Abstract
Breast carcinoma is a vastly heterogeneous disease encompassing a wide array of entities with different morphology, biology, clinical behavior, and prognosis. Special types of breast carcinoma include tumors with morphologies that deviate from invasive carcinoma of no special type (NST). As a group, special types comprise up to 25% of all breast cancers, and encompass entities ranging from low to high-grade, and with different hormone receptor and HER2 status. The recognition of the different special types of breast cancer is of paramount importance, as their proper classification is relevant not only for taxonomic purposes, but has also for therapeutic implications.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
Keywords
Breast carcinoma is a vastly heterogeneous disease encompassing a wide array of entities with different morphology , biology, clinical behavior, and prognosis . Special types of breast carcinoma include tumors with morphologies that deviate from invasive carcinoma of no special type (NST). As a group, special types comprise up to 25% of all breast cancers, and encompass entities ranging from low to high-grade , and with different hormone receptor and HER2 status. The recognition of the different special types of breast cancer is of paramount importance, as their proper classification is relevant not only for taxonomic purposes, but has also therapeutic implications.
15.1 Invasive Lobular Carcinoma
Invasive lobular carcinoma (ILC) is the most common special type of breast cancer and accounts for approximately 15% of breast invasive carcinomas [1]. While the incidence of invasive carcinoma of no special type (NST) has been stable, incidence of ILC appears to have increased [2].
Patients with ILC usually present with an ill-defined palpable mass or diffuse breast nodularity, at an older age, and with larger tumors than patients with invasive carcinoma , NST [3]. ILC has a tendency to occur bilaterally and multicentrically [4]. The most frequent mammographic finding of ILC is a mass with irregular borders, while microcalcifications are rarely seen [5,6,7]. However, mammography has a relatively low sensitivity for the detection of ILC, with up to 30% of false negative cases [7]. On ultrasonogram, ILC is commonly detected as an irregular hypoechoic mass with spiculated borders; posterior acoustic shadowing is observed more frequently than in invasive carcinoma , NST [5]. While the tumor size of ILC is frequently underestimated by mammography and ultrasonogram [8], magnetic resonance imaging (MRI) findings correlate better with the histologic size of the tumor [9].
Classic ILC is composed of discohesive tumor cells arranged in a linear pattern or as single cells. Classic ILC is associated with negligible desmoplasia or host lymphocytic reaction and does not disrupt the normal breast architecture (Fig. 15.1), displaying a targetoid concentric distribution around ducts and lobules (Fig. 15.2). The tumor cells resemble those of lobular carcinoma in situ (LCIS) , and are small and uniform with occasional intracellular lumina, round and uniform nuclei, inconspicuous nucleoli, and infrequent mitotic figures (Fig.15.3).
Classic invasive lobular carcinoma : the carcinoma is composed of discohesive cells growing in a linear pattern without disrupting the normal breast architecture
Classic invasive lobular carcinoma : the tumor cells show a targetoid growth around normal ducts
Classic invasive lobular carcinoma : the carcinoma is composed of small monotonous bland cells
A wide array of ILC variants can be recognized, which differ from classical ILC in their morphology and behavior, including the solid, alveolar, trabecular, tubulolobular, signet ring cell, and pleomorphic variants. ILC histologic variants are found occasionally admixed with classic ILC or with other ILC variants. The solid variant of ILC is characterized by discohesive tumor cells growing in solid nests, and may show pleomorphism or increased mitotic activity (Fig. 15.4) [10]. The alveolar variant of ILC is composed of tumor cells arranged in discrete clusters or aggregates of 20 or more cells, separated by thin fibrous septa (Fig. 15.5) [11]. The trabecular variant of ILC is characterized by tumor cells growing in bands thicker than two cells. The tubulolobular variant of ILC is composed of small cords and tubules of tumor cells arranged in a linear fashion, with a hybrid tubular and lobular morphology [12]. Pleomorphic ILC has the same growth pattern as classic ILC, but the tumor cells show greater cytological atypia and pleomorphism and display a higher mitotic rate (Figs. 15.6 and 15.7) [13].
Solid variant of invasive lobular carcinoma : the carcinoma cells are arranged in sheets
Alveolar variant of invasive lobular carcinoma : the carcinoma cells are arranged in small clusters of cells separated by fibrous septae
Pleomorphic lobular carcinoma : the carcinoma is arranged in solid sheets and is composed of discohesive large atypical cells with marked pleomorphism
Pleomorphic lobular carcinoma : the tumor cells show a high nuclear/cytoplasmic ratio and frequent mitoses
Cytologic smears of ILC show small tumor cells in poorly cohesive clusters or as isolated cells, with occasional single-cell linear alignments (Fig. 15.8) [14]. Despite the challenges associated with the diagnosis ILC on cytology, fine-needle aspiration (FNA ) remains a useful diagnostic tool. Nonetheless, caution should be exerted to distinguish ILC from its mimickers, such as inflammatory cells in mastitis, which may result in a false positive interpretation.
Invasive lobular carcinoma , cytology: FNA smear shows discohesive tumor cells arranged in a linear pattern
The differential diagnosis of ILC includes lymphoma , metastatic carcinoma , tubulolobular carcinoma , and invasive carcinoma NST with lobular features. Classic ILC, and in particular its histologic variants, must sometimes be distinguished from invasive carcinoma NST, and E-cadherin is widely used for this purpose. CDH1 mutations cause loss of expression of E-cadherin, a molecule involved in cell-to-cell adhesion, which results in the facilitation of epithelial to mesenchymal transition and tumorigenesis [15]. The expression of E-cadherin is reduced or completely absent in ILC (Fig. 15.9) [16], although some cases may express E-cadherin aberrantly [17]. Notably, the cadherin-catenin complex appears to be non-functional in ILC with aberrant E-cadherin expression, and the latter should not preclude the diagnosis of ILC in cases with a typical lobular morphology [17]. Immunohistochemical stains for β-catenin, which is reduced in ILC, and p120, which shows a diffuse cytoplasmic expression, are also helpful to define a lobular phenotype. ILCs are generally positive for estrogen receptor (ER) and progesterone receptor (PR), while negative for the human epidermal growth factor receptor 2 (HER2), although ILC variants, such as pleomorphic ILC, may more frequently display a HER2-positive or triple negative phenotype [18]. ILCs are enriched for mutations in CDH1, PTEN, TBX3, and FOXA1 [19], and the majority of them are of luminal A molecular subtype [20].
Invasive lobular carcinoma , immunohistochemical stain for E-cadherin: the carcinoma cells show markedly decreased E-cadherin expression compared to the normal breast epithelium which exhibits strong E-cadherin membranous expression
ILC has a favorable clinical outcome and has a significantly better 5-year disease-free survival than invasive carcinoma NST. Nonetheless, ILC is associated with late recurrences and metastasis in atypical locations [21], and with a higher frequency of positive or close surgical margins than invasive carcinoma NST [22]. Moreover, some histologic variants of ILC, such as pleomorphic ILC, have more aggressive clinicopathologic features. Older age and triple negative phenotype have been shown to significantly correlate with a worse clinical outcome in pleomorphic ILC [23].
15.2 Tubular Carcinoma
Tubular carcinoma is an uncommon histologic subtype, accounting for approximately 1–4% of breast invasive carcinomas [24]. Tubular carcinoma is not commonly associated with a palpable mass and is usually detected as an incidental finding on screening mammography [25]. On mammogram, tubular carcinomas appear as irregularly shaped masses with central densities and spiculated margins, and as hypoechoic masses with irregular margins and posterior acoustic shadowing on ultrasonogram [26].
Tubular carcinomas are composed of tubules with open lumina and oval or angulated contours in a haphazard arrangement. The tubules are lined by a single layer of epithelium with cuboidal or columnar cells with minimal pleomorphism and basally located round-to-oval nuclei (Fig. 15.10) [27]. More than 90% of the tumor should have the aforementioned morphologic features for it to be classified as a pure tubular carcinoma , whereas tumors with >50–75% of tubular component are best categorized as mixed tubular carcinomas .
Tubular carcinoma : neoplastic oval and angular glands with open lumens invading fibroadipose tissue
The diagnosis of tubular carcinoma on FNA smears is challenging. Cytologic features of tubular carcinoma include moderate-to-high cellularity, angular epithelial clusters of oval cells, and dispersed single epithelial cells with minimal atypia in the background [28].
Tubular carcinomas are classically ER-positive and HER2-negative, and have a luminal A phenotype (Fig. 15.11) [29]. Tubular carcinomas belong to the “low-grade breast neoplasia family” and are frequently seen in association with columnar cell lesions, atypical ductal hyperplasia, low-grade ductal carcinoma in situ, and lobular neoplasia [20]. In a way akin to low-grade IDC-NST, ILC, cribriform, and tubulo-lobular carcinomas , tubular carcinomas are characterized by 16q losses coupled to 1q gains [20].
Tubular carcinoma : the tumor cells display strong and diffuse expression of estrogen receptor
Benign sclerosing lesions, such as radial scars or sclerosing adenosis , may show a pseudoinvasive morphology and mimic tubular carcinoma , and myoepithelial markers such as p63 and CD10 have been proven useful to discriminate between these lesions [30]. Microglandular adenosis is another mimicker of tubular carcinoma . However, tubular carcinoma lacks the characteristic eosinophilic secretions and strong S100 positivity characteristic of microglandular adenosis [31].
Tubular carcinoma of the breast is associated with a low rate of nodal metastasis and recurrences, and a life expectancy that is close to normal [24].
15.3 Mucinous Carcinoma
Mucinous carcinomas represent approximately 1.5% of all breast carcinomas [32]. Patients present at a significantly older age than those with IDC-NST [33]. The diagnosis of pure mucinous carcinoma requires >90% of tumor to be admixed with mucin, whereas tumors in which the mucinous component is less than 90% should be classified as mixed mucinous carcinomas (Figs. 15.12 and 15.13) [34].
Pure mucinous carcinoma : the tumor is entirely composed of nests of carcinoma cells floating in pools of mucin
Mixed mucinous carcinoma : the tumor has a predominant mucinous component admixed with a ductal component
On mammography, pure mucinous carcinomas appear as well-circumscribed oval masses, whereas mixed mucinous carcinomas show more aggressive imaging features [35]. On ultrasound, pure and mixed mucinous carcinomas are isoechogenic and hypoechogenic to subcutaneous fat, respectively [35, 36]. Pure mucinous carcinomas show MRI features which may be observed in benign lesions, such as a circumscribed shape, and a very high signal intensity of fat-saturated T2-weighted images, whereas mixed lesions display more suspicious imaging findings [35, 37].
