Invasive Carcinoma: Special Types and Important Considerations

6.1 PURE TUBULAR CARCINOMA VS. RADIAL SCAR

	Pure Tubular Carcinoma	Radial Scar
Age	Any age, more often in postmenopausal women	Adult women, overlapping age with tubular carcinoma
Location	Anywhere in the breast	Anywhere in the breast
Presentation	Indistinguishable from no special type carcinomas; may be multifocal; frequently low stage (pT1) although may rarely may involve one or two low axillary lymph nodes	Usually mammographic abnormality, rarely palpable mass. May mimic invasive carcinoma clinically and radiographically
Imaging findings	Mammogram shows a spiculated mass, which may contain calcifications; up to one half may be incidental to calcifications associated with atypical hyperplasia or ductal carcinoma in situ (DCIS); hypoechoic mass with ill-defined margins and posterior acoustic shadowing on ultrasound	Mammography shows asymmetric density or architectural distortion, often with central translucence; hypoechoic mass or density, parenchymal distortion by ultrasound
Epidemiology	Approximately 2% of invasive breast cancers, more frequently detected (20%) by mammographic screening	Incidence unknown, although more common with high-quality mammography
Histology	Haphazard arrangement of small glandular structures (Fig. 6.1.1) More than 90% of tumor consists of ovoid and “bent teardrop”-shaped tubules (Fig. 6.1.2) Tubules composed of a single layer of cuboidal epithelial cells with low-grade nuclei and inconspicuous nucleoli (Figs. 6.1.3 and 6.1.4) Apical snouts frequently present (Fig. 6.1.4) In addition to tubules, a component of cribriform structures infiltrates basophilic, desmoplastic stroma with irregular extension into fat (Fig. 6.1.5) Often seen in association with ADH, lowgrade DCIS, ALH, or columnar cell lesions with atypia By definition, tubular carcinoma has a low combined histologic grade	Radial arrangement of small glandular structures, emanating from central elastosis (Fig. 6.1.6) Lobulocentric arrangement is maintained, and glandular structures do not infiltrate fat (Fig. 6.1.7) Small glands are associated with dense periductal fibrosis, at least focally (Fig. 6.1.8) Glands of radial scar maintain a myoepithelial and luminal cell layer (Fig. 6.1.9) Myoepithelial cells may be detected by immunohistochemistry, although they may be sparse (Fig. 6.1.10)
Special studies	Strong expression of ER, usually expresses PR; uniformly lacks HER2 amplification. Myoepithelial cells not detected by immunohistochemistry.	Immunohistochemistry for myoepithelial cells may be helpful if present, but occasionally radial scars and other sclerosing lesions may lack myoepithelial cells; use of a battery of markers may be helpful
Genetics	16q loss (75%-85%), 1q gain (50%-60%); 16p gain, loss of 8p, 3p (FHIT locus) and 11q (ATM locus)	None
Treatment	Complete surgical excision is adequate therapy for most cases. Axillary dissection considered unnecessary even in presence of a positive sentinel node; in many cases radiation therapy unnecessary; chemotherapy is not indicated.	Often excised when diagnosed on core biopsy; however, if histology and mammography are concordant, and no risk lesions (i.e., atypical hyperplasia) are present, excision is not necessary
Clinical implication	Excellent prognosis even in the presence of a positive axillary lymph node(s); survival rates similar to the general population; risk of local recurrence extremely low after complete excision	Radial scars (and related complex sclerosing lesions) may mimic invasive carcinomas clinically and mammographically. Subsequent carcinoma risk is that attributed to any epithelial proliferation that may be present within the radial scar, i.e., usual hyperplasia or atypical hyperplasia. The radiology literature suggests that radial scars are a premalignant lesion; however, these studies have selection bias and lack of careful case definition.

Figure 6.1.1 Tubular carcinoma, showing haphazard arrangement of small, angulated tubular structures.

Figure 6.1.6 Glandular structures radiate from an elastotic center in a radial scar.

Figure 6.1.2 Tubular carcinoma characterized by open glands and occasional bent “tear drop” structures.

Figure 6.1.3 Small glands, some with occasional cribriform features, infiltrate fat in pure tubular carcinoma.

