Fig. 9.1
Invasive ductal carcinoma, high nuclear grade. (a) Ultrasound shows a nearly anechoic, “cystic” appearing mass; however, its microlobulated borders and density mammographically (b) portend a more suspicious etiology in this 42-year-old woman. A metallic BB placed on the overlying skin indicates this is palpable to the patient. (c) Pre-contrast sagittal T2-weighted (fluid-sensitive) MRI image shows increased signal around the mass (peritumoral edema) and centrally in the mass (between arrows) that corresponds absence of enhancement on axial post-contrast imaging (d), reflecting central necrosis
Fig. 9.2
Invasive ductal carcinoma, low nuclear grade. (a) Screening mammogram in this 41-year-old woman shows architectural distortion (arrows) in the upper central aspect of the left breast—“straightening” of the parenchymal lines. (b) On ultrasound of the upper inner and outer quadrants, multiple areas of ill-defined hypoechogenicity and disruption of tissue planes are seen, without an expansile mass. (c) Post-contrast axial MRI image demonstrates non-mass enhancement occupying the majority of the parenchyma in the upper quadrants (arrow); the normal right breast is shown for comparison
Mucinous and papillary carcinomas , seen more commonly in postmenopausal women, are less aggressive and metastasize less frequently than IDC, providing for a better prognosis. This may seem counterintuitive as these masses are classically described as “large” and expansile; however, their size comes from their internal matrix. On imaging, these are typically round or oval lobulated masses, and their echogenicity can help predict their histology (Figs. 9.3 and 9.4). Mucinous carcinomas tend to be iso- to slightly hyperechoic and are slow growing. Papillary carcinomas are typically complex solid and cystic and may grow more rapidly depending in part on the cystic component but may also be spiculated and solid. The mucin and fluid in these masses, respectively, also contribute to T2 hyperintensity (fluid signal) on MRI. Additionally, non-enhancing septa may be seen in mucinous cancers, compared with the enhancing solid portions of the vascular papillary carcinoma. Although these may present as large masses, the imaging features should supersede size when trying to confirm radiologic-pathologic concordance; all cancers have a starting point and may be found in early stages when still small. Papillary carcinomas are further described in the chapter “Papillary Lesions.”
Fig. 9.3
Mucinous carcinoma in an 80-year-old woman. (a) Spot compression view after screening callback shows a round equal-density mass with mostly circumscribed and some indistinct margins. (b) On ultrasound this was an iso- to slightly hyperechoic mass (between arrows), relative to subcutaneous fat. (c) Pre-contrast sagittal T2-weighted (fluid-sensitive) MRI image shows a mass of increased signal intensity (arrow) that corresponds to a peripherally enhancing mass on post-contrast images. (d) The central portion of the mass is mucin, which itself does not enhance
Fig. 9.4
Papillary carcinoma in an 84-year-old woman. (a) Spot tangential mammographic view shows an equal-density oval mass with circumscribed and lobulated margins and associated and adjacent coarse calcifications. (b) Orthogonal ultrasound images demonstrate a complex solid (arrows) and cystic (arrowheads) mass. The solid portion was targeted for ultrasound-guided needle biopsy. Although at core biopsy a papillary lesion with involvement by ductal carcinoma in situ was identified, invasive disease was found at lumpectomy. Intraductal and invasive papillary carcinoma may be indistinguishable on imaging
Tubular carcinomas tend to be small (< 1 cm) masses with spiculated margins, or areas of distortion, and are also slow growing. Histologically they may be associated with radial scars or complex sclerosing lesions, which is why excision is recommended for these high-risk lesions if found on imaging-guided core biopsy.
Metaplastic carcinomas are rapidly growing masses with a worse prognosis, with axillary or distant (including hematogenous) metastases possible at the time of diagnosis (Fig. 9.5). By imaging they may be indistinguishable from a high nuclear grade IDC NOS, but histologically they are comprised of glandular, squamous or mesenchymal elements.