Mucinous carcinoma is characterized by an invasive component admixed with varying amounts of extracellular mucin. The tumor cells are arranged in architectural patterns, such as nests, trabeculae, sheets, and cell clusters with glandular lumen formation. According to criteria put forward by Capella et al., two morphologic subtypes may be distinguished: type A and B [38]. Type A mucinous carcinomas are characterized by abundant extracellular mucin, whereas type B tumors have less extracellular mucin and show neuroendocrine differentiation (Figs. 15.14 and 15.15). Tumors with an intermediate morphology are classified as of type AB [38].
Mucinous carcinoma , type A: the tumor is hypocellular and has abundant extracellular mucin
Mucinous carcinoma , type B: the carcinoma is hypercellular
Typically, mucinous carcinomas display strong and diffuse positivity for ER and PR (Fig. 15.16), have a low Ki67 index, and express WT1 more frequently than ER-matched invasive carcinoma NST [39]. Expression of neuroendocrine markers is more frequent in type B mucinous carcinomas [39].
Mucinous carcinoma : the carcinoma cells are strongly and diffusely positive for estrogen receptor
The features of breast mucinous carcinomas in FNA smears include a mucinous background, branching capillaries, and tumor cells in clusters or as single cells (Figs. 15.17 and 15.18) Nevertheless, these findings may be present in other malignant or benign breast lesions, making the identification of mucinous carcinoma on cytology specimens challenging [40].
Mucinous carcinoma , cytology: FNA smear showing cohesive clusters of carcinoma cells in a background of abundant mucin
Mucinous carcinoma , cytology: FNA smear shows tumor cells with a bland appearance admixed with mucin
The main differential diagnoses of stromal mucin in a core-needle biopsy specimen are mucinous carcinomas and mucocele-like lesions, which may be associated with benign, atypical, or malignant epithelium [41, 42].
Pure mucinous carcinomas show more favorable clinicopathologic features than invasive carcinoma NST, such as smaller tumor sizes, lower rates of lymph node positivity, and higher rates of ER and PR positivity [43]. Patients with pure breast mucinous carcinomas have better relapse-free survival than those with invasive carcinoma NST [43]. Even though type A mucinous carcinomas occur in older patients, have a lower nuclear grade, and lower rates of HER2 positivity and nodal involvement than type B tumors [44], the prognostic significance of this morphologic classification is uncertain and warrants further study.
15.4 Micropapillary Carcinoma
Micropapillary carcinoma is rare and accounts for <2% of breast carcinomas [45]. Patients usually present with a palpable mass.
On mammogram, micropapillary carcinomas appear as masses with irregular shape and spiculated margins, frequently associated with microcalcifications [46]. Sonographically, these masses are hypoechoic and lack posterior acoustic enhancement or shadowing [46, 47]. MRI demonstrates masses with irregular or spiculated margins, with initial rapid enhancement and washout [46, 47].
Histologically, breast micropapillary carcinomas are composed of small morule-like clusters of tumor cells lacking fibrovascular cores within empty spaces, which may resemble lymphovascular invasion (Fig. 15.19) [48]. The tumor clusters show reverse polarity (inside-out growth pattern), with the apical aspect of the cells facing the stroma [48]. Pleomorphism and atypia are usually moderate, and mitotic activity is variable. Associated psammomatous calcifications are not infrequent (Fig. 15.20) [49, 50]. Invasive carcinoma NST and other histologic subtypes of breast cancer may be associated with a minor micropapillary component [49].
Micropapillary carcinoma : the tumor is arranged in morule-like clusters, with no fibrovascular cores, in empty spaces separating them from the stroma
Micropapillary carcinoma : the carcinoma cells have high nuclear grade. Psammomatous calcifications are seen
FNA smears of micropapillary carcinomas have a moderate-to-high cellularity and show tightly cohesive angular cell clusters of mildly to moderately pleomorphic tumor cells with high nuclear/cytoplasmic ratio and an inside-out pattern, admixed with single discohesive cells [51].
Micropapillary carcinomas are usually positive for ER and PR, and have variable rates of HER2 expression [52]. Expression of HER2 is restricted to the basolateral membranes of the tumor cells, as it is absent in the membrane aspect facing the stroma [53], posing challenges to its accurate interpretation. Notably, almost half of micropapillary carcinomas with a HER2 score of 1+ by immunohistochemistry (IHC) were found to be HER2 amplified by FISH [54]. Indeed, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines recommend the use of an alternative method for evaluation of HER2 expression in micropapillary carcinomas that show intense but incomplete HER2 expression by IHC [55].
The reverse polarization of the tumor cells in micropapillary carcinomas can be highlighted by MUC1 and EMA, which are positive in the apical, stroma-facing aspect of the tumor cell membranes [56, 57], and by E-cadherin and p120, which have a “cup-shaped” staining pattern, present in the lateral cell borders, and absent in the apical membrane facing the stroma [57, 58]. Vascular markers such as CD31, CD34, factor VIII, and D2-40 may be useful for the discrimination of true lymphovascular invasion from the clear stromal spaces of micropapillary carcinoma [59]. Micropapillary carcinomas are mostly of luminal B molecular subtype [60], and harbor recurrent mutations in NBPF10 and in genes of the mitogen-activated protein kinase (MAPK) family [61].
Micropapillary carcinoma should be distinguished from invasive carcinoma NST with marked retraction artifact, which lacks inside-out morphology . Importantly, in the absence of clear in situ carcinoma , or in the metastatic setting, a panel of immunohistochemical stains including uroplakin, CK20, TTF-1, ER, WT1, PAX8, and mammaglobin might be useful to discriminate breast micropapillary carcinoma from micropapillary carcinoma of other anatomic origins, such as ovary, bladder, lung, salivary glands, and the gastrointestinal tract [62].
Micropapillary carcinoma is associated with more aggressive clinicopathologic features than invasive carcinoma NST, such as larger tumor size, increased incidence of lymphovascular invasion, and a higher rate of lymph node metastasis [63, 64]. Indeed, the majority of patients present with nodal metastasis at diagnosis , and nodal positivity is the most important independent prognostic predictor of recurrence-free survival [64]. Nonetheless, the disease-specific and overall survival of patients with micropapillary carcinoma does not appear to differ from that of patients with invasive carcinoma NST of similar stage [65].
15.5 Mucinous Micropapillary Carcinoma
Mucinous micropapillary carcinoma , also known as micropapillary variant of mucinous carcinoma , is an unusual form of invasive breast cancer that exhibits dual mucinous and micropapillary morphology [66].
Mucinous micropapillary carcinomas display a hybrid histology , characterized by floret-like or pseudoacinar structures of hobnail cells in stromal spaces filled with mucin (Figs. 15.21 and 15.22) [67]. Psammomatous calcifications can be readily identified.
Mucinous micropapillary carcinoma : tumor cells are arranged in morule-like clusters with hobnail cells floating in pools of mucin
Mucinous micropapillary carcinoma : mucinous micropapillary carcinoma (left) with tumor clusters floating in mucin transitions to an area with micropapillary morphology in which the carcinoma cells are present in empty spaces (right)
Akin to micropapillary carcinomas and pure mucinous carcinomas , mucinous micropapillary carcinomas display reverse polarity, which may be highlighted by IHC stains for EMA and MUC1 [67]. These tumors are diffusely positive for ER and PR [67], and show a higher rate of HER2 overexpression/amplification than mucinous carcinomas , which ranges between 10% and 20% [44, 66].
Cytologic preparations have a moderate cellularity, and show micropapillary clusters of tumor cells with nuclear hobnailing in pools of mucin. Single cells in the background are present to a lesser degree than in micropapillary carcinoma , and psammomatous calcifications are not uncommon [68, 69].
Mucinous micropapillary carcinoma displays clinicopathologic features intermediate between mucinous and micropapillary carcinoma , such as an intermediate rate of lymphovascular invasion, nodal metastasis , and HER2 overexpression/amplification. The rate of regional recurrence and distant metastasis of mucinous micropapillary carcinoma is also intermediate, between the rates of recurrence and distant metastasis of mucinous and micropapillary carcinomas [44, 66, 67].
15.6 Carcinoma with Medullary Features
Carcinoma with medullary features is a category encompassing tumors previously designated as medullary carcinoma and atypical medullary carcinoma . Grouping of these entities under this category is recommended due to their overlapping morphology associated with diagnostic challenges and a poor inter-observer reproducibility. Carcinomas with medullary features are rare, and represent <5% of breast invasive carcinomas [70]. Patients with carcinomas with medullary features present at a younger age than those with invasive carcinoma NST [71].
Carcinomas with medullary features present as well-circumscribed masses on mammography and ultrasound. Posterior acoustic enhancement on sonogram is more frequent in typical than in atypical medullary carcinomas [72]. On MRI, carcinomas with medullary features show an oval shape, well-circumscribed borders, and frequent rim enhancement with or without enhancing internal septations [73].
The classic morphologic criteria used to define typical medullary carcinomas include predominant syncytial growth (>75% of the tumor), circumscribed and pushing borders, lack of tubule formation, diffuse prominent stromal lymphoplasmacytic infiltrate, and high nuclear grade (Figs. 15.23 and 15.24) [74]. Tumors that don’t display all these features were called atypical medullary carcinomas .
Carcinoma with medullary features: the tumor has a circumscribed pushing border. The tumor cells grow in a syncytial pattern and are intermixed with marked host lymphoplasmacytic infiltrate
Carcinoma with medullary features: the tumor cells show marked atypia and frequent mitoses
On FNA specimens, carcinomas with medullary features are highly cellular and show distinctive characteristics, such as syncytial sheets of cells with bizarre nuclei and prominent nucleoli, and marked chronic lymphoplasmacytic infiltrate [75].
Carcinomas with medullary features are usually triple negative [76], and display a basal immunophenotype (ER−, PR−, HER2−, CK5/6+ and/or EGFR+) more frequently than does high-grade invasive carcinoma NST [77].
Despite their aggressive morphologic features, carcinomas with medullary features are associated with a favorable prognosis [78], and the outcome of typical and atypical medullary carcinomas does not seem to differ [79]. Notably, the prognosis of carcinoma with medullary features is similar to the one of high-grade ductal carcinoma with prominent inflammatory infiltrate [80], and the excellent outcome of these tumors appears to be related to their associated host inflammatory response, a favorable prognostic and predictive marker of triple negative breast cancer (TNBC) treated with chemotherapy [81].
15.7 Apocrine Carcinoma
Apocrine carcinomas are composed of tumor cells with abundant densely eosinophilic cytoplasm with large nuclei and prominent nucleoli, and represent up to 4% of all breast carcinomas [82, 83]. Apocrine morphology may be present in different breast cancer histologic subtypes, and there is currently a lack of uniformity in the diagnostic criteria for apocrine carcinoma . Some authors advocate to restrict this diagnosis to tumors composed of more than 90% of apocrine cells [84].
