The Spectrum of Mucinous Lesions of the Breast Open Access

Mucinous carcinoma (old terminology: colloid carcinoma, or gelatinous carcinoma) is a subtype of breast carcinoma with its pure form comprising 2%–4% of all breast cancers.¹  It tends to occur in perimenopausal and postmenopausal women (sixth to eighth decades). Presentation can be variable, ranging from palpable abnormality to radiologic finding of a lobulated well-circumscribed mass.²  Grossly, mucinous carcinomas tend to have well-delineated borders and soft gelatinous consistency, the extent of which may vary depending on the cellularity and fibrous stroma of the tumor. Tumors with prominent fibrous stroma may appear firmer. The size range of these tumors can be variable, with a reported range of less than 1 cm to greater than 20 cm, with an average reported size of 3.0 cm.³ 

Mucinous carcinomas have distinctive histologic features that are apparent on low-power view. By definition, greater than 90% of the tumor volume should comprise tumor cells floating within extracellular mucin pools. The architecture of the tumor cells can be glandular, cribriform, micropapillary, or nested with or without areas of intracellular mucin. Usually, the tumor cells are low to intermediate in nuclear grade and show low mitotic activity. Histologically, 2 subtypes of pure mucinous carcinoma exist: (1) type A, also known as Capella type A or low-cellularity type, and (2) type B, Capella type B or high-cellularity type (Figure 1, A and B). While the former is paucicellular and appears to have more extracellular mucin, the latter shows large nests or cribriform glands in less abundant mucin. Type B may show areas of endocrine differentiation that can be highlighted by immunohistochemical markers such as chromogranin, synaptophysin, and CD56.⁴  Neuroendocrine features have been further validated by the presence of neurosecretory granules seen on electron microscopy.⁵  Ductal carcinoma in situ (DCIS) with mucinous and/or nonmucinous features can be seen in association with mucinous carcinomas (Figure 1, C). Characteristically, this carcinoma subtype is positive for hormone receptors, including estrogen receptors (ERs), and progesterone receptors (PRs), with low-level androgen receptor expression, and negative for human epidermal growth factor receptor 2 (HER2).^1,6  Mixed subtypes are not uncommon in cases where some areas show mucinous features while other foci show invasive carcinoma of no special type or lobular carcinoma. Mixed tumors need to be documented as such as they do not have as good a prognosis as pure mucinous carcinomas.⁷  Recently, a subtype of mucinous carcinoma with an intermediate to high nuclear grade and a micropapillary pattern has been described. This tumor type has been referred to as mucinous micropapillary carcinoma (MMC) or mucinous carcinoma with micropapillary pattern. This entity is further discussed separately below.

Mucinous carcinomas are molecularly unique; pure forms show the lowest levels of gene copy-number changes.⁸  Specifically, mucinous carcinomas lack 1q gains and 16q losses, which are the hallmark features of invasive carcinoma of no special type. Also, mucinous carcinomas lack PIK3CA and AKT1 mutations, in contrast with the high frequency of PIK3CA mutations identified in luminal breast cancers.⁹  Pure mucinous carcinomas are usually diploid. Aneuploidy has been seen with higher-stage and lymph node metastases.¹⁰ 

Based on National Comprehensive Cancer Network guidelines, pure mucinous hormone receptor–positive tumors without nodal involvement that are small (< 1 cm) can be treated with surgery alone and adjuvant endocrine therapy may be avoided.¹¹  In tumors that are 1–3 cm in size, endocrine therapy should be considered, and endocrine therapy is recommended in tumors greater than 3 cm.¹¹  In cases of nodal involvement, endocrine therapy is recommended with or without chemotherapy.¹²  In rare cases of mucinous carcinoma treated with neoadjuvant chemotherapy, decreased cellularity or acellularity with persistent pools of mucin can lead to discordant radiologic and pathologic findings.¹³  Pure mucinous carcinomas show lymph node metastasis in 12%–14% of cases compared to 25% in invasive carcinomas of no special type.^14,15  Overall, they have good prognosis with 10-year survival rates of 90.4%.¹⁶  Late tumor recurrences have been described.¹⁷  As expected, tumors with lymph node metastases have a worse prognosis compared to tumors that do not, and lymph node status is considered a strong prognostic factor. Mixed tumors with areas of nonmucinous carcinoma tend to carry a worse prognosis and therefore are critical to classify accurately. One study showed that in mixed tumors, presence of adverse risk factors was inversely proportional to the amount of mucinous component of tumor; for example, tumors with less than 50% mucinous component had more adverse risk factors present compared to tumors with 50%–90% mucinous component.^3,18  No differences were noted in clinicopathologic characteristics of pure mucinous carcinoma type A versus type B.³ 

