Pathologic Spectrum of Secretory and Mucinous Breast Lesions

The lesions in this section all contain an accumulation of secretions within the glandular lumen. In addition, certain lesions also contain intracellular secretions.

Nonneoplastic lesions with intraluminal secretions include pseudolactational hyperplasia, cystic hypersecretory hyperplasia, collagenous spherulosis, and fibrocystic changes.

Neoplastic lesions with intraluminal secretions include microglandular adenosis, secretory carcinoma, cystic hypersecretory carcinoma, and invasive ductal carcinoma, not otherwise specified (with intraluminal secretions). Of note, microglandular adenosis is considered to be a neoplastic precursor lesion.

Pregnancy-like or pseudolactational hyperplasia is an incidental histologic finding with features similar to those seen in pregnant and/or lactating females. The pathogenesis of this condition in nonlactating patients is related to estrogen susceptibility (either endogenous or exogenous). Certain medications, such as antipsychotics, antihypertensives, and exogenous estrogens, have been associated with this condition.²  Morphologically, the lesion consists of an acinar proliferation with minimal intervening connective tissue. The epithelial cells may contain secretory vacuoles, immunoglobulin A, lysozyme, and lactoferrin, or show clear cell change (Figure 1, A and B). Calcifications may develop in association with the luminal secretions, and upon mammographic screening they may become the target of biopsy sampling.²  Invasive carcinoma is rarely associated with pregnancy-like hyperplasia, and it has a good prognosis based on limited studies.^3,4 

Collagenous spherulosis is a benign condition derived from progressive accumulation of extracellular material, including mucopolysaccharides, collagen IV, and laminin, within benign ducts.⁵  These ducts show cribriform architecture lined by benign-appearing epithelial cells. The early stage of mucinous spherulosis evolves into the more developed lesion of collagenous spherulosis with time. The secretory material shows a variable appearance from basophilic to eosinophilic staining, and a fibrillary or scalloped appearance (Figure 1, C and D).⁵  Despite its benign nature, collagenous spherulosis can pose a diagnostic dilemma because on low power it shows a cribriform architecture mimicking low-grade ductal carcinoma in situ.⁶  It can sometimes be associated with carcinoma, almost always lobular carcinoma in situ.⁷  Another differential diagnosis among cribriform lesions with luminal secretions is adenoid cystic carcinoma.⁵  Immunohistochemical profiling can help with this differential diagnosis. The cells of adenoid cystic carcinoma express p63, smooth muscle actin, and CD117 (c-KIT), whereas these immunohistochemical markers are negative in collagenous spherulosis.^8,9  The epithelial cells of collagenous spherulosis are positive for calponin and smooth muscle myosin, which are negative in adenoid cystic carcinoma based on few studies.¹⁰ 

Microglandular adenosis (MGA) is an uncommon lesion of the breast that some authors consider to be a nonobligate neoplastic precursor of invasive carcinoma and others consider to be a neoplastic process.^11,12  Microglandular adenosis has a variable presentation, ranging from microscopic lesions to large palpable masses.¹³  Histologically, MGA shows a haphazard distribution of small, round infiltrative glands in hypocellular fibrous or adipose tissue (Figure 1, E and F).^14,15  Microglandular adenosis lacks the desmoplastic stroma and tear-shaped glands seen in tubular carcinomas, its close mimicker. The lining cells in MGA are characteristically small and cuboidal, with varying amounts of clear to eosinophilic cytoplasm. Dense eosinophilic secretory material is often found intraluminally.¹⁴  Studies evaluating the presence of myoepithelial cells have shown conflicting results; however, in general, myoepithelial cells are usually not demonstrable. Strong epithelial S100 expression is expected in conjunction with an absence of hormone receptors.^16–18  Despite its benign nature, recurrence is possible if the lesion is not completely excised. The association of MGA with carcinoma has been recognized previously.^19–21  Whether the lesion itself progresses to carcinoma or simply serves as a milieu for cancer development is still debated. A lesion with indeterminate atypia between a clearly benign and malignant condition is referred to as an atypical MGA. The atypical tubules are more likely to be irregularly shaped and closely packed together. Atypical MGA shows nuclear abnormalities of enlargement, vesicular chromatin pattern, and frequent prominent nucleoli.²²  Interestingly, molecular analysis of MGA has shown recurrent alterations of TP53, loss of 5q, and gain of 8q. These are similar to the genetic alterations seen in estrogen receptor–negative, basal-like, and breast cancer 1 (BRCA1)–associated breast cancers.²⁰  Not all cases demonstrate these particular genomic changes, indicating that the presence of molecular subgroups likely accounts for the range of clinical outcomes.²³ 