Figure 6.1.4 Glands of tubular carcinoma are lined by a single cell layer with minimal pleomorphism and apocrine snouts.

Figure 6.1.7 The glands of a radial scar maintain a lobulocentric configuration and do not extend into fat.

Figure 6.1.8 The glands of a radial scar lack the haphazard arrangement of tubular carcinoma; lobulocentricity is maintained, and elastosis is present around several of the ducts.

Figure 6.1.9 Two cell layers are present in radial scar.

Figure 6.1.5 Immunohistochemistry using antibodies to p63 shows a lack of myoepithelial cells in tubular carcinoma; three normal ducts retain myoepithelial cells (lower center, right and left).

Figure 6.1.10 Immunohistochemistry using antibodies to p63 shows maintenance of myoepithelial cells in a patchy distribution.

6.2 INVASIVE CRIBRIFORM CARCINOMA VS. CRIBRIFORM DUCTAL CARCINOMA IN SITU

	Invasive Cribriform Carcinoma	Cribriform Ductal Carcinoma In Situ
Age	Adult women, usually 6th decade	Most commonly middle-aged and older women, wide age range
Location	Anywhere in the breast	Anywhere in the breast
Presentation	Mammographic abnormality; rarely palpable mass	Mammographic abnormality, rarely clinically evident
Imaging findings	Spiculated mass, often with microcalcifications	Punctate or linear calcifications, rarely mass forming
Epidemiology	Less than 1.0% of invasive carcinomas; more commonly detected in screening programs; may be multifocal	20%-25% of screen detected breast cancers, 80%-85% detected in absence of clinical findings
Histology	Irregularly placed epithelial islands with cribriform spaces are present in a desmoplastic stroma (Figs. 6.2.1 and 6.2.2) with infiltration into fat (Fig. 6.2.3) Tubular component may comprise up to 50% of tumor	Lobular units and true ducts contain a proliferation of uniform cells (Fig. 6.2.4) Even cell placement results in rigid secondary spaces (Fig. 6.2.5) Cribriform DCIS usually has a low or intermediate nuclear grade (Fig. 6.2.6)
Special studies	Strong expression of ER, usually expresses PR; uniformly lacks HER2 amplification. Myoepithelial cells not detected by immunohistochemistry.	None required; immunohistochemistry for myoepithelial markers may facilitate recognition of a noninvasive process when present
Genetics	16q loss (75%-85%), 1q gain (50%-60%); 16p gain; loss of 8p, 3p (FHIT locus) and 11q (ATM locus)	None to distinguish from low-grade invasive mammary carcinoma
Treatment	Complete surgical excision is adequate therapy for most cases. Axillary dissection considered unnecessary even in presence of a positive sentinel node; chemotherapy is not indicated.	Excision to negative margins ± radiation therapy; antiestrogen therapy may be indicated for some patients
Clinical implication	Excellent prognosis, even in the presence of a positive axillary lymph node(s); survival rates similar to that of pure tubular carcinoma, which is not different from the general population; risk of local recurrence extremely low after complete excision	Risk of local recurrence as DCIS or invasive carcinoma if excision incomplete

Figure 6.2.1 Broad tumor islands with cribriform architecture are irregularly arranged in invasive cribriform carcinoma.

Figure 6.2.2 Cribriform glands have irregular shapes and do not conform to preexisting ductal lobular structures; note infiltration into fat (lower left).

Figure 6.2.3 Invasive cribriform carcinoma with a focal tubular component. Despite superficial resemblance to cribriform DCIS, the cellular islands lack lobulocentricity and are irregularly distributed.

Figure 6.2.4 The original duct and lobular architecture are evident, despite the expansion and distortion by cribriform DCIS.

Figure 6.2.5 Uniform cells delineate crisp secondary spaces in lowgrade cribriform DCIS.

Figure 6.2.6 A fibrous duct wall as well as residual myoepithelial cells are evident in low-grade DCIS, cribriform pattern.