Fig. 9.5
Metaplastic carcinoma . (a) A 50-year-old woman presenting with a palpable mass in the outer central aspect of the left breast (arrows) and palpable axillary adenopathy (arrowhead). (b) 3-D maximum intensity projection reconstructions from a PET/CT scan show persistent disease in the breast (arrow) and to a lesser degree in the axilla (arrowhead) 7 months into chemotherapy and (c) progression of metastases at 11 months despite mastectomy, axillary dissection, and additional chemotherapy
Invasive lobular carcinoma (ILC) , which represents about 10% of all breast cancers, is more common in postmenopausal women and is slow growing. Radiographically, ILC may appear as an area of architectural distortion, developing asymmetry, or mass with spiculated margins, rather than an expansile mass, alluding to its more indolent, “single-file” cell growth pattern. Also because of its histology, ILC may be planar, seen better in one plane (classically the craniocaudal projection) than the orthogonal. Sonographically, these may be quite ill-defined masses with disruption of tissue planes and intense posterior acoustic shadowing, or vague areas of architectural distortion (Fig. 9.6). One uncommon exception is pleomorphic ILC, an aggressive subtype that manifests as an expansile mass, and is treated like a high nuclear grade IDC (Fig. 9.7). ILC may also present with diffuse changes (edema) in the background of an enlarging or shrinking breast.
Fig. 9.6
Invasive lobular carcinoma . (a) Spot compression CC and MLO views done in a 68-year-old woman recalled from a screening mammogram show architectural distortion, “straightening” of the parenchymal lines (arrows). (b) Sonographically, ill-defined hypoechoic to nearly anechoic tissue with echogenic peaks (arrows) that disrupt tissue planes, and posterior acoustic shadowing, all confirmed in orthogonal planes, reflects the distortion seen radiographically
Fig. 9.7
Invasive lobular carcinoma, pleomorphic type . (a) Diagnostic mammogram in a 65-year-old woman with a “lump.” There is skin thickening and retraction overlying the mass (arrows). (b) Skin involvement is confirmed on ultrasound, as this heterogeneous mass is inseparable from the deep dermal layer (arrows). (c) Post-contrast axial MRI image showing an irregular mass with thick rim enhancement extending to the skin. Lobular carcinoma rarely presents as an expansile mass, except for this aggressive subtype that clinically mimics a grade 3 invasive ductal carcinoma
In patients in whom a suspicious mass is seen mammographically, sonography allows for further characterization and biopsy guidance, as well as the opportunity to evaluate the axilla for evidence of lymph node metastasis. As with calcifications, biopsy of the mass can be done with a needle under imaging guidance, or surgically. However, the former is preferred in the majority of cases as it is far less invasive, does not require sedation or special patient preparation (e.g., withholding of anticoagulation), costs less, and can allow for appropriate staging and surgical planning prior to definitive treatment. A metallic clip placed in the mass at the time of biopsy is most useful if the treatment plan includes neoadjuvant chemotherapy that will shrink the lesion to the point that it is occult on preoperative imaging or wire/seed localization; in our experience, in patients in whom lumpectomy (partial or segmental mastectomy) is a first-line treatment because of smaller lesion size (or patient preference), the tumor is still visible on imaging for preoperative localization on or shortly before the day of surgery regardless of a clip. Ultrasound-guided core-needle biopsy (or fine needle aspiration) of axillary adenopathy can be also done in the same setting as for the primary breast mass, providing the surgeon and oncologist additional information with regard to staging. A positive lymph node can also be marked with a clip so that surgical excision can be confirmed with a specimen radiograph.
Once a diagnosis of breast cancer is confirmed by imaging-guided core-needle biopsy, MRI may be used to evaluate the extent of disease to aid in treatment planning. The sensitivity of MRI is higher than that of mammography or ultrasound, some reporting as high as 100% for invasive cancer, and the cancer detection rate is nearly double that of mammography and ultrasound combined, resulting in detection of additional disease that changes management in up to 20% of patients, most commonly shifting from breast-conserving treatment (BCT; lumpectomy and radiation) to mastectomy. This includes finding multifocal or multicentric disease in up to 10–25% and contralateral disease in up to 6%. However, the use of MRI remains controversial because there is also data showing that this test does not significantly improve re-excision or local recurrence rates, suggesting that surgical planning is adequately guided by mammography and ultrasound and that any “undetected” or residual disease after lumpectomy may be treated by subsequent breast radiation and systemic adjuvant chemotherapy without negatively impacting survival. Moreover, by current data, the conversion rate of lumpectomy to mastectomy based on additional MRI findings seems to outnumber the recurrence rates in patients who undergo BCT without a preoperative MRI. Therefore, some have suggested that the additional MRI findings may not lead to future “biologically significant” disease.