MMC, or mucinous carcinoma with micropapillary pattern, was first described in 2002.¹⁹  Distinction of this entity from pure mucinous carcinoma carries prognostic implications. MMCs appear to be associated with aggressive tumor behavior, whereas pure mucinous carcinomas follow a more indolent course.^16,18–22  No defined cutoff values for amounts of micropapillary and conventional mucinous tumor patterns have been proposed for utilization of this category. Although clinical characteristics are not well elucidated given that the category is relatively new, studies show a wide age range of 28–80 years (mean, 55 years) with somewhat less than 50% of patients being peri- or premenopausal.²¹  Both patterns of pure mucinous and micropapillary (nonmucinous) carcinoma can coexist and have been described (Figure 2).²² 

The characteristic histologic features of MMCs are the arrangement of neoplastic cells in floretlike pseudoacinar structures with scalloped or frayed edges and increased amounts of cytoplasm facing outward (Figure 3, A through C). Hobnailing is often observed and the micropapillary clusters are identified within pools of mucin. The nuclear grade tends to be predominantly intermediate (grade 2) and occasionally high (grade 3).¹⁶  The basic criteria of greater than 90% cells in lakes of extracellular mucin still applies for the diagnosis. Psammomatous calcifications can be identified and can be prominent in some cases (Figure 3, B). DCIS can accompany this variant with 1 study showing that more than 50% cases of DCIS had a micropapillary growth pattern. ¹⁶  This entity is different from tumors that have been described to have both mucinous carcinoma and nonmucinous micropapillary carcinoma areas (Figure 2).²²  MMCs are also generally hormone receptor positive; however, unlike pure mucinous carcinomas, greater than 20% of MMCs show HER2 overexpression or gene amplification.¹⁶  Based on limited studies, Ki-67 demonstrates a relatively increased proliferative index in mucinous micropapillary tumors (medium, 15%; range, 5%–50%) over pure mucinous tumors (median, 3%; range, 0%–10%).¹⁶ 

At the molecular level, MMCs are heterogeneous; some tumors show a pattern of somatic genetic alterations similar to mucinous carcinomas such as absence of PIK3CA mutations, 1q gains, and 16q losses, whereas others resemble invasive micropapillary carcinoma (nonmucinous) showing copy-number alterations such as recurrent gains in 1q, 6p, 8q, and 10q; recurrent losses in 16q, 11q, and 13q; and recurrent 8p12-8p11.2 amplification. These findings suggest that MMCs are an overlap entity of mucinous and micropapillary carcinomas rather than a separate unique subtype.²³ 

Most studies associate MMCs with aggressive features such as lymphovascular space invasion, a higher likelihood of lymph node metastases, and decreased overall survival and recurrence-free survival.^16,18–22  Few studies show conflicting results.^14,24  For instance, Xu et al²⁴  studied 75 cases of mucinous carcinoma with 80% of cases showing variable percentages of micropapillary architecture. Based on their study, no statistically significant relationship existed between presence of micropapillae and lymph node metastasis and survival.²⁴  Interestingly, in comparison to invasive micropapillary carcinoma (nonmucinous), MMCs showed decreased lymph node metastases, a lower nuclear grade, higher ER and PR expression, less expression of HER2, and better prognosis.²² 