Cystic hypersecretory hyperplasia and its malignant counterpart, cystic hypersecretory carcinoma (CHC), are the classic entities with luminal pink, proteinaceous, thyroid colloidlike material and cyst formation lined by simple to pseudostratified to micropapillary epithelium. The differential diagnosis and clinicopathologic features of CHC are summarized in the Table. The benign counterpart, CHC, lacks cytologic atypia (Figure 1, G and H).²⁴  The differential diagnosis of cystic hypersecretory hyperplasia includes pregnancy-like hyperplasia with few shared histologic features, and studies have reported that the two entities may coexist within the same lesion.² 

Clinical presentation of CHC is variable, presenting as a mass lesion, mammographic cluster of calcifications, or nipple discharge. Cellular atypia is manifested as enlarged, hobnail cells with vacuolated or microvesicular cytoplasm (Figure 2, A through C).²⁵  Cases with indeterminate cytologic atypia are referred to as atypical hypersecretory changes and could be excised without the need for adjuvant therapy. Cystic hypersecretory carcinoma can be associated with in situ carcinomas without luminal secretions and with micropapillary features. Uncommonly, the epithelial lining can show subnuclear vacuoles similar to secretory endometrium. The invasive carcinomas associated with hypersecretory cancers can be small and lack hypersecretory features.^26,27  Benign proliferations that can mimic CHC at low power include fibrocystic disease, juvenile papilloma, and mucocele-like lesions. Malignant conditions in the differential diagnosis of CHC include mucinous and secretory carcinoma.²⁶  Secretory carcinoma may be the closest mimic; however, generally secretory carcinoma shows a microcystic “honeycomb” appearance, whereas CHC tends to have large cysts.

The original description of CHC was that of an intraductal carcinoma with luminal secretions and micropapillary architecture, with the potential to give rise to invasive, poorly differentiated carcinoma.^24–27  Importantly, extravasation of cyst contents into adjacent tissue is insufficient to diagnose invasion, and identifying nests of tumor cells is a prerequisite for this diagnosis. Extensive tumor sampling is recommended because invasion may be focal and often poorly differentiated.²⁵  Regarding the hormone status, earlier studies reported CHC to be negative for estrogen and progesterone receptors; however, a recent study has reported expression of these markers in most cases. Human epidermal growth receptor 2 (HER2/neu) is negative in most of the cases.²⁵ 

Secretory carcinoma (analogous to juvenile carcinoma) constitutes most of the breast cancers cases seen in young patients and may be seen in adults as well.²⁸  The low-power morphology shows varying patterns of solid, ductal, or microcystic tumor nests.²⁹  Nuclei tend to be small and bland with low mitotic activity (Figure 2, D and E). A large amount of intracellular and extracellular eosinophilic secretion material that stains positive for diastase-resistant periodic acid–Schiff is characteristically seen.²⁸  Most cases are associated with a t(12;15) creating an ETV6-NTRK3 gene fusion.³⁰  Interestingly, the same translocation is also associated with other nonepithelial malignancies, including congenital fibrosarcoma, cellular mesoblastic nephroma, and acute myeloid leukemia.³¹  The differential diagnosis for secretory carcinoma includes cystic hypersecretory lesions, which also show cystic spaces that are lined by bland cells without significant atypia.³²  In such challenging cases, age and molecular/cytogenetic studies can be helpful in narrowing down the differential diagnosis. Secretory carcinoma represents a carcinoma with a favorable prognosis despite its triple-negative phenotype and expression of basal markers. Therefore, it is important to recognize and categorize it accurately.^33,34 

The lesions in this section all contain an accumulation of extracellular and/or extravasated mucin material. They may show focal or diffuse extravasated mucin production, and criteria exist to divide the pure and mixed forms.