A large SEER database study showed that patients present with apocrine carcinoma at an older age and with larger tumors than patients with invasive carcinoma NST [85]. Sonographic, mammographic, and MRI findings of apocrine carcinomas do not differ from those of invasive carcinoma NST [86,87,88].
Apocrine carcinomas may be composed of type A cells, which have an abundant eosinophilic granular cytoplasm, type B cells, which have a foamy and vacuolated cytoplasm, or a combination of both. The tumor cells exhibit large centrally to eccentrically located nuclei, prominent nucleoli, and distinctive cell borders (Figs. 15.25, 15.26, and 15.27).
Apocrine carcinoma : the tumor is composed of cells with abundant eosinophilic cytoplasm and cells with foamy cytoplasm. Scattered intracytoplasmic vacuoles can be seen
Apocrine carcinoma : the tumor has a nested architecture with focal glandular formation. The tumor cells have an intermediate nuclear grade
Apocrine carcinoma : the tumor cells show marked pleomorphism and prominent nucleoli
Apocrine carcinomas are mostly negative for ER and PR [83, 84], although it has been shown that they frequently express ER-α36, an isoform of ER [89]. Approximately half of apocrine carcinomas display HER2 overexpression/amplification [90], and most of them are positive for androgen receptor (AR) [90]. Indeed, some authors consider tumors that display apocrine morphology , are negative for ER and PR, and positive for AR as “pure apocrine” carcinomas , while those that exhibit ER or PR positivity, and are negative for AR are considered “apocrine-like carcinomas ” [91]. Apocrine carcinomas belong to the luminal androgen receptor transcriptomic subtype of TNBC [92], and harbor a higher rate of mutations in PIK3CA and other genes of the Phosphoinositide 3-kinase (PI3K) pathway, and a lower frequency of TP53 mutations and MYC gains compared to other TNBCs [93, 94].
The diagnosis of apocrine carcinoma in cytology specimens is challenging due to their morphologic overlap with benign apocrine lesions [95, 96]. FNA smears of apocrine carcinomas are usually highly cellular and show tumor cells arranged in sheets, clusters, and singly scattered. The tumor cells show moderate-to-marked pleomorphism, a dense granular cytoplasm, large nuclei with coarse chromatin, prominent nucleoli, and occasional intranuclear inclusions (Fig. 15.28) [95, 96].
Apocrine carcinoma : FNA smear shows tumor cells with moderate pleomorphism, dense granular cytoplasm and large nuclei with prominent nucleoli
The recurrence-free survival of patients with apocrine carcinomas appears to be similar to that of patients with non-apocrine ductal carcinomas when matched for stage [97]. Nonetheless, a study indicated that patients with “pure apocrine” carcinoma have a worse outcome that those with invasive carcinoma NST [91].
15.8 Metaplastic Breast Carcinoma
Metaplastic carcinomas encompass a heterogenous group of carcinomas characterized by non-glandular morphology , including squamous or mesenchymal differentiation, such as spindle, chondroid, and osseous features [98]. There is currently no consensus regarding the extent of metaplastic elements required for the diagnosis of metaplastic carcinoma , and a wide range of cutoffs have been used [99, 100]. Although most metaplastic carcinomas are high-grade tumors, low-grade variants are also recognized. Metaplastic carcinomas are rare and account for 0.2–5% of breast carcinomas [98].
Patients with metaplastic carcinoma present usually with a palpable mass, and at an older age and with larger tumors than patients with invasive carcinoma NST [101, 102]. Most metaplastic carcinomas are identified as masses on mammogram and ultrasound, and show enhancing, and not uncommonly central necrosis on MRI [103]. Areas of calcification in metaplastic carcinomas with osseous or chondroid differentiation are occasionally detected by imaging [104]. Although the imaging features of metaplastic carcinomas show overlap with those of invasive carcinoma NST [105, 106], features of malignancy, such as irregular shape, spiculated margins, pleomorphic calcifications in a segmental distribution, and posterior acoustic shadowing have been reported to be less frequent in metaplastic carcinomas than in invasive carcinomas NST [107].
Morphologically, metaplastic carcinomas are a heterogeneous group of tumors with marked inter- and intra-tumor heterogeneity. Several subtypes are recognized, including squamous cell carcinoma , metaplastic carcinoma with mesenchymal differentiation, spindle cell carcinoma , including intermediate- and high-grade spindle cell carcinomas , as well as the low-grade fibromatosis -like spindle cell carcinoma and low-grade adenosquamous carcinoma .
Confirmation of epithelial differentiation, such as focal epithelial morphology , presence of ductal carcinoma in situ (DCIS), or positivity for epithelial or myoepithelial markers is required for the diagnosis of metaplastic carcinoma .
The diagnosis of squamous cell carcinoma is reserved for tumors composed of least 90% of squamous elements. Squamous cell carcinomas are frequently associated with cysts (Fig. 15.29) and are composed of polygonal cells with abundant eosinophilic and occasionally clear cytoplasm infiltrating the stroma, frequently associated with marked host lymphocytic reaction (Figs. 15.30 and 15.31). A spindle cell component may be present. Breast squamous cell carcinomas are morphologically similar to squamous cell carcinomas arising in other locations [108, 109].
Squamous cell carcinoma : the carcinoma is associated with cystic areas
Squamous cell carcinoma : nests of tumor cells with marked keratinization associated with host inflammatory infiltrate
Squamous cell carcinoma : tumor cells show abundant eosinophilic cytoplasm, focal clearing, and marked pleomorphism
Metaplastic carcinomas with mesenchymal differentiation are tumors with an overt carcinoma component associated with a mesenchymal component with chondroid or osseous differentiation (Figs. 15.32 and 15.33), or less frequently with rhabdomyosarcomatous, liposarcomatous, or angiosarcomatous differentiation. Matrix-producing carcinomas were classically defined as those in which the carcinoma component directly transitions to chondroid or osseous matrix, without the presence of intervening spindle cells or osteoclastic giant cells (Fig.15.34). The matrix-producing component may occasionally display a mucoid appearance and mimic mucinous carcinoma (Fig. 15.35) [110].
Metaplastic carcinoma with chondroid differentiation: the carcinoma shows chondroid morphology
Metaplastic carcinoma with osseous differentiation: the carcinoma shows osteoid production
Metaplastic carcinoma , matrix-producing: poorly differentiated carcinoma transitioning to a hypocellular matrix area with focal necrosis
Metaplastic carcinoma , matrix-producing: poorly differentiated carcinoma admixed with matrix material with a mucin-like morphology
Metaplastic spindle cell carcinomas may arise in association with fibrosclerotic lesions of the breast , like papillomas, complex sclerosing lesions and nipple adenomas [111]. Metaplastic spindle cell carcinomas have infiltrative margins and are composed of spindle cells with moderate-to-marked atypia, arranged haphazardly, or in fascicular, herringbone, and storiform architectural patterns, and frequently show associated inflammatory infiltrate (Fig. 15.36) [112]. Necrosis and numerous mitoses and are common (Fig. 15.37). Focal clusters of cells with more epithelioid morphology or squamous differentiation or focal areas of conventional invasive carcinoma , usually poorly differentiated, and ductal carcinoma in situ (DCIS) may be present (Figs. 15.38 and 15.39) [112].
Metaplastic carcinoma , spindle cell: the spindle cells are arranged haphazardly and are associated with peritumoral lymphocytic infiltrate
Metaplastic carcinoma , spindle cell: the tumor cells display marked atypia and frequent mitoses
Metaplastic carcinoma , spindle cell: the spindle carcinoma cells are admixed with clusters of cells with epithelioid morphology
Metaplastic carcinoma , spindle cell: focal high-grade DCIS is identified admixed with the spindle cell carcinoma
Low-grade fibromatosis -like metaplastic spindle cell carcinoma (LG-FLMC) is a low-grade form of spindle cell carcinoma with morphologic resemblance to fibromatosis . LG-FLMCs have irregular infiltrative margins with fingerlike projections (Figs. 15.40 and 15.41), and are composed of bland spindle cells with absent-to-minimal atypia, arranged in wavy fascicles in more than 95% of the tumor (Fig. 15.42). LG-FLMCs range from hypocellular to hypercellular and are intermixed with collagenous areas [113]. The spindle cells are frequently admixed with few clusters of glandular or squamous epithelial cells [113].
Low-grade fibromatosis -like metaplastic spindle cell carcinoma : bland-appearing spindle cells infiltrate adipose tissue
Low-grade fibromatosis -like metaplastic spindle cell carcinoma : the carcinoma has an infiltrative growth with finger-like projections
Low-grade fibromatosis -like metaplastic spindle cell carcinoma : the tumor cells are arranged in wavy fascicles surrounded by collagenous stroma
Low-grade adenosquamous carcinomas (LGASC) have a stellate configuration with poorly defined borders, and are composed of elongated or ovoid infiltrating glands with tumor cells of low nuclear grade and various degrees of squamous differentiation (Fig. 15.43). The LGASC glands appear to blend with the surrounding stroma, which ranges from hyalinized to cellular (Fig. 15.44). Lymphocytic aggregates are frequently seen in the periphery of the lesions [114, 115].
Low-grade adenosquamous carcinoma : neoplastic cells are arranged in nests and glands with an infiltrative pattern
Low-grade adenosquamous carcinoma : angulated gland with tumor cells with low nuclear grade and squamous differentiation, surrounded by a hypocellular stroma
FNA smears of metaplastic carcinomas are usually highly cellular and frequently show necrosis. Clues for the diagnosis of metaplastic carcinoma on cytology material include squamous carcinoma cells, atypical spindle cells, and heterologous elements fragments (Fig. 15.45) [116,117,118]. Nonetheless, identification of both epithelial and heterologous elements in cytology specimens is uncommon, and the diagnosis of metaplastic carcinoma on cytology material is challenging (Fig. 15.46).
Metaplastic carcinoma , spindle cell, cytology: FNA smear shows large clusters of spindle tumor cells in a background of red blood cells
Metaplastic carcinoma , matrix-producing, cytology: FNA smear shows tumor cells admixed with matrix
Metaplastic carcinomas are usually triple negative, have a basal immunophenotype [119, 120], and are of basal-like molecular subtype [112, 121, 122]. The identification of epithelial differentiation in metaplastic carcinomas requires a broad panel of epithelial and myoepithelial markers, as the immunoreactivity of metaplastic carcinomas to cytokeratins or myoepithelial markers is highly variable and may be focal, and no individual marker has been found to be uniformly positive. The majority (70–80%) of metaplastic carcinomas are positive for broad spectrum cytokeratins (AE1/AE3 and MNF116) and for high molecular weight cytokeratins (34βE12, CK5/6, CK14 and CK17), whereas low molecular weight cytokeratins (CK8/18, CK7 and CK19) are less frequently positive in metaplastic carcinomas (30–60%) (Fig. 15.47) [120]. Myoepithelial markers, such as p63, are frequently positive [112]. Metaplastic breast carcinomas share the complex genetic abnormalities and high frequency of TP53 mutations with conventional TNBCs, and are associated with mutations in PIK3CA, PIK3R1, PTEN, FAT1 and AXIN1 resulting in an increased activation of the PI3K and Wnt pathways [123, 124].
