Examples of pseudoneoplastic lesions in the breast and their related neoplastic mimes.
Radial scar (low-grade ductal adenocarcinoma). Choristoma (hamartoma) (metaplastic carcinoma). Proliferative adenosis (low-grade ductal adenocarcinoma). Extramedullary hematopoiesis (invasive lobular carcinoma). Collagenous spherulosis (adenoid cystic carcinoma or intraductal carcinoma). Pseudoangiomatous stromal hyperplasia (angiosarcoma).
Cell membrane surface-bound receptor TK, encoded by HER2/neu, a proto-oncogene. The gene is on 17q21-q22. HER2, neu, and ErbB-2 are all the same gene.
How do you distinguish between LCIS and ALH?
Both are characterized by a monomorphic population of discohesive cells in the terminal duct lobular unit. In LCIS, greater than 50% of the acini are filled and distended. Distention has been defined as 8 or more cells across the diameter of an acinus. In ALH, less than 50% of the spaces are filled, and the acini are partially to completely filled with cells, but minimal distention is present.
In the 2013 ASCO/CAP guideline recommendations for HER2 IHC, what are cutoff values for considering a tumor HER2 positive/equivocal/negative?
Positive: IHC 3+ (circumferential membrane staining that is complete and intense in >10% of invasive tumor cells). Equivocal: IHC 2+ (circumferential membrane staining that is incomplete and/or weak/moderate and within >10% of the invasive tumor cells, or complete and circumferential membrane staining that is intense and within 10% or less of the invasive tumor cells). Negative: IHC 1+ (incomplete membrane staining that is faint/barely perceptible and within >10% of the invasive tumor cells. Also negative: IHC 0 (no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within 10% or less of the invasive tumor cells).
IHC for breast UDH vs. ADH/LG-DCIS.
The former will have a polymorphic cell population (luminal and basal), while the latter will have a monomorphic population (usually just luminal, rarely just basal). Hence, UDH will have lots of positivity with basal cell markers, while ADH/LG-DCIS will not.
IHC to differentiate classic LCIS from LG DCIS and PLCIS from HG DCIS?
Lobular neoplasia generally exhibits loss of membrane staining of E-cadherin due to inactivation of the E-cadherin gene, while DCIS lacks this inactivation and retains linear membranous staining. p120 catenin binds E-cadherin on the internal aspect of the cell membrane, aiding in stabilization of the E-cadherin complex. Disregulation of the E-cadherin complex in LN results cytoplasmic redistribution of p120 catenin. DCIS maintains the E-cadherin complex, and hence p120 catenin remains membranous in distribution.
Immunoreactivity of normal breast epithelia: Luminal cells (4), Basal cells (3), Myoepithelial cells (9).
Luminal cells: CKs 7, 8, 18, 19. Basal cells: CKs 5/6, 14, 17. Myoepithelial cells: CKs 5, 14, 17, CD10, S100, SMA, SMMHC, calponin, p63 (the most sensitive and specific are the last 3).
Oncotype DX (Genomic Health Inc.), MammaPrint (Agendia), Mammostrat (Clarient). How do they work?
Oncotype DX is a real-time RT-PCR assay measuring RNA expression in 16 cancer-related genes and five reference genes, using paraffin-embedded tissue. Results are given as a recurrence score between 0 and 100, which are translated as low risk (a score of 18 or lower), medium risk (19 to 30), or high risk (31 or above). MammaPrint microarray measures expression of 70 genes in fresh or FFPE tissue; it categorizes patients as either high risk, (a so-called poor signature), or low risk (a so-called good signature) for recurrence. Mammostrat is an IHC test measuring five markers: p53, HTF9C, CEACAM5, NDRG1, and SLC7A5. The results are combined into a quantitative risk index: low, moderate, and high. Oncotype DX and MammaPrint are send-out tests, with TATs of 10-14 days, while results from the IHC-based Mammostrat, also a send-out test, are available to local pathologists within 48-72 hours. As of 3/2014, only MammaPrint has FDA clearance.