Given that MMC is a relatively new subtype, it is underrecognized in pathology practice. Also complicating matters, it is unclear what percentages of mucinous and micropapillary features need to be present for the MMC designation. Perhaps in the presence of micropapillary features in an otherwise mucinous carcinoma, a descriptive diagnosis such as mucinous carcinoma with micropapillary growth pattern with a percentage of micropapillary pattern may be considered. In order to differentiate MMC from micropapillary carcinoma (nonmucinous), it is important to recognize pools of mucin in which the tumor cells float. Artifactual cleft spaces, a feature of micropapillary carcinoma, can mimic pools of mucin and high-power microscopic examination should suffice in distinguishing the two. To recognize the micropapillary pattern of mucinous carcinoma, immunohistochemisty for epithelial membrane antigen may aid in the assessment of micropapillae by highlighting the reverse-polarity staining pattern. This may be hard to exhibit on cell-block cytology material as specimen processing with vigorous centrifugation leads to distortion of membrane antigen and unusual cytoplasmic staining.¹⁹  MUC1 and E-cadherin can also help confirm the “inside-out” luminal borders defining the micropapillary phenotype.²¹ 

Mucinous DCIS is an intraductal neoplastic epithelial cell proliferation characterized by cells that meet cytomorphologic features of DCIS and have areas of extracellular mucin. Architectural features of DCIS can vary, including cribriform, solid, papillary, micropapillary, and flat forms. The usual criteria of involvement of 2 complete ducts or greater than 2-mm focus is still required for the diagnosis (Figure 4, A and B). In mucinous carcinoma, the in-situ component is present in 60%–75% of the cases and mucinous DCIS is a precursor lesion to mucinous carcinoma.²⁵  One study has shown 2 patterns of transition from mucinous DCIS to mucinous carcinoma.²⁵  In type A mucinous tumors, mucinous DCIS showed areas of luminal mucinous distention, focal flattening, and attenuation of epithelium with disruption of the duct wall resulting in a mucocele-like extravasation of malignant epithelium with escaping mucin and transition to type A mucinous carcinoma. The second transition pattern involved epithelial outpouching, formation of a cleft with accumulation of mucin around the epithelium, and transition into mucin pools with floating tumor cell clusters. This gives rise to type B or mixed types of mucinous carcinomas.²⁵  Another study proposed that transition from DCIS to carcinoma starts with DCIS having intracellular mucin production, followed by extrusion of mucin into the extracellular space, recruitment of capillaries (neovascularization) into the mucin, distention of the ducts involved, extravasation of mucin and tumor cells outside the basement membrane, and then microinvasion before frankly invasive carcinoma.²⁶  The diagnostic dilemma here lies in distinguishing between mucocele-like lesion (MLL) with atypia (atypical ductal hyperplasia), DCIS with a ruptured duct, and early microinvasive mucinous carcinoma associated with DCIS. Utilization of myoepithelial markers and abiding by criteria established to differentiate atypical ductal hyperplasia and DCIS can help in reaching the correct diagnosis.

MLL is a descriptive term applied to lesions associated with ruptured cysts and extracellular mucin. MLLs can be associated with benign cyst lining, atypical lining, or malignant proliferation. They were originally described by Rosen²⁷  as benign mucin-filled cysts lined by flat to cuboidal epithelium with or without extravasated mucin. However, given that MLL can be associated with a spectrum of atypia, it is a descriptive term rather than a diagnosis that stands alone. When diagnosing MLL, a specific description of the epithelial lesion associated with the MLL should be clarified in the pathology report as these findings guide future management. MLLs are identified in ∼0.2% of core needle biopsies.²⁸  Mean age of presentation is 54 years (age range: 27–82 years). They commonly present as indeterminate calcifications that are clustered, round, or pleomorphic on screening mammography. Alternatively, they can present as masses or as an incidental finding. In mass-forming lesions, they are described as round or lobular masses, single or multiple with a “rosary-like appearance.”²⁹ 

MLLs can have variable gross appearances ranging from multi-loculated cystic nodules to gelatinous mucoid cut surfaces to yellow flecks with a gritty texture due to prominent calcifications. While the size range reported is 0.5–10 cm, most measure less than 2 cm.^30,31 

