency for cribriform glands to be associated with foci of tubular morphology. To qualify for invasive cribriform carcinoma, a tumor is required to show >90% of cribriform growth pattern or >50% of cribriform glands with a second component of tubular morphology. Invasive cribriform carcinoma is similar to tubular carcinoma histologically and biologically. Both are categorized as luminal A molecular subtype and carry an excellent prognosis.
Contrary to the lobulocentric distribution and the smooth contour as seen in cribriform DCIS, the glands in invasive cribriform carcinoma assume an apparent infiltrative growth and have an irregular or angulated configuration. There is usually a prominent desmoplastic cellular stromal reaction. The cribriform glands are lined by a uniform population of luminal type epithelial cells that often exhibit apical cytoplasmic snouts and show mild to moderate nuclear pleomorphism. Basophilic secretions and microcalcifications may be present within the gland lumens. A subset of tumors have a minor (<50%) component of tubular morphology. Ductal carcinoma in situ is identified in 80% of the lesions and is usually of cribriform pattern. Tumors metastatic to axillary lymph nodes usually retain the cribriform architecture.
It may be difficult to distinguish invasive cribriform carcinoma from cribriform DCIS on H&E sections. Furthermore, the in situ component of invasive cribriform carcinoma often exhibits cribriform architecture. Immunostains are very helpful in highlighting the intact myoepithelial cell layer in cribriform DCIS and its absence in invasive cribriform carcinoma. Similar to cribriform DCIS, the neoplastic cells are consistently positive for ER and LMW keratins and lack expression of CK5/6.

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma is one of the salivary gland-type tumors that can be observed in the breast. Although these tumors are hormone receptor and HER2 negative (i.e. triple negative) and show basal-like phenotype, they have an excellent prognosis, unlike conventional invasive ductal carcinomas with a basal-like phenotype and unlike ACC at extra-mammary sites.


Breast ACC is morphologically analogous to its salivary gland counterpart and demonstrates three architectural patterns: cribriform, trabecular-tubular and solid. This presentation focuses on those with a predominant cribriform pattern. At low power evaluation, the tumor shows a diffuse growth pattern. The cribriform glands usually have smooth and round contours, but may reveal an irregular and anastomosing configuration, especially in lesions also displaying solid architecture. The neoplasm is composed of biphasic basaloid/myoepithelial-like cells and ductal epithelial cells. The basaloid cells predominate and are characterized by scant cytoplasm and hyperchromatic nuclei; the ductal epithelial cells exhibit more abundant eosinophilic cytoplasm. Tumor cells may rarely demonstrate squamous or sebaceous differentiation. In ACC, two distinct types of lumens are appreciated. The pseudolumens are surrounded by the basaloid cells and contain basement membrane-like material that may appear myxoid or collagenous. True glandular lumens are lined by the ductal epithelial cells and contain eosinophilic granular secretions. Perineural invasion may be present.
The dominant basaloid/myoepithelial-like cells express p63, SMA, and high molecular weight keratins (CK14, CK5/6, 34E12), but are negative for calponin and SMM. The ductal epithelial cells are positive for CK7. Expression of CD117 (C-KIT), a transmembrane receptor-type tyrosine kinase and but also regarded as a basal marker, is identified in virtually all adenoid cystic carcinomas. These tumors are typically negative for ER and PR, and consistently lack HER2 overexpression.
Adenoid cystic carcinoma of the breast harbors a specific t(6;9) translocation, resulting in a novel MYB-NFIB fusion gene and overexpression of the MYB oncoprotein detected by immunohistochemistry. In fact, MYB-NFIB fusion transcripts have been identified in ACC from various anatomic sites, suggesting that ACCs arising in different locations not only share morphologic features but also probably evolve through activation of the same molecular pathway. Although overexpression of C-KIT is noted in the tumor cells, mutation of the C-kit gene has not been reported. Unlike common forms of triple-negative and basal-like breast cancers, breast ACC has rather simple genomes with low level of genetic instability and lacks mutations in TP53 and PIK3CA.

Breast ACC has an indolent clinical behavior with greater than 90% of 10-year survival rate. Axillary nodal metastasis is uncommon (~5%). Most patients are not eligible for hormonal therapy due to negative hormonal receptor status. Adjuvant radiotherapy has been shown to improve survival after breast-conserving surgery. The role of systemic chemotherapy in ACC remains controversial.



Table 1 summarizes the distinctive morphologic features and characteristic immunoprofile helpful in the differential diagnosis of cribriform breast lesions.
Table 1. Distinguishing Pathologic Features for Cribriform Breast Lesions





Cribriform DCIS

Collagenous Spherulosis

Invasive Cribriform Carcinoma

Adenoid Cystic Carcinoma

Growth pattern

Lobulocentric

Lobulocentric

Diffuse

Diffuse

Epithelial types

Luminal type epithelial cells

Dual myoepithelial and epithelial cells

Luminal type epithelial cells

Dual basaloid and epithelial cells

Lumens

True lumens

Pseudolumens and true lumens

True lumens

Pseudolumens and true lumens

Luminal content

± calcifications

Pseudolumens: hyaline/mucoid; True lumen: eosinophilic

± mucin or calcifications

Pseudolumens: hyaline/mucoid; True lumen: eosinophilic

LMW keratins

CAM5.2 diffusely +

CAM5.2 + in epithelial cells

CAM5.2 diffusely +

CK7 + in epithelial cells

P63, SMA

+ at periphery of ducts

+ in myoepithelial cells around pseudolumens and at periphery of ducts

-

p63 + in basaloid cells, SMA often + in basaloid cells

Calponin and SMM

+ at periphery of ducts

+ around pseudolumens and at periphery of ducts

-

Variable, usually -

ER

Diffusely +

- to patchy +

Diffusely +

Typically -

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