These arguments are somewhat counterintuitive for many reasons encountered in day to day practice, one being the principle of confirming the extent of disease suspected on routine imaging, namely, mammographically or sonographically. For example, if a patient has several centimeters of segmentally distributed suspicious calcifications, the accepted practice is to biopsy 2 sites, the two extremes in terms of location, that are far enough away from each other to “prove” that all of the involved and intervening tissue must be resected. Or if multiple separate, suspicious masses are seen on sonography, biopsy of more than 1 is typically done to prove multifocal or multicentric disease, and guide excision, if a patient desires breast conservation treatment. So if we are actively seeking out and biopsying additional disease to develop a complete, definitive treatment plan, one could argue that an MRI, which is more sensitive, is in keeping with this practice of establishing extent of disease. Many use the aforementioned argument that MRI-detected disease is not biologically significant; however, one could also counter that MRI-detected disease is biologically significant because its detection relies on properties unique to cancer: neovascularity and vascular permeability (tumor characteristics that result in the rapid, avid uptake of contrast). Iaconni et al. reported that MRI-detected multicentric disease was invasive in 76% of their studied patients, and larger than 1 cm or the index cancer in up to 25%, suggesting biological relevance.
Moreover, patients are routinely taken back to the operating room for re-excision in the case of positive surgical margins, regardless of the use of preoperative MRI. If the disease potentially “left behind” that would be found by MRI is of no consequence, treated effectively with radiation and chemotherapy, at no detriment to survival, why incur the additional cost, risk, and recovery of another surgery for re-excision of disease “left behind” in the setting of positive margins?
In this vein, surgical practices and breast-conserving treatment plans are evolving, such as more precise excisions with smaller volumes (margins) of tissue removed, multiple lumpectomies for multicentric disease (previously, multicentric disease was a contraindication to BCS), advanced oncoplastic reconstructive techniques, accelerated partial breast irradiation (versus whole breast irradiation), and use of recurrence risk assessment scores that may obviate the need for adjuvant chemotherapy. Therefore, the case could be made for using the most sensitive methods to accurately measure disease burden and exclude other sites of cancer preoperatively, thereby allowing for a more precise, patient-specific treatment plan before definitive surgery. Needless to say, these issues do not address the impact of preoperative MRI on detection of contralateral disease that could be treated simultaneously as the index lesion.
To address some of the controversies and conflicting data, at this time a multicenter, randomized controlled trial is in place to determine the effect of preoperative MRI with regard to staging and local regional control, with attention also on cost-effectiveness, quality of life, re-excision rates, and disease-free survival, among many other objectives.
In the meantime, in practice, while some advocate breast MRI should be done in all newly diagnosed patients, practice variations (and preferences of patients, surgeons, and oncologists) may focus efforts for MRIs in patients with cancer who are high risk, have dense breast tissue, and have triple negative disease or DCIS (given that it can be discontinuous and uncalcified), or ILC (which, due to its ill-defined appearance, can be underestimated with regard to size even on ultrasound and can have up to 30% risk of synchronous or contralateral disease). Additional suspicious lesions found on MRI should be worked up with a biopsy to help determine if the patient is still a candidate for breast conservation treatment.
Chapter 2 of this text contains some discussion on the pathology approach to diagnosis of invasive carcinomas. All invasive carcinomas of the breast must be staged based on the most current AJCC Cancer Staging Manual. Selected radiologic-pathologic correlation of invasive carcinomas is highlighted below.