Microscopically, MLLs are composed of cysts containing mucinous contents that rupture, expelling mucinous secretions into surrounding stroma and adipose tissue. In benign lesions, the epithelium is flat and cuboidal, and lacks atypia (Figure 5, A). The epithelial lining can detach from the cyst wall either spontaneously or following a needle procedure and float in the mucin. These detached epithelial fragments should not be misdiagnosed as carcinoma. Granular calcifications and columnar cell changes are frequently associated with MLLs.³²  MLLs can also be associated with variable proliferative ductal lesions ranging from usual ductal hyperplasia (UDH) to flat epithelial to atypical ductal hyperplasia and DCIS (Figure 5, B through D). Architectural and cytologic criteria for atypia follow predefined rules for the entities. In core needle biopsies, MLLs have atypia present in 34%–66% of the cases.³³  Overall, only a minor subset of MLLs is associated with invasive mucinous carcinomas and clues are usually apparent on core biopsies. In order to characterize a lesion as invasive carcinoma, malignant epithelium floating in pools of mucin with absence of myoepithelial cell layer should be identified.

Prognosis of MLLs is variable depending on the identified associated lesions. Historically, excision has been recommended for all MLLs on core needle biopsy due to the possibility of associated invasive carcinoma. Interestingly, the literature suggests that only a minor subset of MLLs without atypia on core biopsy show in-situ or invasive carcinoma (1.3% and 1.8% of cases) on excision, whereas core needle biopsies showing MLL with atypia on biopsy show in-situ and invasive carcinoma in 14% and 4.7% of the cases on excision, respectively.^34–40  Biopsies showing MLLs should be subjected to serial sectioning and deeper levels of examination to exclude the presence of a more significant lesion. Given the small rate of upgrade of MLLs without atypia on core needle biopsy, some authors suggest that in cases where clinical, radiologic, and pathology findings are concordant, no atypical epithelium is identified despite serial sections, and no mass lesion is evident on imaging, conservative management may be considered.^40,41 

The most critical differential diagnosis of MLL is invasive mucinous carcinoma. This differential diagnosis is especially challenging on small core biopsies where differentiating strips of dislodged benign epithelium of cyst lining from malignant epithelial nests of invasive carcinoma on quantitatively scant material can sometimes be impossible. The key here becomes evaluating the atypia in the strips of cells and the presence or absence of background lesions. Clues that favor benign MLL include scant free-floating cells, benign cytomorphology, retained myoepithelial cell layer, and history of prior biopsy in the area of detached epithelium. Myoepithelial cell markers can be very helpful in instances where commonly detached strips of benign epithelium will likely retain some myoepithelial cells while myoepithelial cells are absent in floating nests of neoplastic tumor cells. However, this interpretation should be performed judiciously as rarely even benign dislodged and misplaced epithelium may show decreased or absent myoepithelial cell staining. One must be cautious as MLLs with atypical ductal hyperplasia and DCIS without mucinous carcinoma can also have detached epithelium that may lack myoepithelial cells. Context is key, and a low threshold for requesting excision should be maintained for biopsy material. Rarely, in cases with DCIS without overt invasive mucinous carcinoma, the significance of certain areas of loose epithelial clusters may be difficult to ascertain, and this uncertainty must be appropriately relayed as the possibility of a small focus of carcinoma cannot be excluded or is favored.

MCA, a rare breast carcinoma subtype, can mimic MLL on radiology as it can present as a multiloculated cystic mass.³³  However, histologically MCA is characterized by tumor cells that are tall and columnar with intracytoplasmic mucin and complex architecture including tufting, papillary proliferations, and thin fibrovascular cores—all cytomorphologic features that are absent in MLLs. Additionally, MCAs are hormone negative, unlike MLLs.