Metaplastic carcinoma , spindle cell: the spindle cell metaplastic carcinoma shows diffuse positivity for 34βE12
The differential diagnosis of metaplastic carcinoma is broad. Therefore, metastatic squamous cell carcinoma from a distant anatomical site or direct extension from a squamous cell carcinoma arising in the overlying skin should be excluded before rendering the diagnosis of breast squamous cell carcinoma . Phyllodes tumor with stromal overgrowth should be considered in the differential diagnosis of spindle cell metaplastic carcinomas , and cytokeratins and p63 are useful IHC markers in this scenario. Nevertheless, caution should be exerted, as a subset of phyllodes tumors may be focally positive for p63 and cytokeratins [125]. CD34 is consistently negative in metaplastic carcinomas and may help differentiate metaplastic carcinomas from phyllodes tumors [120]. Discrimination of LG-FLMC from fibromatosis might be particularly challenging due to their marked morphologic overlap. While fibromatosis is negative for cytokeratins and shows nuclear β-catenin expression [126], β-catenin may also be expressed in metaplastic carcinomas , and should not be used as the sole marker for the distinction between these entities [123]. LGASCs may show morphologic overlap with tubular carcinoma , adenomyoepithelioma , and syringomatous tumor of the nipple [127]. A study using lineage-tracing analysis suggested that LGASCs and syringomatous tumors of the nipple are identical or nearly identical lesions [127].
Metaplastic carcinomas show a lower rate of nodal metastasis than invasive carcinoma NST [101, 102, 128]. Like other TNBCs, metaplastic carcinomas may develop distant metastasis in the absence of nodal metastasis [106]. These tumors show a lower response rate to neoadjuvant and adjuvant chemotherapy [129,130,131]. Several studies indicate that metaplastic carcinomas have a worse prognosis than invasive carcinoma NST [122, 129, 132,133,134], although a multi-institutional study that included over 400 cases showed that when matched for grade, nodal status, and ER/HER2 receptor status, metaplastic carcinomas have an outcome similar to invasive carcinoma NST. In the aforementioned study, spindle cell carcinoma had a worse outcome than other subtypes of metaplastic carcinoma [119]. Unlike other types of metaplastic carcinomas , LGASCs and LG-FLMCs have an indolent clinical behavior and a good prognosis [135, 136].
15.9 Adenoid Cystic Carcinoma
Adenoid cystic carcinoma (AdCC) typically arises in the salivary glands, but may also originate at other anatomic locations, such as the respiratory and gastrointestinal tracts, skin, and breast [137]. Breast AdCCs account for approximately 0.1% of breast carcinomas [138]. The usual clinical presentation of AdCC is a palpable mass, frequently located in the subareolar region.
On mammography, AdCCs appear as irregular or lobulated masses [139], and are usually heterogenous or hypoechoic on sonogram [140]. On MRI they display suspicious enhancement kinetics [140].
AdCCs are biphasic tumors, composed of epithelial and myoepithelial cells arranged in different patterns, histologically indistinguishable from their counterparts arising in other anatomic locations [141]. The most characteristic growth pattern of AdCC is the cribriform one. Cribriform AdCCs are composed of islands of tumor cells with smooth contours and a sieve-like appearance with pseudolumina formed by the invagination of the stroma, containing eosinophilic PAS-positive hyaline and/or alcian blue-positive myxoid material, and less frequent true glandular spaces surrounded by epithelial cells (Figs. 15.48 and 15.49) [142]. Other AdCC morphologies include the tubular/glandular, trabecular/reticular, and solid patterns (Fig. 15.50 and 15.51) [141]. A solid variant of AdCC with basaloid features has been described, and is characterized by large infiltrative solid nests of basaloid cells with marked nuclear atypia within hyalinized, myxoid, or desmoplastic stroma [143].
Adenoid cystic carcinoma : the carcinoma shows a cribriform growth pattern with basophilic secretions within pseudolumina
Adenoid cystic carcinoma : the pseudolumina contained myxoid material or invaginated collagenous stroma
Adenoid cystic carcinoma : the tumor shows a tubular/glandular growth pattern
Adenoid cystic carcinoma : the carcinoma displays a trabecular growth pattern
The luminal epithelial component of AdCC is positive for low molecular weight cytokeratins, such as CK7, CK8/18, and for EMA and CD117, whereas the myoepithelial cells are positive for basal cytokeratins, like CK5/6, CK14, and for myoepithelial markers such as smooth muscle actin and p63 [144,145,146]. Breast AdCCs generally have a triple negative phenotype and are of basal-like molecular subtype [20, 147]. Akin to their salivary gland counterparts, breast AdCCs are underpinned by the t(6;9)(q22–23;p23–24) translocation, which results in the MYB-NFIB fusion gene and subsequent overexpression of the MYB oncogene [148], a sensitive and specific finding for AdCC [149]. Recently, breast MYB-NFIB fusion gene -negative AdCCs have been shown to be driven by alternative genetic alterations, such as MYBL1 rearrangements and MYB amplification [150].
Cytologic preparations of breast AdCCs show cellular smears with three-dimensional clusters of basaloid and epithelial cells surrounding extracellular metachromatic spherules (Figs. 15.52 and 15.53) [151, 152].
Adenoid cystic carcinoma , cytology: FNA smear shows cohesive clusters of basaloid cells surrounding spheres of basement metachromatic material. Numerous bare nuclei are present in the background
Adenoid cystic carcinoma , cytology: FNA smear show small uniform cells with scant cytoplasm and round-to-oval nuclei surrounding amorphous acellular material
The differential diagnosis of breast AdCC includes invasive cribriform carcinoma , cribriform DCIS, and collagenous spherulosis . The distinction of AdCC from collagenous spherulosis might be particularly challenging in core-needle biopsies. CD117, which is positive in AdCC and negative in collagenous spherulosis , and calponin and smooth muscle myosin heavy chain, which is negative in AdCC but strongly positive in collagenous spherulosis , may be useful for such diagnostic distinction [153].
Breast AdCCs show a low rate of nodal metastasis [154], and unlike their salivary gland counterparts and conventional TNBC, they have a favorable clinical course [155]. Nevertheless, transformation to high-grade TNBC has been described [156].
15.10 Secretory Carcinoma
Secretory carcinoma was originally described in children and initially named juvenile carcinoma [157]. However, it occurs at a later age than initially recognized, with the median age at diagnosis of 53 years [158]. Secretory carcinomas are extremely rare and represent less than 0.1% of breast carcinomas [158].
The imaging features of secretory carcinomas are variable and nonspecific. Mammographic findings range from well-circumscribed isodense masses to suspicious lesions with spiculated margins [159]. On sonography, they appear as well-circumscribed or partially microlobulated iso- or hypoechoic nodules [159, 160].
Secretory carcinomas grow in different architectural patterns (microcystic, tubular, solid, and papillary), which often coexist (Figs. 15.54 and 15.55) [161, 162]. Tumor cells have a granular eosinophilic-to-clear cytoplasm with low-grade nuclei, inconspicuous nucleoli, and minimal mitotic activity. The hallmark of secretory carcinomas is abundant intra- and extracellular dense PAS-positive eosinophilic secretions, which may resemble thyroid colloid when found in association with microcystic regions (Fig. 15.56) [162].
Secretory carcinoma : the carcinoma shows a microcystic growth pattern.
Secretory carcinoma : the carcinoma shows a papillary growth pattern with a focal microcystic component
Secretory carcinoma : the carcinoma displays abundant intra and extracellular secretions
Although few cases have been reported to weakly express hormone receptors, most secretory carcinomas are triple negative and show a basal-like immunoprofile [161]. Secretory carcinomas are positive for S-100, mammaglobin, alpha-lactalbumin, EMA, MUC4, and SOX10 [162,163,164,165].
Akin to mammary analog secretory carcinomas (MASCs) in salivary glands or skin, breast secretory carcinomas are underpinned by the t(12;15)(p13;q25) translocation, which results in the ETV6-NTRK3 fusion gene [165]. In contrast to high-grade TNBC, secretory carcinomas show a low mutational burden, no pathogenic mutations in genes frequently altered in breast cancer , and few copy number alterations [165].
Cytologic preparations of breast secretory carcinomas are of low cellularity and show bland tumor cells with cytoplasmic vacuoles admixed with colloid material [166, 167].
The differential diagnosis of secretory carcinoma includes entities with cystic architecture and prominent secretions, such as acinic cell carcinoma and cystic hypersecretory carcinoma [168]. Cystic hypersecretory carcinomas are mostly in situ lesions, composed by large cysts and abundant secretions, and are generally ER-positive, whereas secretory carcinomas frequently display a microcystic pattern and are triple negative [169]. Unlike secretory carcinomas , acinic cell carcinomas are positive for amylase, lysozyme and α1-antytripsin [170]. Importantly, the ETV6-NTRK3 fusion gene is pathognomonic for secretory carcinoma in a breast -specific context [171].
Secretory carcinomas have an excellent outcome, even in the presence of nodal involvement [158].
15.11 Solid Papillary Breast Carcinoma Resembling the Tall Cell Variant of Papillary Thyroid Neoplasms/Solid Papillary Carcinoma with Reverse Polarity
These tumors have been described by different names, including solid papillary carcinoma resembling the tall cell variant of papillary thyroid neoplasms (BPTC), and solid papillary carcinoma with reverse polarity (SPCRP). They constitute a vanishingly rare histologic type of breast carcinoma , with less than 50 cases reported in the literature to date [172,173,174,175,176,177]. They have a benign appearance with regular margins on mammography or ultrasound [177].
BPTCs/SPCRPs have a very distinctive morphology , reminiscent of the morphology of the tall cell variant of papillary thyroid carcinoma . They are composed of circumscribed tumor nodules with solid, papillary, and follicular architectural patterns, and often coexist in the same case. The follicular structures contain a colloid-like eosinophilic material (Fig. 15.57). The tumor cells are cuboidal-to-columnar with eosinophilic granular cytoplasm and apically polarized nuclei, simulating reverse polarization (Fig. 15.58), although MUC1 is expressed in the apical cellular border [175]. Akin to papillary thyroid carcinomas , SPCRPs have nuclei with clear chromatin, grooves, and pseudoinclusions (Fig. 15.59 and 15.60) [172].
Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms/solid papillary carcinoma with reverse polarity: tumor nodules with solid papillary and follicular patterns. Thick eosinophilic material is identified within the follicles
Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms/solid papillary carcinoma with reverse polarity: the tumor cells appear to have a reverse polarization with nuclei located in the apical aspect of the cells
Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms/solid papillary carcinoma with reverse polarity: the carcinoma cells show nuclear clearing and nuclear grooves
Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms/solid papillary carcinoma with reverse polarity: the carcinoma cells show occasional nuclear pseudoinclusions
Despite their resemblance to papillary thyroid neoplasms, BPTCs/SPCRPs are negative for thyroid markers, such as thyroglobulin and TTF-1 [172, 175, 178], and show focal positivity for GCDFP-15 and GATA-3 [172, 177]. These tumors are HER2-negative, and two-thirds of cases are also negative for ER and PR [172, 175, 177].
BPTCs/SPCRPs are underpinned by highly recurrent IDH2 R172 hotspot mutations or TET2 mutations, with frequent concurrent mutations targeting genes of the PI3K pathway [175, 176]. Despite their morphological overlap with the tall cell variant of papillary thyroid carcinoma , no RET/PTC and BRAF genetic alterations have been described in these tumors [172, 173, 179].
Due to their remarkably similar morphology , metastasis from a tall cell variant of papillary thyroid carcinoma should be considered in the differential diagnosis of BPTCs/SPCRPs. IHC stains for thyroglobulin and TTF-1 are useful for this distinction. BPTCs/SPCRPs may show morphologic overlap with secretory carcinomas , another low-grade TNBC, and assessment of the IDH2 mutational status and of the presence of ETV6-NTRK3 fusion gene might be useful in this scenario.
BTPCs/SPCRPs have an indolent behavior and a favorable course, and there have been only occasional reports of regional or distant metastasis [173, 175, 177, 178, 180].
15.12 Inflammatory Breast Cancer
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer . This phenotype is characterized clinically by acute inflammatory changes of the breast presenting, within ≤3 months, diffuse erythema and edema, with or without palpable mass.
IBC accounts for 1–2% of all invasive breast cancer [181]. It is characterized by a higher risk of early recurrence, distant metastases, and metastases to the central nervous system compared with non-inflammatory locally advanced cancer.
The classic histologic finding in IBC on biopsy of affected skin is dermal lymphatic invasion by tumor cells (Fig. 15.61). These malignant cells form tumor emboli which are responsible for both the local signs and symptoms and for the development of metastatic disease [182].
Inflammatory breast carcinoma . (a) Dermal lymphovascular invasion is present. (b) Tumor cells showing staining with estrogen receptor
Inflammatory breast cancer includes basal (20–40%), HER2 (20–40%) and luminal A and B subtypes. Loss of heterozygosity is detected in approximately one-half of IBC, and the most frequently loss alleles are at 3p, 6p, 8p, 11q, 13q, and 17q [183].
The differential diagnosis includes:
-
Infection (mastitis, cellulitis, abscess). Mammary infection should be distinguished from IBC clinically. Mastitis typically develops rapidly over a few days; erythema is associated with tenderness and typically occupies a wedge-shaped quadrant of breast . However, symptomatic women improvement should occur within 24–48 h of initiation of antibiotics.
-
Locally advanced carcinoma with skin invasion. Large carcinomas may directly invade into skin and cause skin ulceration. Focal dermal lymph vascular invasion may be present adjacent to the area of skin invasion. This type of cancer should not be classified as IBC.
References
McCart Reed AE, Kutasovic JR, Lakhani SR, Simpson PT. Invasive lobular carcinoma of the breast: morphology, biomarkers and omics. Breast Cancer Res. 2015;17:12.
Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289(11):1421–4.
Chen Z, Yang J, Li S, Lv M, Shen Y, Wang B, et al. Invasive lobular carcinoma of the breast: a special histological type compared with invasive ductal carcinoma. PLoS One. 2017;12(9):e0182397.
Lewis TR, Casey J, Buerk CA, Cammack KV. Incidence of lobular carcinoma in bilateral breast cancer. Am J Surg. 1982;144(6):635–8.
Kim SH, Cha ES, Park CS, Kang BJ, Whang IY, Lee AW, et al. Imaging features of invasive lobular carcinoma: comparison with invasive ductal carcinoma. Jpn J Radiol. 2011;29(7):475–82.
Le Gal M, Ollivier L, Asselain B, Meunier M, Laurent M, Vielh P, et al. Mammographic features of 455 invasive lobular carcinomas. Radiology. 1992;185(3):705–8.
Porter AJ, Evans EB, Foxcroft LM, Simpson PT, Lakhani SR. Mammographic and ultrasound features of invasive lobular carcinoma of the breast. J Med Imaging Radiat Oncol. 2014;58(1):1–10.
Gruber IV, Rueckert M, Kagan KO, Staebler A, Siegmann KC, Hartkopf A, et al. Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer. BMC Cancer. 2013;13:328.
Parvaiz MA, Yang P, Razia E, Mascarenhas M, Deacon C, Matey P, et al. Breast MRI in invasive lobular carcinoma: a useful investigation in surgical planning? Breast J. 2016;22(2):143–50.
Fechner RE. Histologic variants of infiltrating lobular carcinoma of the breast. Hum Pathol. 1975;6(3):373–8.
Shousha S, Backhous CM, Alaghband-Zadeh J, Burn I. Alveolar variant of invasive lobular carcinoma of the breast. A tumor rich in estrogen receptors. Am J Clin Pathol. 1986;85(1):1–5.
Esposito NN, Chivukula M, Dabbs DJ. The ductal phenotypic expression of the E-cadherin/catenin complex in tubulolobular carcinoma of the breast: an immunohistochemical and clinicopathologic study. Mod Pathol. 2007;20(1):130–8.
Butler D, Rosa M. Pleomorphic lobular carcinoma of the breast: a morphologically and clinically distinct variant of lobular carcinoma. Arch Pathol Lab Med. 2013;137(11):1688–92.
Menet E, Becette V, Briffod M. Cytologic diagnosis of lobular carcinoma of the breast: experience with 555 patients in the Rene Huguenin Cancer Center. Cancer. 2008;114(2):111–7.
Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10(5):437–49.
Moriya T, Kozuka Y, Kanomata N, Tse GM, Tan PH. The role of immunohistochemistry in the differential diagnosis of breast lesions. Pathology. 2009;41(1):68–76.
Da Silva L, Parry S, Reid L, Keith P, Waddell N, Kossai M, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. 2008;32(5):773–83.
Sahin S, Karatas F, Erdem GU, Hacioglu B, Altundag K. Invasive pleomorphic lobular histology is an adverse prognostic factor on survival in patients with breast cancer. Am Surg. 2017;83(4):359–64.
Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, et al. Comprehensive molecular portraits of invasive lobular breast cancer. Cell. 2015;163(2):506–19.
Weigelt B, Geyer FC, Reis-Filho JS. Histological types of breast cancer: how special are they? Mol Oncol. 2010;4(3):192–208.
Mamtani A, King TA. Lobular breast cancer: different disease, different algorithms? Surg Oncol Clin N Am. 2018;27(1):81–94.
Sakr RA, Poulet B, Kaufman GJ, Nos C, Clough KB. Clear margins for invasive lobular carcinoma: a surgical challenge. Eur J Surg Oncol. 2011;37(4):350–6.
Monhollen L, Morrison C, Ademuyiwa FO, Chandrasekhar R, Khoury T. Pleomorphic lobular carcinoma: a distinctive clinical and molecular breast cancer type. Histopathology. 2012;61(3):365–77.
Rakha EA, Lee AH, Evans AJ, Menon S, Assad NY, Hodi Z, et al. Tubular carcinoma of the breast: further evidence to support its excellent prognosis. J Clin Oncol. 2010;28(1):99–104.
Leibman AJ, Lewis M, Kruse B. Tubular carcinoma of the breast: mammographic appearance. AJR Am J Roentgenol. 1993;160(2):263–5.
Sheppard DG, Whitman GJ, Huynh PT, Sahin AA, Fornage BD, Stelling CB. Tubular carcinoma of the breast: mammographic and sonographic features. AJR Am J Roentgenol. 2000;174(1):253–7.
Rakha E, Pinder SE, Shin SJ, Tsuda H. Tubular carcioma and cribriform carcinoma. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, MJvd V, editors. WHO classification of tumours of the breast. Lyon: IARC; 2012.
Cangiarella J, Waisman J, Shapiro RL, Simsir A. Cytologic features of tubular adenocarcinoma of the breast by aspiration biopsy. Diagn Cytopathol. 2001;25(5):311–5.
Dieci MV, Orvieto E, Dominici M, Conte P, Guarneri V. Rare breast cancer subtypes: histological, molecular, and clinical peculiarities. Oncologist. 2014;19(8):805–13.
de Moraes Schenka NG, Schenka AA, de Souza Queiroz L, de Almeida Matsura M, Alvarenga M, Vassallo J. p63 and CD10: reliable markers in discriminating benign sclerosing lesions from tubular carcinoma of the breast? Appl Immunohistochem Mol Morphol. 2006;14(1):71–7.
Spruill L. Benign mimickers of malignant breast lesions. Semin Diagn Pathol. 2016;33(1):2–12.
Albrektsen G, Heuch I, Thoresen SO. Histological type and grade of breast cancer tumors by parity, age at birth, and time since birth: a register-based study in Norway. BMC Cancer. 2010;10:226.
Di Saverio S, Gutierrez J, Avisar E. A retrospective review with long term follow up of 11,400 cases of pure mucinous breast carcinoma. Breast Cancer Res Treat. 2008;111(3):541–7.
Tan PH, Tse GM, Bay BH. Mucinous breast lesions: diagnostic challenges. J Clin Pathol. 2008;61(1):11–9.
Bitencourt AG, Graziano L, Osório CA, Guatelli CS, Souza JA, Mendonça MH, et al. MRI features of mucinous cancer of the breast: correlation with pathologic findings and other imaging methods. AJR Am J Roentgenol. 2016;206(2):238–46.
Lam WW, Chu WC, Tse GM, Ma TK. Sonographic appearance of mucinous carcinoma of the breast. AJR Am J Roentgenol. 2004;182(4):1069–74.
Linda A, Zuiani C, Girometti R, Londero V, Machin P, Brondani G, et al. Unusual malignant tumors of the breast: MRI features and pathologic correlation. Eur J Radiol. 2010;75(2):178–84.