Syringomatous adenoma of the nipple.
A benign but locally infiltrating and destructive neoplasm of the nipple. May originate from a pluripotent adnexal keratinocyte capable of both follicular and sweat gland differentiation. Usually presents as a solitary firm mass near the nipple. Mean age at presentation is 40. Histopathologic diagnostic criteria of SAN include: (1) location in dermis and subcutis of nipple or areola; (2) irregular, compressed, or comma-shaped tubules infiltrating into smooth muscle bundles and/or nerves; (3) presence of myoepithelial cells around the tubules; (4) presence of cysts lined by stratified squamous epithelium and filled with keratinous material; and (5) absence of mitotic activity and necrosis. SAN can be mistaken for nipple adenoma, a benign variant of intraductal papilloma associated with serous or bloody nipple discharge. Both entities can have squamous metaplasia, however, nipple adenomas exhibit epithelial hyperplasia arising from a lactiferous duct displacing the nipple stroma while SAN displays stromal infiltration. SAN can be mistaken for tubular carcinoma of the breast, however, tubular carcinomas have open lumina with apocrine-like snouts and basophilic secretions, and SAN generally shows compressed lumina. Tubular carcinomas are often associated with micropapillary or cribriform LGDCIS, while SAN often have squamous metaplasia. Also in the differential diagnosis is LG adenosquamous carcinoma of the breast.
The majority of adult fibroadenomas have ___ or ___ growth patterns.
The majority of adult fibroadenomas have intracanalicular or pericanalicular growth patterns. The intracanalicular pattern is produced when the stroma is sufficiently abundant to compress ducts into elongated linear branching structures with slit-like lumens. The stroma exhibits a radial growth with deposition of reticulin fibers perpendicular to the epithelial elements. The pericanalicular pattern is produced when the ducts are not compressed by the stroma. The stroma proliferates in a random or concentric fashion around tubular ducts. Fibroadenomas with a prominent intracanalicular pattern may be mistaken for benign phyllodes tumors, especially in needle core biopsies.
The only benign proliferative lesion of the breast lacking a myoepithelial cell layer?
What is PASH?
PseudoAngiomatous Stromal Hyperplasia. A relatively common lesion in the breast. Most often presents as incidental microscopic foci, but can be a solitary palpable mass, multifocal nodules, or as a diffuse massive process. MC in premenopausal women and in postmenopausal women on estrogen. Also seen in 20-47% of gynecomastia. Histologically, there is interlobular stromal expansion with irregular spacing of the mammary lobules. There are interanastomosing, angulated, slitlike empty channels separated by dense, keloidlike, wavy, acellular colagenous stroma. The spaces are falsely lined by attenuated spindle to oval myofibroblasts, which can be plump but not atypical. No hemorrhage or necrosis. The stromal myofibroblastic cells are positive for vimentin, desmin, CD34, PR, SMA, and BCL-2. They are focally and weakly positive for ER. They are negative for CD31, Factor VIII, CK, S100, and p63. Clinically, radiologically, and cytologically, PASH can resemble FA in younger women, and phyllodes tumor in older women. Histologically, PASH can be confused with a LG angiosarcoma.
What is PLCIS?
PLCIS is a pleomorphic subtype of lobular neoplasia. This form exhibits larger cells with the characteristic discohesive nature of LN but with pleomorphic nuclei, typically grade 3 using modified Scarff-Bloom-Richardson grading criteria, and more obvious nucleoli. These cells often exhibit apocrine differentiation and can show necrosis and microcalcifications mimicking HG DCIS. PLCIS is best recognized by its association with classic LN in the nearby vicinity.
Which immunostain is + in ductal breast carcinoma and - in lobular breast carcinoma?
Breast carcinoma has a few characteristic patterns in fluid cytology, one of which is the presence of large morules (also called proliferation spheres or “cannonballs”). Describe.