Cystic hypersecretory lesions of the breast, which also have a spectrum from hyperplasia to carcinoma, rarely pose a challenge in this differential diagnosis and bear a superficial resemblance to MLLs. Cystic hypersecretory lesions have dense eosinophilic luminal secretions resembling colloid of the thyroid gland that retracts from the surrounding epithelium, unlike MLLs, which have mucin with a blue hue and wrinkled tissue-paper quality without evidence of retraction from the epithelium.

Primary MCA of the breast is extremely rare and recently described as a variant of primary breast carcinoma in the World Health Organization (WHO) 2019 Update on Classification of Breast Tumors.⁴  It was first described in 1998 by Koenig and Tavassoli⁴²  and since then fewer than 30 cases have been reported.^43–46  The reported age range is 49–96 years with median age of 65 years (postmenopausal).⁴³ 

Primary MCA of the breast is histologically similar to its counterpart identified in other organs such as pancreas, ovary, and gastrointestinal tract. The usual clinical presentation is a palpable mass that can range in size from 0.8 to 19 cm with a median tumor size of 3 cm.⁴  Macroscopically, it is characterized as a well-circumscribed lesion with multiple cystic spaces filled with gelatinous material. Microscopically, the cystic structures are lined by tall columnar cells in varying architectural patterns and abundant intracellular as well as extracellular mucin. The neoplastic cells have basally located nuclei with variable cytologic atypia, mucinous or eosinophilic cytoplasm, and absence of myoepithelial cells in the periphery. Tumor cells can be stratified, show tufting, and even show complex papillary formations. Extravasation of mucin into the adjacent stroma has been described; however, this is not a constant feature.⁴⁷  Adjacent DCIS and areas of conventional invasive carcinoma of no special type (ductal) can also be identified. While this tumor can have areas that show conventional mucinous carcinoma histology, it is easy to distinguish from mucinous carcinoma given its triple-negative immunophenotype, multicystic architecture, and intracellular mucin.

Immunophenotypically, the tumor cells are positive for CK7 while negative for CK20 and CDX2. Some tumors can be focally positive for mammoglobin or GCDFP-15.⁴⁷  The latter feature is especially helpful in cases where metastatic pancreatobiliary adenocarcinoma is in the differential diagnosis. When considering this diagnosis, a broad immunohistochemical panel of CK7, CK20, CDX2, PAX8, WT1, CA19-9, GCDFP-15, mammaglobin, GATA3, ER, and PR can be helpful to rule out metastases from other sites.⁴⁷  While the tumor tends to be ER, PR, and HER2 negative (triple-negative), few HER2-positive cases have been documented.^48,49–51  The Ki-67 proliferative index has been shown to be high, ranging from 20.5% to 90%.⁵² 

The literature lacks large-scale genetic profiling information on breast MCAs given their rarity. One case report documents absence of KRAS, NRAS, and BRAF mutations.⁵³  Another case showed mutations in TP53, RB1, and BAP1 genes on next-generation sequencing, suggesting that tumor-suppression genes play a key role in tumorigenesis.⁵⁴  It would be of interest to see if additional studies identify overlapping alterations in the KRAS gene as seen in ovarian and pancreatic counterparts.

Optimal management strategy cannot be assessed in this very rare tumor that has not yet been studied in detail. The characteristics and biological behavior of the tumor are not well known. Based on limited studies with only short-term follow-up, favorable outcome seems to be the general outlook despite the triple-negative immunoprofile, which is generally considered to be a poor prognostic factor in breast carcinomas. Local recurrence 8 years following lumpectomy with negative margins has been described in 1 case.⁴⁷  Low rates of lymph node metastases have been reported, seen in about 5 cases.^{42,49,55–57} 

Invasive lobular carcinoma, the second most common subtype of invasive breast carcinoma, is not uncommonly associated with intracellular mucin production in the form of intracytoplasmic lumina and signet-ring cells; however, extracellular mucin production is not commonly associated with a lobular phenotype. A new variant, invasive lobular carcinoma with extracellular mucin, was first described in 2009 by Rosa et al⁵⁸  and approximately 30 cases have been described since then.^58,59  The 5th edition of the WHO Classification of Tumors⁴  briefly mentions this variant and states that it is unknown whether invasive lobular carcinoma with extracellular mucin is a variant of lobular or mucinous carcinoma. Reported patient age range is 38 to 87 years (median age of 64 years) and median tumor size is 43 mm.⁵⁹ 