6.3 PURE MUCINOUS CARCINOMA VS. NO SPECIAL TYPE CARCINOMA WITH MUCIN PRODUCTION

	Pure Mucinous Carcinoma	No Special Type Carcinoma with Mucin Production
Age	Middle-aged and older women; most patients older than 55 years	Middle-aged and older women; most patients older than 55 years
Presentation	Mammographic abnormality, less frequently presents as a palpable mass	Mammographic abnormality or palpable mass
Location	Anywhere in the breast	Anywhere in the breast
Imaging findings	Well-circumscribed lesion on mammography, frequently suggests a benign process; hypoechoic mass on ultrasound	Circumscribed or spiculated mass depending on amount of mucin present
Epidemiology	Approximately 2% of invasive breast cancers	Approximately 5% of invasive breast cancers
Histology	Small nests, trabeculae, or sheets of epithelial cells, which appear suspended in pools of extracellular mucin (Fig. 6.3.1) Delicate fibrous septae containing capillaries are scattered throughout the mucin (Fig. 6.3.2) Epithelial component must be of low nuclear grade and represent a minor component of the lesion; mitotic figures should not be evident (Fig. 6.3.3) Must be at least 90% pure in pattern to diagnose pure mucinous carcinoma; any other minor component must be low grade	Nests, trabeculae, or sheets of intermediate-or high-grade carcinoma entirely or partially suspended in mucin (Fig. 6.3.4) May show invasive micropapillary features (Fig. 6.3.5) Mitotic figures may be frequent (Fig. 6.3.6) Special studies Strong expression of ER and PR; HER2 not amplified Vary widely on intensity and extent of ER expression; subset shows HER2 amplification
Genetics	16q loss (75%-85%), 1q gain (50%-60%), similar to pure tubular carcinoma	Similar to other intermediate and high-grade, no special type invasive carcinomas
Treatment	Excision to negative margins ± radiation therapy, ± antiestrogen therapy; chemotherapy not indicated	Excision to negative margins + radiation therapy, chemotherapy frequently given; antiestrogen therapy if ER-positive
Clinical implication	10 year survival rates similar to age-matched controls without carcinoma (80%-100%)	Worse prognosis and higher rates of lymph node metastases compared with pure mucinous carcinoma

Figure 6.3.1 Small glandular structures appear suspended in extracellular mucin in pure mucinous carcinoma.

Figure 6.3.2 Delicate fibrovascular structures permeate pools of mucin in pure mucinous carcinoma.

Figure 6.3.3 The paucicellular proliferation of pure mucinous carcinoma has a low nuclear grade without mitoses.

Figure 6.3.4 Invasive mammary carcinoma, no special type with extracellular mucin production: Although extracellular mucin is prominent, the degree of cellularity is too great to consider pure mucinous carcinoma.

Figure 6.3.5 More than 50% of the tumor is composed of neoplastic epithelium, a feature that supports the diagnosis of invasive mammary carcinoma, no special type with extracellular mucin production, rather than pure mucinous carcinoma.

Figure 6.3.6 Grade 2 nuclei are not a feature of pure mucinous carcinoma. The amount of epithelium relative to the amount of mucin also supports the diagnosis of a no special type carcinoma with extracellular mucin production.