Capella C, Eusebi V, Mann B, Azzopardi JG. Endocrine differentiation in mucoid carcinoma of the breast. Histopathology. 1980;4(6):613–30.
Lacroix-Triki M, Suarez PH, MacKay A, Lambros MB, Natrajan R, Savage K, et al. Mucinous carcinoma of the breast is genomically distinct from invasive ductal carcinomas of no special type. J Pathol. 2010;222(3):282–98.
Laucirica R, Bentz JS, Khalbuss WE, Clayton AC, Souers RJ, Moriarty AT. Performance characteristics of mucinous (colloid) carcinoma of the breast in fine-needle aspirates: observations from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. Arch Pathol Lab Med. 2011;135(12):1533–8.
Tang SL, Yang JQ, Du ZG, Tan QW, Zhou YT, Zhang D, et al. Clinicopathologic study of invasive micropapillary carcinoma of the breast. Oncotarget. 2017;8(26):42455–65.
Edelweiss M, Corben AD, Liberman L, Kaplan J, Nehhozina T, Catalano JP, et al. Focal extravasated mucin in breast core needle biopsies: is surgical excision always necessary? Breast J. 2013;19(3):302–9.
Cao AY, He M, Liu ZB, Di GH, Wu J, Lu JS, et al. Outcome of pure mucinous breast carcinoma compared to infiltrating ductal carcinoma: a population-based study from China. Ann Surg Oncol. 2012;19(9):3019–27.
Ranade A, Batra R, Sandhu G, Chitale RA, Balderacchi J. Clinicopathological evaluation of 100 cases of mucinous carcinoma of breast with emphasis on axillary staging and special reference to a micropapillary pattern. J Clin Pathol. 2010;63(12):1043–7.
Paterakos M, Watkin WG, Edgerton SM, Moore DH 2nd, Thor AD. Invasive micropapillary carcinoma of the breast: a prognostic study. Hum Pathol. 1999;30(12):1459–63.
Alsharif S, Daghistani R, Kamberoğlu EA, Omeroglu A, Meterissian S, Mesurolle B. Mammographic, sonographic and MR imaging features of invasive micropapillary breast cancer. Eur J Radiol. 2014;83(8):1375–80.
Adrada B, Arribas E, Gilcrease M, Yang WT. Invasive micropapillary carcinoma of the breast: mammographic, sonographic, and MRI features. AJR Am J Roentgenol. 2009;193(1):W58–63.
Yang YL, Liu BB, Zhang X, Fu L. Invasive micropapillary carcinoma of the breast: an update. Arch Pathol Lab Med. 2016;140(8):799–805.
Nassar H. Carcinomas with micropapillary morphology: clinical significance and current concepts. Adv Anat Pathol. 2004;11(6):297–303.
Siriaunkgul S, Tavassoli FA. Invasive micropapillary carcinoma of the breast. Mod Pathol. 1993;6(6):660–2.
Kelten EC, Akbulut M, Duzcan SE. Diagnostic dilemma in cytologic features of micropapillary carcinoma of the breast: a report of 2 cases. Acta Cytol. 2009;53(4):463–6.
Vingiani A, Maisonneuve P, Dell'orto P, Farante G, Rotmensz N, Lissidini G, et al. The clinical relevance of micropapillary carcinoma of the breast: a case-control study. Histopathology. 2013;63(2):217–24.
Yang W, Wei B, Chen M, Bu H. Evaluation of immunohistochemistry HER2 results interpretation in invasive micropapillary carcinoma of the breast. Zhonghua Bing Li Xue Za Zhi. 2015;44(1):48–52.
Stewart RL, Caron JE, Gulbahce EH, Factor RE, Geiersbach KB, Downs-Kelly E. HER2 immunohistochemical and fluorescence in situ hybridization discordances in invasive breast carcinoma with micropapillary features. Mod Pathol. 2017;30(11):1561–6.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013.
Nassar H, Pansare V, Zhang H, Che M, Sakr W, Ali-Fehmi R, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol. 2004;17(9):1045–50.
Pettinato G, Manivel CJ, Panico L, Sparano L, Petrella G. Invasive micropapillary carcinoma of the breast: clinicopathologic study of 62 cases of a poorly recognized variant with highly aggressive behavior. Am J Clin Pathol. 2004;121(6):857–66.
Lepe M, Kalife ET, Ou J, Quddus MR, Singh K. ‘Inside-out’ p120 immunostaining pattern in invasive micropapillary carcinoma of the breast; additional unequivocal evidence of reversed polarity. Histopathology. 2017;70(5):832–4.
Ueng SH, Mezzetti T, Tavassoli FA. Papillary neoplasms of the breast: a review. Arch Pathol Lab Med. 2009;133(6):893–907.
Marchiò C, Iravani M, Natrajan R, Lambros MB, Savage K, Tamber N, et al. Genomic and immunophenotypical characterization of pure micropapillary carcinomas of the breast. J Pathol. 2008;215(4):398–410.
Natrajan R, Wilkerson PM, Marchiò C, Piscuoglio S, Ng CK, Wai P, et al. Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. J Pathol. 2014;232(5):553–65.
Lotan TL, Ye H, Melamed J, Wu XR, Shih IM, Epstein JI. Immunohistochemical panel to identify the primary site of invasive micropapillary carcinoma. Am J Surg Pathol. 2009;33(7):1037–41.
Guo X, Chen L, Lang R, Fan Y, Zhang X, Fu L. Invasive micropapillary carcinoma of the breast: association of pathologic features with lymph node metastasis. Am J Clin Pathol. 2006;126(5):740–6.
Chen HL, Ding A. Comparison of invasive micropapillary and triple negative invasive ductal carcinoma of the breast. Breast. 2015;24(6):723–31.
Chen AC, Paulino AC, Schwartz MR, Rodriguez AA, Bass BL, Chang JC, et al. Population-based comparison of prognostic factors in invasive micropapillary and invasive ductal carcinoma of the breast. Br J Cancer. 2014;111(3):619–22.
Liu F, Yang M, Li Z, Guo X, Lin Y, Lang R, et al. Invasive micropapillary mucinous carcinoma of the breast is associated with poor prognosis. Breast Cancer Res Treat. 2015;151(2):443–51.
Barbashina V, Corben AD, Akram M, Vallejo C, Tan LK. Mucinous micropapillary carcinoma of the breast: an aggressive counterpart to conventional pure mucinous tumors. Hum Pathol. 2013;44(8):1577–85.
Madur B, Shet T, Chinoy R. Cytologic findings in infiltrating micropapillary carcinoma and mucinous carcinomas with micropapillary pattern. Acta Cytol. 2007;51(1):25–32.
Jain S, Khurana N, Rao S, Garg A, Kaza R. Psammomatous colloid carcinoma of the breast with micropapillary pattern. Breast J. 2012;18(2):178–80.
Pedersen L, Zedeler K, Holck S, Schiødt T, Mouridsen HT. Medullary carcinoma of the breast. Prevalence and prognostic importance of classical risk factors in breast cancer. Eur J Cancer. 1995;31A(13–14):2289–95.
Wang XX, Jiang YZ, Liu XY, Li JJ, Song CG, Shao ZM. Difference in characteristics and outcomes between medullary breast carcinoma and invasive ductal carcinoma: a population based study from SEER 18 database. Oncotarget. 2016;7(16):22665–73.
Yilmaz E, Lebe B, Balci P, Sal S, Canda T. Comparison of mammographic and sonographic findings in typical and atypical medullary carcinomas of the breast. Clin Radiol. 2002;57(7):640–5.
Jeong SJ, Lim HS, Lee JS, Park MH, Yoon JH, Park JG, et al. Medullary carcinoma of the breast: MRI findings. AJR Am J Roentgenol. 2012;198(5):W482–7.
Ridolfi RL, Rosen PP, Port A, Kinne D, Mike V. Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer. 1977;40(4):1365–85.
Racz MM, Pommier RF, Troxell ML. Fine-needle aspiration cytology of medullary breast carcinoma: report of two cases and review of the literature with emphasis on differential diagnosis. Diagn Cytopathol. 2007;35(6):313–8.
Xu R, Feiner H, Li P, Yee H, Inghirami G, Delgado Y, et al. Differential amplification and overexpression of HER-2/neu, p53, MIB1, and estrogen receptor/progesterone receptor among medullary carcinoma, atypical medullary carcinoma, and high-grade invasive ductal carcinoma of breast. Arch Pathol Lab Med. 2003;127(11):1458–64.
Rodriguez-Pinilla SM, Rodríguez-Gil Y, Moreno-Bueno G, Sarrió D, Martin-Guijarro Mdel C, Hernandez L, et al. Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype: an immunohistochemical and gene amplification study. Am J Surg Pathol 2007;31(4):501–8.
Huober J, Gelber S, Goldhirsch A, Coates AS, Viale G, Öhlschlegel C, et al. Prognosis of medullary breast cancer: analysis of 13 International Breast Cancer Study Group (IBCSG) trials. Ann Oncol. 2012;23(11):2843–51.
Mateo AM, Pezzi TA, Sundermeyer M, Kelley CA, Klimberg VS, Pezzi CM. Atypical medullary carcinoma of the breast has similar prognostic factors and survival to typical medullary breast carcinoma: 3,976 cases from the National Cancer Data Base. J Surg Oncol. 2016;114(5):533–6.
Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO, et al. The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast. Eur J Cancer. 2009;45(10):1780–7.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7.
O'Malley FP, Bane A. An update on apocrine lesions of the breast. Histopathology. 2008;52(1):3–10.
Tanaka K, Imoto S, Wada N, Sakemura N, Hasebe K. Invasive apocrine carcinoma of the breast: clinicopathologic features of 57 patients. Breast J. 2008;14(2):164–8.
Vranic S, Schmitt F, Sapino A, Costa JL, Reddy S, Castro M, et al. Apocrine carcinoma of the breast: a comprehensive review. Histol Histopathol. 2013;28(11):1393–409.
Zhang N, Zhang H, Chen T, Yang Q. Dose invasive apocrine adenocarcinoma has worse prognosis than invasive ductal carcinoma of breast: evidence from SEER database. Oncotarget. 2017;8(15):24579–92.
Gilles R, Lesnik A, Guinebretière JM, Tardivon A, Masselot J, Contesso G, et al. Apocrine carcinoma: clinical and mammographic features. Radiology. 1994;190(2):495–7.
Yuen S, Uematsu T, Kasami M, Tanaka K, Kimura K, Sanuki J, et al. Breast carcinomas with strong high-signal intensity on T2-weighted MR images: pathological characteristics and differential diagnosis. J Magn Reson Imaging. 2007;25(3):502–10.