The majority of described tumors show both mucinous and nonmucinous areas. Mucinous areas show pools of extracellular mucin and floating neoplastic cells with features of invasive lobular carcinoma including signet-ring cell morphology, discohesion, and single-file growth (Figure 6). Signet-ring cell forms were identified in majority of these cases. A few cases of pleomorphic lobular carcinoma with extracellular mucin have also been described.⁶⁰ 

By immunohistochemistry, loss of expression of membranous E-cadherin and cytoplasmic staining with p120 similar to that of conventional invasive lobular carcinoma is noted.⁶¹  The tumors are predominantly positive for ERs and PRs. HER2 positivity has been reported in a few cases, the frequency of which is more than that expected for classic invasive lobular carcinoma.⁶²  Hybrid-capture next-generation sequencing performed on 8 cases showed lobular-type molecular profiles including copy-number variations in 1q and 16q and FOXA1 and PIK3CA gene mutations. Frameshift or deleterious mutations in the CDH1 gene were identified in all cases.⁶³ 

Given the rarity of this tumor type, therapeutic and prognostic information is very limited. Singh et al⁶²  reported axillary lymph node metastases in 50% of cases (13/26). Based on 2 studies with 18 total cases and relatively short-term follow-up (≤ 3 years), the breast cancer–specific mortality was 20% and 40%.^60,61,63  These data may reflect presentation at a higher tumor stage rather than an inherently worse prognosis of this tumor type.⁶³  Further studies are needed for definitive prognosis assessment.

The differential diagnosis includes other lesions discussed in this review such as mucinous carcinoma, mixed mucinous–no-special-type carcinoma, SPC, and metaplastic matrix-producing carcinoma. However, the key and distinguishing feature here is recognizing the lobular features of single-cell filing, cell discohesion, loss of E-cadherin membranous expression, signet-ring cells, and an overall homogeneous nuclear grade throughout the tumor. In cases that are HER2 positive, this feature further helps distinguish it from conventional invasive lobular carcinoma. ER positivity can lend support in the differential diagnosis from metaplastic breast carcinoma, which tends to be triple-negative.

SPC of the breast was first reported in 1995.⁶⁴  Considered to be a low-grade breast carcinoma, it comprises solid nodules of neoplastic cells separated by inconspicuous fibrovascular cores. It mainly affects postmenopausal women in the seventh decade.^65,66  SPCs usually present as solitary or multiple masses that are self-palpated or mammographically detected. Without evidence of stromal invasion, tumors that are well circumscribed are considered in-situ disease despite absence of myoepithelial cells at the periphery.^66,67 

SPCs tend to be well circumscribed, nodular, and soft, sometimes with hemorrhagic and cystic components. In cases with mucin-rich areas, gelatinous foci can be grossly appreciated. Reported tumor size range is wide, from less than 1 cm to 15 cm.^{64,66,68–70} 

Microscopically, on low power, they tend to form nodules separated by fibrous stroma. The nodules are composed of ducts that are filled with solid nests of neoplastic cells that are monomorphic and low to intermediate in nuclear grade (Figure 7). The tumor cells can be cuboidal, plasmacytoid, and/or spindled, and frequently show neuroendocrine differentiation. Spindling can mimic UDH. Extracellular mucin production can be present. Albeit rare, signet-ring cell morphology has also been seen.^64,71  Cells tend to lack obvious papillary or cribriform architecture; however, inconspicuous fibrovascular cores can be seen and are an important clue to arrive at the right diagnosis. Mitoses can be common. Approximately 50% of the tumors show associated invasive carcinoma.^66,69  Invasive carcinoma can be focal or multifocal and can have variable morphologies. Pattern of invasion can be infiltrative or geographic and jigsawlike. While the former pattern is easier to recognize, the geographic pattern is more difficult to ascertain as invasive. Clues of geographic invasion include irregular borders, background mucin, and areas of desmoplastic stroma. In cases with extracellular mucin but smooth borders it may be impossible to assess for definite invasion, and in such cases, uncertainty should be relayed. Described variants of invasive carcinoma associated with SPC include pure mucinous or mixed mucinous carcinoma, neuroendocrine-like carcinoma, tubular carcinoma, and invasive carcinoma of no special type. Exceedingly rare cases of lobular carcinoma have also been described.⁷²  In one study, mucinous carcinoma was the most frequently seen invasive pattern.⁶⁶ 