6.4 PURE MUCINOUS CARCINOMA VS. MUCOCELE-LIKE LESION ASSOCIATED WITH DCIS

	Pure Mucinous Carcinoma	Mucocele-Like Lesion Associated with DCIS
Age	Middle-aged and older women, most patients older than 55 years	Any age, usually women in 5th and 6th decade
Location	Anywhere in the breast	Anywhere in the breast; if associated with intraductal papilloma, may be retroareolar
Presentation	Mammographic abnormality, less frequently presents as a palpable mass	Mammographic abnormality, rarely palpable mass or associated with bloody nipple discharge
Imaging findings	Well-circumscribed lesion on mammography, frequently suggesting a benign process; hypoechoic mass on ultrasound	Irregular density, may be associated with calcifications; ultrasound shows hypoechoic mass
Epidemiology	Approximately 2% of invasive breast cancers	Rare finding associated with DCIS with abundant mucin production
Histology	Small nests, trabeculae, or sheets of epithelial cells, which appear suspended in pools of extracellular mucin (Fig. 6.4.1). By definition, mucinous carcinoma should be paucicellular Delicate fibrous septae containing capillaries are present within mucin pools (Fig. 6.4.2) Epithelial component must be of low nuclear grade and represent a minor component of the lesion; mitotic figures should not be evident (Fig. 6.4.3) Must be at least 90% pure in pattern to diagnose pure mucinous carcinoma; any other minor component must be low grade	Traumatic or iatrogenic disruption of mucin-producing DCIS with extrusion of mucin and DCIS fragments into the surrounding stroma (Fig. 6.4.4) Extracellular mucin follows contours of preexisting ducts (Fig. 6.4.5) Some mucin pools contain a peripheral layer of epithelium (Fig. 6.4.6), a remnant of a disrupted duct Solid or cribriform architecture of DCIS maintained in extruded epithelial fragments containing uniform cells of low nuclear grade (Figs. 6.4.5 and 6.4.6)
Special studies	Uniformly expresses ER and PR; no amplification of HER2	None; myoepithelial cells maintained in epithelial fragments which remain associated with a basement membrane. ER expression routinely evaluated to assess the potential for response adjuvant endocrine therapy; multigene assay may predict which patients may be spared radiation.
Genetics	16q loss (75%-85%), 1q gain (50%-60%), essentially the same as pure tubular carcinoma	Loss of 16q, 17p
Treatment	Excision to negative margins ± radiation therapy, antiestrogen therapy; chemotherapy not indicated	Complete excision with negative margins, ± adjuvant radiation; sentinel lymph node biopsy not indicated
Clinical implication	10 y survival rates similar to age-matched controls without carcinoma	Development of invasive carcinoma in approximately 30% of cases if DCIS incompletely excised; with complete excision recurrence rate approximately 5%-8% without radiation

Figure 6.4.1 Pure mucinous carcinoma, with a characteristic bland, paucicellular epithelial component “floating” in extracellular mucin.

Figure 6.4.2 Thin fibrous strands containing capillaries traverse areas of mucin in pure mucinous carcinoma.

Figure 6.4.3 Grade 1 nuclei and lack of mitotic activity are characteristic of pure mucinous carcinoma.

Figure 6.4.4 Low-grade DCIS with a mucocele-like lesion. An epithelial proliferation conforms to preexisting terminal ducts/lobular units and is associated with extracellular mucin.

Figure 6.4.5 A solid, expansile nodule of low-grade DCIS has intermixed mucin. Epithelial disruption is also evident, although most collections of mucin are partially lined by ductal cells.

Figure 6.4.6 Expanded and disrupted ducts contain mucin, with residual ductal epithelium lining at least part of the mucin-filled spaces in this mucocele-like lesion associated with low-grade DCIS.

6.5 INVASIVE LOBULAR CARCINOMA VS. NO SPECIAL TYPE CARCINOMA WITH LOBULAR FEATURES

	Invasive Lobular Carcinoma	No Special Type Carcinoma with Lobular Features
Age	Women in 6th and 7th decade, slightly older than women with invasive mammary carcinoma of no special type	Women in 6th and 7th decade, slightly older than women with invasive mammary carcinoma of no special type
Location	Anywhere in the breast	Anywhere in the breast
Presentation	Ill-defined palpable mass or mammographic abnormality	Ill-defined palpable mass or palpable abnormality
Imaging findings	Spiculated mass or architectural distortion	Spiculated mass or architectural distortion
Epidemiology	5%-15% of invasive breast cancers	5%-15% of breast cancers
Histology	Single-file infiltration by neoplastic cells, comprises at least 90% of tumor (Figs. 6.5.1 and 6.5.2) Residual normal ducts and lobular units may be present Single-file growth of cells lacks cohesion (Fig. 6.5.3). May encircle pre-existing structures in a “targetoid” pattern Intracytoplasmic inclusions are frequent (Fig. 6.5.4) Often nuclear grade 2, although mitotic activity is rare	Single-file growth pattern composes a portion of the carcinoma, but less than required for a diagnosis of pure invasive lobular carcinoma (Fig. 6.5.5). Small cellular clusters and glands are also present. Single-file growth may encircle preexisting structures, so-called “tagetoid” pattern, similar to pure invasive lobular carcinoma (Fig. 6.5.6) Usually nuclear grade 2, and mitotic activity low (Fig. 6.5.7) Small neoplastic glands and solid nests are intermixed with the neoplastic cells showing single-file growth (Fig. 6.5.8)
Special studies	None required for diagnosis; strongly ER-positive; invasive lobular carcinoma usually lacks expression of E-cadherin; p120 expression maintained	Usually ER-positive; loss of E-cadherin expression may be seen in lobular component
Genetics	Loss of 16q, contains locus for E-cadherin	16q loss, 1q gain
Treatment	Same as invasive carcinoma of no special type: neoadjuvant or adjuvant endocrine therapy, surgical excision to negative margins and adjuvant radiation therapy. Breast conservation not contraindicated. The single-file growth pattern may make obtaining clear surgical margins difficult, requiring mastectomy.	Adjuvant or neoadjuvant endocrine therapy, surgical excision to negative margins and adjuvant radiation; Adjuvant chemotherapy for higher grade lesions
Clinical implication	Stage and grade dictate prognosis. Prognosis intermediate between special types (tubular, cribriform, and mucinous) and carcinomas of no special type. Specific metastatic patterns often associated with ILC, including bone-only disease, spread to gastrointestinal tract, uterus, ovary, serosal surfaces and meninges as well as the occurrence of metastasis many years after treatment of the primary breast carcinoma.	Stage and grade dictate prognosis; lobular component may have similar pattern of spread as pure invasive lobular carcinoma