This category is comprised of mucocele-like lesions.

Neoplastic lesions with extravasated mucin include mucinous carcinoma and invasive micropapillary carcinoma with extracellular mucin.

Mucocele-like lesions describe mucin-producing cysts that are prone to rupture with extravasation of mucin into the surrounding stroma.³⁵  The cyst lining cells are usually flat and/or cuboidal, with minimal atypia and stratification. Calcifications are common and are a frequent reason for undergoing a biopsy (Figure 3). The presence of a mucocele-like lesion on core biopsy warrants serial-sectioning to exclude a focus of mucinous carcinoma.³⁶  In the absence of atypical epithelial cells on biopsy, excision is still recommended for a definitive diagnosis. A recent review of 102 cases of mucocele-like lesions revealed that despite an association with atypical hyperplasias, in women older than 45 years mucocele-like lesions do not convey an additional risk of breast cancer beyond that associated with the presence of proliferative disease. Additionally, in younger patients (younger than 45 years) with these lesions, there was a nonsignificant increase in risk of breast cancer compared with the general population.³⁷ 

Atypical ductal hyperplasia and ductal carcinoma in situ can occasionally show extravasated mucin. Distinction between atypical ductal hyperplasia, ductal carcinoma in situ, and invasive carcinoma involving a mucocele-like lesion can sometimes be challenging, and in these cases cytologic and architectural features of atypical ductal hyperplasia and ductal carcinoma in situ should be carefully scrutinized before rendering a final diagnosis. The diagnosis of invasive mucinous carcinoma should only be rendered in the presence of atypical cells floating within the mucin.³⁸ 

Mucinous carcinomas usually present as well-differentiated tumors that by definition contain more than 90% mucin, whereas the tumors containing 50% to 90% mucin are characterized as mixed mucinous/ductal carcinomas. These tumors are generally diagnosed at more advanced ages (median age of 71 years versus 61 years for ductal carcinoma, not otherwise specified).³⁹ The differential diagnosis includes the more clinically aggressive invasive micropapillary carcinoma with extracellular mucin production. The low-power views of mucinous and micropapillary carcinoma may be similar; however, on higher magnification invasive micropapillary carcinoma with extracellular mucin displays micropapillary arrangements, high-grade nuclear atypia, and psammomatous calcifications, in contrast to the bland-appearing tumor cells of mucinous carcinoma (Figure 4).⁴⁰ 

Additional tumors that can show extracellular mucin include solid papillary carcinomas that are associated with neuroendocrine differentiation.⁴¹  Mucinous carcinoma usually expresses both estrogen and progesterone receptors, and lacks HER2/neu amplification. Lymph node involvement is rarely identified.³⁹ 

Secretory breast lesions we have described represent a morphologic spectrum, including benign, borderline, and malignant entities. The morphologic heterogeneity is also reflected in their immunohistochemical profiles, with frequent overlap between them. The full spectrum of benign to malignant lesions can be present even within the same lesion. As such, one should employ a low threshold for recommending reexcision on a core biopsy containing benign-appearing secretory glands. The diagnostic approach should involve a combination of morphology and immunohistochemistry for hormone receptors and myoepithelial markers. Currently, genetic testing is of limited value unless secretory carcinoma is in the differential diagnosis, in which case t(12;15)ETV6-NTRK3 fusion can help confirm the diagnosis.

The important first step in the histologic examination is identifying the location of the secretions: intracellular, intraluminal, or extracellular/stromal. Cytologically, the presence of enlarged, hyperchromatic nuclei represents at least a borderline lesion. Another area of concern is diagnosing invasive ductal carcinoma, not otherwise specified, in the presence of hypersecretory morphology. It is imperative to correctly identify them as unique subtypes of invasive ductal carcinoma, not otherwise specified. Additionally, when rendering the diagnosis of triple-negative carcinoma in practice, it is important to consider the lesions discussed in this review as well. Despite their triple-negative phenotypes, these secretory lesions tend to be associated with a good prognosis, and most of these patients do not require adjuvant chemotherapy.

The authors would like to thank Alessandro Bombonati, MD, for his assistance with providing some images for this publication and the manuscript editing process.