Use of myoepithelial markers in cases of SPC is helpful in the differential diagnosis of SPC from DCIS as the former lacks myoepithelial cells while the latter shows a retained myoepithelial cell layer. Invasion is apparent on hematoxylin-eosin–stained slides in most cases of SPC. Immunohistochemical stains for myoepithelial cells are not helpful in the differential diagnosis of invasive versus noninvasive SPCs, as both lack a myoepithelial cell layer. SPCs are generally ER and PR positive and HER2 negative. Proliferation index tends to be low to intermediate. Neuroendocrine markers such as synaptophysin and chromogranin can be positive, particularly when associated with a mucinous component.⁷³ 

The genomic profiles of encapsulated, solid, and invasive papillary carcinomas are homogeneous in regard to gene copy-number alterations; however, differences in the transcriptomic profiles likely account for the histologic differences among the 3 subtypes.⁷⁴  Papillary carcinomas have similar copy-number alterations to invasive ductal carcinoma including 16q losses, 16p gains, and 1q gains.⁷⁵  Compared to invasive ductal carcinoma, papillary carcinomas show lower levels of expression of proliferation-related, cell assembly and organization, and cellular movement and migration genes.⁷⁴ PIK3CA mutations have been identified in up to 43% of papillary carcinomas.⁷⁵ 

While SPC without invasion is considered to have a good prognosis, the prognosis of SPC with invasion is dictated by the invasive component.^66,70  Based on one study, no lymph node or distant metastases were reported in cases without invasion.⁶⁶  The management of SPCs varies from breast-conserving surgery to mastectomy and the role of sentinel lymph node biopsy remains unclear. Axillary lymph node metastasis is present in 3%–12% of the patients with invasion.⁷⁶  Frequency of distant metastasis according to retrospective studies is approximately 2.8%.⁶⁵ 

This entity warrants a discussion in this review as it can show areas of intracellular and extracellular mucin within the lesion as well as in the associated invasive component. Its main differential diagnoses are florid UDH, lobular neoplasia, and DCIS. Given the spindled histology, UDH can be considered; however, findings of mitoses, inconspicuous fibrovascular cores, and mucin production are not features of UDH and should be clues to the diagnosis of SPC. E-cadherin staining pattern and absence of cell discohesion can help rule out lobular neoplasia. DCIS is the hardest differential diagnosis, especially on core biopsies. Clues favoring the diagnosis of SPC over solid DCIS are absence of a myoepithelial cell layer around the periphery, subtle fibrovascular network (inconspicuous papillae), nuclear palisading, and pseudorosette formation around capillaries.^65,68 

Primary breast mucoepidermoid carcinoma is a rare entity with approximately 50 reported cases.^77,78  It warrants a mention in this review given it comprises tumor cells with mucin in addition to squamous, intermediate, and basaloid cells.

Histologically, it is akin to mucoepidermoid carcinoma of the salivary glands. Grading can be performed using criteria for salivary gland tumors or breast carcinoma as results tend to be similar. It is in the differential diagnosis of mucinous lesions of the breast, especially in cases with low-grade cytology and large cystic areas with mucin. Immunohistochemical stains show that central nests of epidermoid or mucus-secreting cells and cysts are positive for CK7. Basaloid cells are positive for cytokeratin 14 and intermediate cells are positive for CK5/6 and p63. Unlike this panel, mucinous carcinomas of the breast are diffusely positive for CK7, and this differentiating immunoprofile can be very helpful. Also, mucoepidermoid carcinomas of the breast can show patchy or diffuse GATA3 and mammoglobin expression, unlike mucoepidermoid carcinomas of the salivary gland, in which these markers are absent or focal (≤ 10%).⁷⁹  These tumors have a basal phenotype with negative ER, PR, and HER2 expression.