Figure 6.5.1 Invasive lobular carcinoma, characterized by diffuse single-file growth pattern.

Figure 6.5.2 Invasive lobular carcinoma should be composed of at least 90% single-file growth pattern.

Figure 6.5.3 The morphologic correlate of lack of E-cadherin expression in invasive lobular carcinoma is its dyshesive growth.

Figure 6.5.5 Although part of this invasive carcinoma has a single-file growth pattern, more than half of the tumor is composed of small nests and cords, denying a diagnosis of pure invasive lobular carcinoma.

Figure 6.5.6 Targetoid growth pattern may be seen in invasive carcinoma, no special type with lobular features.

Figure 6.5.7 Grade 2 nuclei are present in strands and cords in this example of invasive carcinoma, no special type with lobular features.

Figure 6.5.4 Nuclei are round and regular with minimal pleomorphism; intracytoplasmic inclusions are frequent in invasive lobular carcinoma.

Figure 6.5.8 Solid nests and small glandular structures are admixed with tumor growing in a single file pattern, supporting the diagnosis of invasive carcinoma of no special type, with lobular features.

6.6 NO SPECIAL TYPE CARCINOMA WITH MEDULLARY FEATURES VS. HIGH-GRADE, NO SPECIAL TYPE CARCINOMA WITH ASSOCIATED LYMPHOCYTIC INFILTRATE

	No Special Type Carcinoma with Medullary Features	High-Grade, No Special Type Carcinoma with Associated Lymphocytic Infiltrate
Age	Any age, but often young women in 3rd and 4th decade	Any age, generally older than women with carcinomas showing medullary features
Location	Anywhere in the breast	Anywhere in the breast
Presentation	Often presents as a palpable mass or mammographic abnormality	Palpable mass or mammographic abnormality
Imaging findings	Nodular density; ultrasound shows a hypoechoic mass with smooth borders	Nodular density; ultrasound lacks smooth borders
Epidemiology	Less than 1% of breast cancers	30%-40% of high-grade, no special type carcinomas
Histology	Neoplastic epithelial proliferation associated with a smooth pushing border (Fig. 6.6.1) Neoplastic epithelium must be arranged in a sheet-like (syncytial) growth pattern (Fig. 6.6.2) Stroma between cellular syncytia contains a dense lymphoplasmacytic infiltrate (Fig. 6.6.3) By definition, carcinomas with medullary features have a high combined histologic grade (Fig. 6.6.4)	Expansile growth pattern but lacks syncytial growth (Fig. 6.6.5) Small nests of neoplastic cells infiltrate fat (Fig. 6.6.6) Lymphocytic infiltrate present within tumor nests, rather than confined to stroma (Fig. 6.6.7) High-grade nuclei and frequent mitoses are characteristic (Fig. 6.6.8)
Special studies	Negative for expression of ER and PR; HER2 not amplified	None to distinguish from medullary carcinoma; usually lacks expression of ER and PR; may be HER2 amplified
Genetics	Basal-like genomic profile; TP53 mutations are most common alteration; BRCA1 mutations frequent	TP53 mutations most common alteration; ± BRCA1 mutations
Treatment	Neoadjuvant chemotherapy followed by surgical excision is currently preferred therapy	Neoadjuvant chemotherapy followed by surgical excision
Clinical implication	Older literature supports good prognosis for node negative medullary carcinoma, although currently, concerns about reproducibility in applying criteria, triple-negative receptor status and frequent presentation in young women prompts administration of taxane chemotherapy	Prognosis based on stage, although highgrade, triple-negative carcinomas often have the poorest prognosis