Seo KJ, An YY, Whang IY, Chang ED, Kang BJ, Kim SH, et al. Sonography of invasive apocrine carcinoma of the breast in five cases. Korean J Radiol. 2015;16(5):1006–11.
Vranic S, Gatalica Z, Deng H, Frkovic-Grazio S, Lee LM, Gurjeva O, et al. ER-alpha36, a novel isoform of ER-alpha66, is commonly over-expressed in apocrine and adenoid cystic carcinomas of the breast. J Clin Pathol. 2011;64(1):54–7.
Vranic S, Marchiò C, Castellano I, Botta C, Scalzo MS, Bender RP, et al. Immunohistochemical and molecular profiling of histologically defined apocrine carcinomas of the breast. Hum Pathol. 2015;46(9):1350–9.
Dellapasqua S, Maisonneuve P, Viale G, Pruneri G, Mazzarol G, Ghisini R, et al. Immunohistochemically defined subtypes and outcome of apocrine breast cancer. Clin Breast Cancer. 2013;13(2):95–102.
Turner NC, Reis-Filho JS. Tackling the diversity of triple-negative breast cancer. Clin Cancer Res. 2013;19(23):6380–8.
Weisman PS, Ng CK, Brogi E, Eisenberg RE, Won HH, Piscuoglio S, et al. Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology. Mod Pathol. 2016;29(5):476–88.
Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 2014;16(4):406.
Agarwal C, Pujani M, Sharma N, Rana D, Prajapati D. Apocrine carcinoma of breast: a rare entity posing cytological challenge. Diagn Cytopathol. 2017;45(12):1156–8.
Ng WK. Fine needle aspiration cytology of apocrine carcinoma of the breast. Review of cases in a three-year period. Acta Cytol. 2002;46(3):507–12.
Abati AD, Kimmel M, Rosen PP. Apocrine mammary carcinoma. A clinicopathologic study of 72 cases. Am J Clin Pathol. 1990;94(4):371–7.
Weigelt B, Eberle C, Cowell CF, Ng CK, Reis-Filho JS. Metaplastic breast carcinoma: more than a special type. Nat Rev Cancer. 2014;14(3):147–8.
Downs-Kelly E, Nayeemuddin KM, Albarracin C, Wu Y, Hunt KK, Gilcrease MZ. Matrix-producing carcinoma of the breast: an aggressive subtype of metaplastic carcinoma. Am J Surg Pathol. 2009;33(4):534–41.
Yamaguchi R, Horii R, Maeda I, Suga S, Makita M, Iwase T, et al. Clinicopathologic study of 53 metaplastic breast carcinomas: their elements and prognostic implications. Hum Pathol. 2010;41(5):679–85.
Pezzi CM, Patel-Parekh L, Cole K, Franko J, Klimberg VS, Bland K. Characteristics and treatment of metaplastic breast cancer: analysis of 892 cases from the National Cancer Data Base. Ann Surg Oncol. 2007;14(1):166–73.
Nelson RA, Guye ML, Luu T, Lai LL. Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis. Ann Surg Oncol. 2015;22(1):24–31.
Langlands F, Cornford E, Rakha E, Dall B, Gutteridge E, Dodwell D, et al. Imaging overview of metaplastic carcinomas of the breast: a large study of 71 cases. Br J Radiol. 2016:20140644.
Lang R, Fan Y, Fu X, Fu L. Metaplastic breast carcinoma with extensive osseous differentiation: a report of two cases and review of the literature. Tumori. 2011;97(4):e1–5.
Leddy R, Irshad A, Rumboldt T, Cluver A, Campbell A, Ackerman S. Review of metaplastic carcinoma of the breast: imaging findings and pathologic features. J Clin Imaging Sci. 2012;2:21.
McKinnon E, Xiao P. Metaplastic carcinoma of the breast. Arch Pathol Lab Med. 2015;139(6):819–22.
Yang WT, Hennessy B, Broglio K, Mills C, Sneige N, Davis WG, et al. Imaging differences in metaplastic and invasive ductal carcinomas of the breast. AJR Am J Roentgenol. 2007;189(6):1288–93.
Nayak A, Wu Y, Gilcrease MZ. Primary squamous cell carcinoma of the breast: predictors of locoregional recurrence and overall survival. Am J Surg Pathol. 2013;37(6):867–73.
DeLair DF, Corben AD, Catalano JP, Vallejo CE, Brogi E, Tan LK. Non-mammary metastases to the breast and axilla: a study of 85 cases. Mod Pathol. 2013;26(3):343–9.
Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma. Hum Pathol. 1989;20(7):628–35.
Gobbi H, Simpson JF, Jensen RA, Olson SJ, Page DL. Metaplastic spindle cell breast tumors arising within papillomas, complex sclerosing lesions, and nipple adenomas. Mod Pathol. 2003;16(9):893–901.
Carter MR, Hornick JL, Lester S, Fletcher CD. Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases. Am J Surg Pathol. 2006;30(3):300–9.
Dwyer JB, Clark BZ. Low-grade fibromatosis-like spindle cell carcinoma of the breast. Arch Pathol Lab Med. 2015;139(4):552–7.
Kawaguchi K, Shin SJ. Immunohistochemical staining characteristics of low-grade adenosquamous carcinoma of the breast. Am J Surg Pathol. 2012;36(7):1009–20.
Geyer FC, Lambros MB, Natrajan R, Mehta R, Mackay A, Savage K, et al. Genomic and immunohistochemical analysis of adenosquamous carcinoma of the breast. Mod Pathol. 2010;23(7):951–60.
Lui PC, Tse GM, Tan PH, Jayaram G, Putti TC, Chaiwun B, et al. Fine-needle aspiration cytology of metaplastic carcinoma of the breast. J Clin Pathol. 2007;60(5):529–33.
Murata T, Ihara S, Kato H, Tanigawa K, Higashiguchi T, Imai T, et al. Matrix-producing carcinoma of the breast: case report with radiographical and cytopathological features. Pathol Int. 1998;48(10):824–8.
Joshi D, Singh P, Zonunfawni Y, Gangane N. Metaplastic carcinoma of the breast: cytological diagnosis and diagnostic pitfalls. Acta Cytol. 2011;55(4):313–8.
Rakha EA, Tan PH, Varga Z, Tse GM, Shaaban AM, Climent F, et al. Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study. Br J Cancer. 2015;112(2):283–9.
Rakha EA, Coimbra ND, Hodi Z, Juneinah E, Ellis IO, Lee AH. Immunoprofile of metaplastic carcinomas of the breast. Histopathology. 2017;70(6):975–85.
Davis WG, Hennessy B, Babiera G, Hunt K, Valero V, Buchholz TA, et al. Metaplastic sarcomatoid carcinoma of the breast with absent or minimal overt invasive carcinomatous component: a misnomer. Am J Surg Pathol. 2005;29(11):1456–63.
Lester TR, Hunt KK, Nayeemuddin KM, Bassett RL Jr, Gonzalez-Angulo AM, Feig BW, et al. Metaplastic sarcomatoid carcinoma of the breast appears more aggressive than other triple receptor-negative breast cancers. Breast Cancer Res Treat 2012;131(1):41–48.
Lacroix-Triki M, Geyer FC, Lambros MB, Savage K, Ellis IO, Lee AH, et al. Beta-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast. Mod Pathol. 2010;23(11):1438–48.
Ng CKY, Piscuoglio S, Geyer FC, Burke KA, Pareja F, Eberle CA, et al. The landscape of somatic genetic alterations in metaplastic breast carcinomas. Clin Cancer Res. 2017;23(14):3859–70.
Cimino-Mathews A, Sharma R, Illei PB, Vang R, Argani P. A subset of malignant phyllodes tumors express p63 and p40: a diagnostic pitfall in breast core needle biopsies. Am J Surg Pathol. 2014;38(12):1689–96.
Rungta S, Kleer CG. Metaplastic carcinomas of the breast: diagnostic challenges and new translational insights. Arch Pathol Lab Med. 2012;136(8):896–900.
Boecker W, Stenman G, Loening T, Andersson MK, Sinn HP, Barth P, et al. Differentiation and histogenesis of syringomatous tumour of the nipple and low-grade adenosquamous carcinoma: evidence for a common origin. Histopathology. 2014;65(1):9–23.
Cimino-Mathews A, Verma S, Figueroa-Magalhaes MC, Jeter SC, Zhang Z, Argani P, et al. A clinicopathologic analysis of 45 patients with metaplastic breast carcinoma. Am J Clin Pathol. 2016;145(3):365–72.
Hennessy BT, Giordano S, Broglio K, Duan Z, Trent J, Buchholz TA, et al. Biphasic metaplastic sarcomatoid carcinoma of the breast. Ann Oncol. 2006;17(4):605–13.
Jung SY, Kim HY, Nam BH, Min SY, Lee SJ, Park C, et al. Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer. Breast Cancer Res Treat. 2010;120(3):627–37.
Nagao T, Kinoshita T, Hojo T, Tsuda H, Tamura K, Fujiwara Y. The differences in the histological types of breast cancer and the response to neoadjuvant chemotherapy: the relationship between the outcome and the clinicopathological characteristics. Breast. 2012;21(3):289–95.
El Zein D, Hughes M, Kumar S, Peng X, Oyasiji T, Jabbour H, et al. Metaplastic carcinoma of the breast is more aggressive than triple-negative breast cancer: a study from a single institution and review of literature. Clin Breast Cancer. 2017;17(5):382–91.
Zhang Y, Lv F, Yang Y, Qian X, Lang R, Fan Y, et al. Clinicopathological features and prognosis of metaplastic breast carcinoma: experience of a major Chinese cancer center. PLoS One. 2015;10(6):e0131409.
Lai HW, Tseng LM, Chang TW, Kuo YL, Hsieh CM, Chen ST, et al. The prognostic significance of metaplastic carcinoma of the breast (MCB)—a case controlled comparison study with infiltrating ductal carcinoma. Breast. 2013;22(5):968–73.
Tan QT, Chuwa EW, Chew SH, Lim-Tan SK, Lim SH. Low-grade adenosquamous carcinoma of the breast: a diagnostic and clinical challenge. Int J Surg. 2015;19:22–6.
Gobbi H, Simpson JF, Borowsky A, Jensen RA, Page DL. Metaplastic breast tumors with a dominant fibromatosis-like phenotype have a high risk of local recurrence. Cancer. 1999;85(10):2170–82.
Jaso J, Malhotra R. Adenoid cystic carcinoma. Arch Pathol Lab Med. 2011;135(4):511–5.
Treitl D, Radkani P, Rizer M, El Hussein S, Paramo JC, Mesko TW. Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature. Breast Cancer. 2017. https://doi.org/10.1007/s12282-017-0780-1.