Case 1
Invasive ductal carcinoma, low nuclear grade. (a) Screening mammogram in a 41-year-old woman shows architectural distortion (arrows) in the upper central aspect of the left breast—“straightening” of the parenchymal lines. (b) On ultrasound of the upper inner and outer quadrants, multiple areas of ill-defined hypoechogenicity and disruption of tissue planes are seen, without an expansile mass. (c) Invasive ductal carcinoma. Epithelial cells in nests, cords, and tubules infiltrate a desmoplastic stroma. (d) The low-grade nuclei show minimal pleomorphism and uniform chromatin
Case 2
Invasive ductal carcinoma, low nuclear grade with neuroendocrine differentiation. (a) Spot tangential view of a palpable “lump” (marked on skin with a metallic BB) in a 62-year-old woman. The mass is irregular, with high density and with indistinct and spiculated margins. (b) Orthogonal ultrasound images show similar features. In addition, there is disruption of normal tissue planes and the mass approaches the skin (arrow). (c and d) Core-needle biopsy with infiltrating cells in solid nests/insular pattern with focal peripheral palisading, low nuclear grade, and fine chromatin. Necrosis is not identified. (e) The cells are diffusely positive for synaptophysin. (f) Expression of E-cadherin is preserved. The p63 stain was negative (not pictured)
Case 3
Invasive ductal carcinoma, high nuclear grade. (a) A 54-year-old woman with a palpable (designated by metallic BB) nodular asymmetry in the upper outer quadrant of the right breast, which corresponds to an irregular, nearly anechoic but solid mass with angular and indistinct margins on ultrasound (b) and an irregular mass with heterogeneous enhancement on MRI (c, arrow). (d) Epithelial cells in small solid nests and cords infiltrate the desmoplastic stroma. (e) The high grade nuclei show pleomorphism and visible nucleoli
Case 4
Invasive ductal carcinoma, intermediate nuclear grade with apocrine features. (a) CC and (b) MLO spot compression views of a mass (arrow) in the right breast in a 62-year-old woman with known locally advanced left breast cancer (not shown). (c) Targeted ultrasound shows a nearly anechoic mass. Because it is not clearly a cyst, biopsy is done. (d and e) Note the cells with abundant granular, eosinophilic cytoplasm, and mildly pleomorphic round nuclei with prominent nucleoli
Case 5
Invasive ductal carcinoma, intermediate nuclear grade, with mucinous features/mucinous carcinoma. (a) An 80-year-old woman with a history of right lumpectomy and radiation for breast cancer, with new subcentimeter round mass with partially circumscribed and indistinct margins found in the left breast on annual mammogram. (b) Targeted ultrasound shows an isoechoic to slightly hyperechoic mass (between arrows) with circumscribed margins. (c) Central nonenhancement on the MRI with corresponding increased T2 (fluid) signal (d) reflects mucin (arrows). (e and f) Core-needle biopsies show nests of epithelial cells in pool of extracellular mucin, consistent with mucinous carcinoma. (g and h) Mucinous carcinoma in the excision specimen shows epithelial cells in in pool of extracellular mucin. A pure mucinous carcinoma must composed of more than 90% mucinous carcinoma, making the diagnosis difficult sometimes on core needle biopsy as the entire lesion is cannot be evaluated
Case 6
Invasive carcinoma with squamous features. (a) A palpable mass with mostly circumscribed margins and coarse calcifications is marked with an overlying metallic BB in this 87-year-old woman. (b) Complex solid and cystic mass is seen sonographically; ultrasound-guided biopsy targeted the solid (deeper) portion. (c and d) Invasive carcinoma shows extensive squamous features. This is a variant of metaplastic carcinoma
Case 7
Invasive ductal carcinoma, with lobular features. (a and b) CC and MLO spot compression views of a screening detected mass in a 64-year-old woman. The irregular mass is developing at the edge of the parenchyma in the right breast and has spiculated margins. (c and d) Orthogonal ultrasound images confirm an irregular mass (arrows) with indistinct margins and heterogeneous echogenicity and that disrupts tissue planes. (e and f) Core-needle biopsies show invasive carcinoma, with cells infiltrating as nests, as well as individual cells in linear distribution. (g) Similar histological features are seen in the excision specimen. (h) The e-cadherin stain is diffusely positive, arguing against invasive lobular carcinoma
Case 8