Few tumors showing CRTC1::MAML2 fusion have been described, thus suggesting that these tumors are closer to salivary gland cancers rather than triple-negative breast carcinomas in their pathogenesis.⁷⁹  Of note, MAML2 rearrangements have also been described in clear cell hidradenoma, an uncommon adnexal tumor that can rarely occur in the breast and shows morphologic and immunophenotypic overlap with low-grade mucoepidermoid carcinoma.^80,81 

Grade of the tumor remains a critical prognostic factor, with high-grade tumors being associated with axillary and distant metastases while low-grade tumors show good prognosis.

While metastases to the breast are rare, they do occur and have an incidence of 0.5%–6%.⁸²  Described in the literature are metastases from contralateral breast, melanoma, lymphoma, neuroendocrine tumor and carcinoma, lung, thyroid, stomach, cervix, uterus, and prostate.^83,84  In children, metastatic rhabdomyosarcoma has been described.⁸²  Among these, lung carcinomas can be mucin-rich with extracellular and/or intracellular mucin and can be in the differential diagnosis of mucinous lesions. Clinical history is key in arriving at the right diagnosis. Other clues that can be helpful include smooth nodular contours, absence of calcifications, absence of an in-situ component, and negative hormone status in an otherwise gland-forming tumor. Immunohistochemical stain panels are helpful when considering metastases: TTF-1 and napsin-A for lung; PAX-8 and thyroglobulin for thyroid; CDX-2, SATB2, and CK20 for gastrointestinal tract; NKX3.1, PSA, and PSAP for prostate; and SOX10, S100, melan-A, and HMB-45 for melanoma.

Lesions with myxoid change and basal lamina material can be included in the differential diagnosis of mucinous lesions of the breast. For example, adenoid cystic carcinomas characteristically comprise cribriform structures and tubule formation lined by epithelial and myoepithelial cells. They tend to have pseudolumina that are filled with stromal matrix composed of basement membrane that, when basophilic, can mimic mucin. However, characteristic architectural features can be identified, albeit they may be focal. In difficult cases, use of epithelial and myoepithelial cell markers and their pattern of arrangement can easily sort out other differentials.

Nodular mucinosis is a benign breast lesion seen in the subareolar region of young women. Grossly, it presents as a well-circumscribed lesion with nodular myxoid appearance. Microscopically, it is comprised of multiple nodules of pink myxoid tissue with scattered fibroblasts, no mitoses, and low cellularity (Figure 8). The nodules are separated by fibrous septae that contain delicate vessels. The pink myxoid tissue is positive for Alcian blue and Hale colloidal iron as it is composed of acid mucopolysaccharides and is negative for mucicarmine and periodic acid–Schiff. The staining pattern contrasts with mucinous breast lesions that are positive for periodic acid–Schiff and mucicarmine, which stain neutral polysaccharides.⁸⁵  Additionally, nodular mucinosis lacks epithelial cells; this can be another distinguishing feature from other mucinous lesions. Rarely, other lesions with myxoid change such as myxoid fibroadenoma, myxoid nerve sheath tumor of the breast, myxoma, myxoid fibroblastoma, and benign mixed tumor with prominent myxoid change can also be in the differential diagnosis of mucinous breast lesions.

Mucinous lesions of the breast include a heterogeneous group of entities with varying treatments and prognoses. Among the ones discussed in this review (Table), MLLs and mucinous carcinomas are the 2 most encountered in practice. In order to make an accurate diagnosis, radiologic, clinical, and pathologic correlation is of utmost importance. Small tissue samples may not be entirely representative, and a low threshold should be maintained to obtain additional tissue from an excisional biopsy for a thorough pathologic diagnosis.