Figure 6.6.1 Carcinoma with medullary features, showing the characteristic smooth pushing border with adjacent fat.

Figure 6.6.2 The diagnosis of carcinoma with medullary features requires a sheet-like (syncytial) growth pattern, with neoplastic epithelium separated by fibrous stroma containing lymphocytes and plasma cells.

Figure 6.6.3 Lymphocytes and plasma cells are confined to the fibrous stroma and are not prominent within the epithelial sheets in carcinomas with medullary features.

Figure 6.6.5 Invasive carcinoma, no special type, showing an overall rounded contour with adjacent fat, but neoplastic nests infiltrate fat in an irregular pattern.

Figure 6.6.6 Invasive carcinoma, no special type showing small infiltrating glands, rather than syncytial growth.

Figure 6.6.7 Invasive carcinoma, no special type, showing lymphocytes percolating within neoplastic nests, rather than confined to the adjacent fibrous stroma, as is required in carcinomas with medullary features.

Figure 6.6.4 High nuclear grade and frequent mitotic activity are characteristic of carcinomas with medullary features.

Figure 6.6.8 High-grade nuclei and frequent mitotic figures are present in this invasive carcinoma of no special type. Scattered lymphocytes are present, but the distribution and growth pattern are not defining for medullary carcinoma.

6.7 SMALL CELL CARCINOMA VS. NO SPECIAL TYPE CARCINOMA WITH NEUROENDOCRINE DIFFERENTIATION

	Small Cell Carcinoma	No Special Type Carcinoma with Neuroendocrine Differentiation
Age	Adult women, mean age 65 years	Adult women, commonly 6th and 7th decade
Location	Anywhere in the breast	Anywhere in the breast
Presentation	Mammographic abnormality or palpable mass; up to 40% with metastatic disease at presentation	None to distinguish from no special type carcinomas without neuroendocrine differentiation; mammographic abnormality or palpable mass
Imaging findings	Spiculated mammographic mass	Indistinguishable from other no special type carcinomas
Epidemiology	Less than 1% of invasive breast cancers	Less than 1% of invasive breast carcinomas
Histology	Morphologically indistinguishable from small cell carcinoma of lung and other sites (Fig. 6.7.1) Sheets and nests of diffusely infiltrating neoplastic associated with desmoplastic stroma (Figs. 6.7.2 and 6.7.3) Hyperchromatic cells with scant cytoplasm (Fig. 6.7.4) High mitotic activity, apoptotic bodies, focal necrosis, and crush artifact (Fig. 6.7.4) DCIS component common Associated lymphovascular invasion common	Cellular, solid nests and trabeculae of tumor cells in a fibrovascular stroma (Figs. 6.7.5, 6.7.6, 6.7.7, 6.7.8) Cells are spindled to plasmacytoid (Figs. 6.7.6, 6.7.7, 6.7.8) Most are low or intermediate grade (Fig. 6.7.8)
Special studies	Half express chromogranin and synaptophysin; approximately 50% ER-positive	50% express chromogranin and 15% express synaptophysin; almost always ER-positive
Genetics	No distinguishing genetic features	No distinguishing genetic features
Treatment	High dose taxane-based chemotherapy and etoposide similar to that used for small cell carcinoma of the lung. Addition of radiation therapy does not improve survival.	Same as invasive carcinoma of no special type of same stage and grade; presence of neuroendocrine features is of no clinical significance
Clinical implication	Poorer prognosis than invasive mammary carcinoma of no special type of similar grade and stage	Prognosis depends on grade and stage