Invasive ductal carcinoma, high nuclear grade. (a) A 65-year-old woman with a round mass (arrows) in the retroglandular fat detected on screening mammogram. (b) Ultrasound shows an irregular, hypoechoic mass with mostly circumscribed and few indistinct margins. Posterior acoustic enhancement (between arrows) is nonspecific; this should not be mistaken for a complicated cyst. (c and d) Core biopsy: invasive ductal carcinoma, high nuclear grade, with papillary architecture. (e and f) Histologic variant of IDC, high nuclear grade with invasive ductal carcinoma consisting of solid nests of tumor cells with pleomorphic nuclei with coarse chromatin and prominent nucleoli
Case 9
Invasive ductal carcinoma, high nuclear grade (micropapillary type). (a) Spot compression view of a screening detected irregular mass with partially circumscribed and spiculated margins, in a 51-year-old woman. The mass is just anterior to the pectoralis major. (b) Similar features are seen on ultrasound. (c) Needle core biopsy shows invasive ductal carcinoma with micropapillary architecture: with morular-like or nest of cells without fibrovascular core, surrounded by empty stromal spaces. The empty stromal spaces are likely fixation artifact and not lymphatic spaces. (d) Same micropapillary features are seen in the surgical excision specimen. (e) This variant of invasive carcinoma is often associated with lymph node metastasis
Case 10
Diffuse, locally advanced invasive ductal carcinoma. (a) Diagnostic mammogram in a 64-year-old woman shows the right breast is shrunken, retracted, and edematous with skin and trabecular thickening. There is also global parenchymal asymmetry, on which malignant-type calcifications are superimposed. A second primary is seen as a low-density mass in the upper outer quadrant posteriorly (arrow). Axillary adenopathy is partially imaged (arrowhead), but evaluated sonographically and subsequently biopsy proven to be metastatic (not shown). (b and c) Invasive ductal carcinoma with pleomorphic nuclei with coarse chromatin and mitoses (arrow)
Case 11
Papillary carcinoma . (a) A 77-year-old woman with a palpable mass containing calcifications at prior lumpectomy site, marked on skin with metallic BB. Overlying skin retraction is from surgical scarring. Vascular calcifications incidentally noted (arrowheads). (b) Lobulated complex solid and cystic mass seen on ultrasound; echogenic foci are calcifications (arrow). (c–e) Needle core biopsies show carcinoma with solid areas arranged around thin fibrovascular cores and collagenized stroma. The circumscribed border is characteristic of solid intraductal papillary carcinoma. Tissue fragmentation is sometimes noted. The p63 stain highlights rare myoepithelial cells at the periphery (arrow)
Case 12
Invasive lobular carcinoma . (a) Screening mammogram in a 56-year-old woman. Prior lumpectomy changes in the left breast include smaller size, skin retraction, and architectural distortion amid and inferior to vascular clips (arrowheads). (b) Palpable developing asymmetry (increasing density amidst the clips) at and inferior to lumpectomy site 1 year later. (c and d) Core-needle biopsies show solid sheet of discohesive cells, some of which are plasmacytoid (arrows). (e) Invasive lobular carcinoma may infiltrate as small nests in the breast adipose tissue. (f) Tumor cells are usually discohesive and low nuclear grade with single file infiltrative pattern in stromal fibrous tissue (and no desmoplasia), characteristic to lobular carcinoma. The tumor often has a concentric pattern around normal duct (not shown)
Case 13
Invasive lobular carcinoma, pleomorphic type. (a) Diagnostic mammogram in a 65-year-old woman with a “lump.” There is skin thickening and retraction overlying the mass (arrows). (b) Skin involvement is confirmed on ultrasound, as this heterogeneous mass is inseparable from the deep dermal layer (arrows). (c) Post-contrast axial MRI image showing an irregular mass with thick rim enhancement extending to the skin. (d and e) Core-needle biopsies show high nuclear grade invasive carcinoma with eccentrically placed nuclei (arrow), infiltrative patterns and apparent discohesion, suggestive of pleomorphic lobular carcinoma and confirmatory negative stain for e-cadherin (f)
Case 14