Boujelbene N, Khabir A, Boujelbene N, Jeanneret Sozzi W, Mirimanoff RO, Khanfir K. Clinical review—breast adenoid cystic carcinoma. Breast. 2012;21(2):124–7.
Glazebrook KN, Reynolds C, Smith RL, Gimenez EI, Boughey JC. Adenoid cystic carcinoma of the breast. AJR Am J Roentgenol. 2010;194(5):1391–6.
Foschini MP, Morandi L, Asioli S, Giove G, Corradini AG, Eusebi V. The morphological spectrum of salivary gland type tumours of the breast. Pathology. 2017;49(2):215–27.
Marchiò C, Weigelt B, Reis-Filho JS. Adenoid cystic carcinomas of the breast and salivary glands (or ‘The strange case of Dr Jekyll and Mr Hyde’ of exocrine gland carcinomas). J Clin Pathol. 2010;63(3):220–8.
Shin SJ, Rosen PP. Solid variant of mammary adenoid cystic carcinoma with basaloid features: a study of nine cases. Am J Surg Pathol. 2002;26(4):413–20.
Mastropasqua MG, Maiorano E, Pruneri G, Orvieto E, Mazzarol G, Vento AR, et al. Immunoreactivity for c-kit and p63 as an adjunct in the diagnosis of adenoid cystic carcinoma of the breast. Mod Pathol. 2005;18(10):1277–82.
Azoulay S, Laé M, Fréneaux P, Merle S, Al Ghuzlan A, Chnecker C, et al. KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. Mod Pathol. 2005;18(12):1623–31.
Nakai T, Ichihara S, Kada A, Ito N, Moritani S, Kawasaki T, et al. The unique luminal staining pattern of cytokeratin 5/6 in adenoid cystic carcinoma of the breast may aid in differentiating it from its mimickers. Virchows Arch. 2016;469(2):213–22.
Wetterskog D, Lopez-Garcia MA, Lambros MB, A'Hern R, Geyer FC, Milanezi F, et al. Adenoid cystic carcinomas constitute a genomically distinct subgroup of triple-negative and basal-like breast cancers. J Pathol. 2012;226(1):84–96.
Persson M, Andrén Y, Mark J, Horlings HM, Persson F, Stenman G. Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proc Natl Acad Sci U S A. 2009;106(44):18740–4.
Poling JS, Yonescu R, Subhawong AP, Sharma R, Argani P, Ning Y, et al. MYB labeling by immunohistochemistry is more sensitive and specific for breast adenoid cystic carcinoma than MYB labeling by FISH. Am J Surg Pathol. 2017;41(7):973–9.
Kim J, Geyer FC, Martelotto LG, Ng CKY, Lim RS, Selenica P, et al. MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene. J Pathol. 2017. https://doi.org/10.1002/path.5006.
Saqi A, Mercado CL, Hamele-Bena D. Adenoid cystic carcinoma of the breast diagnosed by fine-needle aspiration. Diagn Cytopathol. 2004;30(4):271–4.
Ilkay TM, Gozde K, Ozgur S, Dilaver D. Diagnosis of adenoid cystic carcinoma of the breast using fine-needle aspiration cytology: a case report and review of the literature. Diagn Cytopathol. 2015;43(9):722–6.
Rabban JT, Swain RS, Zaloudek CJ, Chase DR, Chen YY. Immunophenotypic overlap between adenoid cystic carcinoma and collagenous spherulosis of the breast: potential diagnostic pitfalls using myoepithelial markers. Mod Pathol. 2006;19(10):1351–7.
Welsh JL, Keeney MG, Hoskin TL, Glazebrook KN, Boughey JC, Shah SS, et al. Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast? J Surg Oncol. 2017;116(6):690–5.
Ghabach B, Anderson WF, Curtis RE, Huycke MM, Lavigne JA, Dores GM. Adenoid cystic carcinoma of the breast in the United States (1977 to 2006): a population-based cohort study. Breast Cancer Res. 2010;12(4):R54.
Fusco N, Geyer FC, De Filippo MR, Martelotto LG, Ng CK, Piscuoglio S, et al. Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer. Mod Pathol. 2016;29(11):1292–305.
McDivitt RW, Stewart FW. Breast carcinoma in children. JAMA. 1966;195(5):388–90.
Horowitz DP, Sharma CS, Connolly E, Gidea-Addeo D, Deutsch I. Secretory carcinoma of the breast: results from the survival, epidemiology and end results database. Breast. 2012;21(3):350–3.
Mun SH, Ko EY, Han BK, Shin JH, Kim SJ, Cho EY. Secretory carcinoma of the breast: sonographic features. J Ultrasound Med. 2008;27(6):947–54.
Paeng MH, Choi HY, Sung SH, Moon BI, Shim SS. Secretory carcinoma of the breast. J Clin Ultrasound. 2003;31(8):425–9.
Del Castillo M, Chibon F, Arnould L, Croce S, Ribeiro A, Perot G, et al. Secretory breast carcinoma: a histopathologic and genomic spectrum characterized by a joint specific ETV6-NTRK3 gene fusion. Am J Surg Pathol. 2015;39(11):1458–67.
Li D, Xiao X, Yang W, Shui R, Tu X, Lu H, et al. Secretory breast carcinoma: a clinicopathological and immunophenotypic study of 15 cases with a review of the literature. Mod Pathol. 2012;25(4):567–75.
Lamovec J, Bracko M. Secretory carcinoma of the breast: light microscopical, immunohistochemical and flow cytometric study. Mod Pathol. 1994;7(4):475–9.
Lae M, Fréneaux P, Sastre-Garau X, Chouchane O, Sigal-Zafrani B, Vincent-Salomon A. Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. Mod Pathol. 2009;22(2):291–8.
Krings G, Joseph NM, Bean GR, Solomon D, Onodera C, Talevich E, et al. Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas. Mod Pathol. 2017;30(8):1086–99.
Shanthi V, Rama Krishna BA, Rao NM, Sujatha C. Cytodiagnosis of secretory carcinoma of the breast. J Cytol. 2012;29(1):63–5.
Jayaram G, Looi LM, Yip CH. Fine needle aspiration cytology of secretory carcinoma of breast: a case report. Malays J Pathol. 1997;19(1):69–73.
Osako T, Takeuchi K, Horii R, Iwase T, Akiyama F. Secretory carcinoma of the breast and its histopathological mimics: value of markers for differential diagnosis. Histopathology. 2013;63(4):509–19.
D'Alfonso TM, Ginter PS, Liu YF, Shin SJ. Cystic hypersecretory (in situ) carcinoma of the breast: a clinicopathologic and immunohistochemical characterization of 10 cases with clinical follow-up. Am J Surg Pathol. 2014;38(1):45–53.
Peintinger F, Leibl S, Reitsamer R, Moinfar F. Primary acinic cell carcinoma of the breast: a case report with long-term follow-up and review of the literature. Histopathology. 2004;45(6):645–8.
Geyer FC, Pareja F, Weigelt B, Rakha E, Ellis IO, Schnitt SJ, et al. The spectrum of triple-negative breast disease: high- and low-grade lesions. Am J Pathol. 2017;187(10):2139–51.
Eusebi V, Damiani S, Ellis IO, Azzopardi JG, Rosai J. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: report of 5 cases. Am J Surg Pathol. 2003;27(8):1114–8.
Cameselle-Teijeiro J, Abdulkader I, Barreiro-Morandeira F, Ruiz-Ponte C, Reyes-Santias R, Chavez E, et al. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: a case report. Int J Surg Pathol. 2006;14(1):79–84.
Masood S, Davis C, Kubik MJ. Changing the term “breast tumor resembling the tall cell variant of papillary thyroid carcinoma” to “tall cell variant of papillary breast carcinoma”. Adv Anat Pathol. 2012;19(2):108–10.
Chiang S, Weigelt B, Wen HC, Pareja F, Raghavendra A, Martelotto LG, et al. IDH2 mutations define a unique subtype of breast cancer with altered nuclear polarity. Cancer Res. 2016;76(24):7118–29.
Bhargava R, Florea AV, Pelmus M, Jones MW, Bonaventura M, Wald A, et al. Breast tumor resembling tall cell variant of papillary thyroid carcinoma: a solid papillary neoplasm with characteristic immunohistochemical profile and few recurrent mutations. Am J Clin Pathol. 2017;147(4):399–410.
Foschini MP, Asioli S, Foreid S, Cserni G, Ellis IO, Eusebi V, et al. Solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms: a unique invasive tumor with indolent behavior. Am J Surg Pathol. 2017;41(7):887–95.
Tosi AL, Ragazzi M, Asioli S, Del Vecchio M, Cavalieri M, Eusebi LH, et al. Breast tumor resembling the tall cell variant of papillary thyroid carcinoma: report of 4 cases with evidence of malignant potential. Int J Surg Pathol. 2007;15(1):14–9.
Hameed O, Perry A, Banerjee R, Zhu X, Pfeifer JD. Papillary carcinoma of the breast lacks evidence of RET rearrangements despite morphological similarities to papillary thyroid carcinoma. Mod Pathol. 2009;22(9):1236–42.
Colella R, Guerriero A, Giansanti M, Sidoni A, Bellezza G. An additional case of breast tumor resembling the tall cell variant of papillary thyroid carcinoma. Int J Surg Pathol. 2015;23(3):217–20.
Robertson FM, Bondy M, Yang W, Yamauchi H, Wiggins S, Kamrudin S, et al. Inflammatory breast cancer: the disease, the biology, the treatment. CA Cancer J Clin. 2010;60(6):351–75.
Cristofanilli M, Valero V, Buzdar AV, Kau SW, Broglio KR, Gonzalez-Angulo AM, et al. Inflammatory breast cancer (IBC) and patterns of recurrence: understanding the biology of a unique disease. Cancer. 2007;110(7):1436–44.
Raghav K, French JT, Ueno NT, Lei X, Krishnamurthy S, Reuben JM, et al. Inflammatory Breast Cancer: a distinct clinicopathologic entity transcending histological distinction. PLoS One. 2016;11(1):e0145534.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Arias-Stella, J.A., Alvarado-Cabrero, I., Pareja, F. (2018). Special Types of Invasive Breast Carcinoma. In: Stolnicu, S., Alvarado-Cabrero, I. (eds) Practical Atlas of Breast Pathology . Springer, Cham. https://doi.org/10.1007/978-3-319-93257-6_15
Download citation
DOI: https://doi.org/10.1007/978-3-319-93257-6_15
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-93256-9
Online ISBN: 978-3-319-93257-6
eBook Packages: MedicineMedicine (R0)