Metaplastic carcinoma with axillary metastases. (a) A 50-year-old woman with a palpable mass in the outer central aspect of the left breast (arrows) and axillary adenopathy (arrowhead). (b) Ultrasound shows solid round breast mass and (c) axillary adenopathy (enlarged lymph nodes with thickened cortices and no identifiable fatty hila). (d–f) Progression of breast mass and axillary metastases after 5 months on chemotherapy. (g) PET/CT 7 months into treatment and (h) after mastectomy, 11 months into treatment, shows continued progression. (i) Core needle biopsies showing atypical spindle cell proliferation. (j) The atypical spindle cells are adjacent to or surround non-neoplastic breast epithelium. (k) Pleomorphism of the atypical spindle cells is noted in some areas at higher power. (l and m) The atypical spindle cells are positive for pancytokeratin (l) and p63 (m)
Invasive Breast Cancer: Diagnosis and Management Considerations
Breast cancer is the most frequently diagnosed cancer globally and is the leading cause of cancer-related death in women [1]. Although the majority are initially identified by radiologic imaging, however, some suggest that a clinically suspicious mass detected by a patient or physician should also be biopsied, regardless of imaging findings, as about 15 percent of such lesions can be mammographically occult [2]. Breast canceris a heterogeneous disease which comprises of many biologically different entities with distinct pathological features and clinical implications. These in turn exhibit different behaviors necessitating a tailored approach to their treatment strategies.
Breast Cancer Subtypes and Their Diagnostic Evaluation
All patients diagnosed with breast cancer should be assigned a clinical stage based on its involvement of the breast and/or nodal regions. Staging allows for efficient identification of local and systemic therapy options and provides baseline prognostic information. Pathologists who confirm the diagnosis of invasive cancer should obtain additional biomarkers for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) in accordance withprotocols laid down by the College of American Pathologists (CAP). An essential component of breast cancer treatment is complete knowledge of extent of disease and its biological features. These factors assist in estimation of risk of cancer recurrence after local therapies and provide information that predicts response to systemic therapy. Multidisciplinary coordination among breast and reconstructive surgeons, radiation and medical oncologists, radiologists, and pathologists facilitates treatment planning and streamlines patient care [3].
An important aspect of initial evaluation of women diagnosed with locally advanced breast cancer or those with persistent symptoms affecting a particular organ system includes assessment of metastatic disease with additional imaging such as CT scan, bone scan, or PET scan. Women with child-bearing potential must be offered fertility counselling. Patients diagnosed with breast cancers that are less than 40 years of age or those who have significant family history suggestive of hereditary syndromes should undergo genetic counselling and testing that may impact their surgical decision.
Classical biomarkers such as ER, PR, and HER2 together with traditional clinicopathological variables including tumor size, tumor grade, and nodal status are conventionally used to determine patient prognosis and management approach. The advent of platforms for gene expression analysis such as microarrays and RT-PCR have shown that response to treatment is not determined merely by anatomical prognostic factors but also by the molecular characteristics of individual tumors [4]. These molecular subtypes of breast cancer are also called intrinsic subtypes. The ER-positive intrinsic subtypes are called luminal tumors since the expression profiles are reminiscent of the luminal epithelial component of the breast. At least two subtypes exist within luminal-like tumors—luminal A and luminal B. Luminal A tumors have higher expression of ER-related genes and lower expression of proliferative genes than luminal B cancers. Luminal B tumors may have HER2 expression. Another intrinsic subtype called HER2-enriched tumors is characterized by overexpression of HER2. A more aggressive subtype called basal-like tumors has expression profiles that mimic that of the basal epithelial cells in normal breast tissue. This subtype is highly proliferative and is characterized by absence of expression of both hormone receptors and HER2 [5]. Despite the growing number of clinically relevant molecular subtypes being identified, current breast cancer management still depends on traditional pathology assessment supplemented with biomarker testing (tumor biology) using validated commercial assays (i.e., Oncotype Dx, MammaPrint, etc.).
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