“Cannonballs” are large, tightly cohesive balls of relatively uniform, neoplastic epithelial cells. Very few single malignant epithelial cells may be present. The borders of the cell groups are smooth - so-called “community” borders. In contrast, malignant cell clusters in mesothelioma are more commonly “knobby.” Although cannonballs are suggestive of breast origin, they may also be seen in carcinomas from other sites (e.g., ovary, lung, GI tract).
How do you distinguish fibroadenoma from phyllodes tumor on breast FNA?
FAs characteristically appear at age 20-30, while phyllodes tumors appear at age 40-50. Aspirates of phyllodes tumors typically contain the same triad of features as FAs, and the epithelial component is usually indistinguishable from FA. The main differentiating diagnostic feature is the stromal component: large, highly cellular, stromal fragments; single, intact mesenchymal cells; stromal cell atypia; and mitotic activity in stromal cells favors phyllodes tumor.
How do you distinguish fibroadenoma from papillary neoplasms in the breast on FNA?
Papillary neoplasms, including benign papillomas and invasive and noninvasive papillary carcinomas, may clinically mimic FAs. A subareolar location and nipple discharge favor a papillary neoplasm. FNAs from papillary neoplasms may be similar to those of FAs. However, 3D clusters containing fibrovascular cores are a feature of papillary neoplasms and not of FAs. In addition, the stromal component is usually sparse or absent in papillary neoplasms. Tall, columnar, epithelial cells are characteristic of papillary neoplasms, but may be seen in FAs as well.
What genetic abnormality do mesoblastic nephroma, infantile fibrosarcoma, and secretory carcinoma of the breast share?
Phyllodes tumors in general are graded based on the presence of adverse features including…
Phyllodes tumors in general are graded based on the presence of adverse features including tumor size, stromal overgrowth (at least one 40x field without epithelium), high mitotic rate (usually >10 / 10 HPF), sarcomatous stroma (with nuclear pleomorphism and atypia) and an infiltrative margin. Tumors can be classified as benign, borderline or malignant, but many authors favor a low grade versus high grade system, because of the variable behavior of so called borderline tumors, and the variable use of adverse factors in determining the borderline category.
What is the difference between total/simple mastectomy, modified radical mastectomy, and radical mastectomy?
In a total AKA simple mastectomy, the surgeon removes the entire breast, but does not perform an axillary lymph node dissection. No muscles are removed. In a modified radical mastectomy, the surgeon removes the entire breast, and performs an axillary lymph node dissection (levels I and II removed). No muscles are removed. In a radical mastectomy, the surgeon removes the entire breast, and performs an axillary lymph node dissection (levels I, II, and III removed). Also, the chest wall muscles are removed.
Microscopic appearance of microglandular adenosis and atypical microglandular adenosis in the breast?
Microglandular adenosis: Haphazardly infiltrating collection of small uniform, rounded, open glands with eosinophilic secretions, irregularly distributed in fibrous or adipose tissue. Glands lined by single layer of cuboidal/flat cells with vacuolated/granular cytoplasm and bland nuclei. No apocrine snouts, no nucleoli, no/variable myoepithelial layer, but thick basement membrane. Atypical microglandular adenosis: Pleomorphic glands and microacini. Budding glandular units and luminal bridging, mild cytologic atypia, reduced intraluminal secretions, occasional mitotic figures.
Microglandular adenosis in the breast. Positive and negative immunostains?
Positive: CAM 5.2, AE1, S100, p63 (secretory epithelium), CK8/18, EGFR. PAS+ diastase resistant secretions. Variable SMA, vimentin, type IV collagen and laminin (around glands).
Negative: ER, PR, HER2. Actin, calponin, p63 (myoepithelial markers). EMA, GCDFP-15. p53, low Ki-67.
How can you differentiate microglandular adenosis from tubular carcinoma in the breast?
Microglandular adenosis: Infiltrative, ill-defined lesion. Glands are small, uniform, rounded, and open with dense eosinophilic secretions in lumens. Glands lined by single layer of cuboidal/flat cells with vacuolated/granular cytoplasm and bland nuclei; no snouting or nucleoli. EMA-, S100+.
Tubular carcinoma: Stellate growth pattern, desmoplastic stroma. Glands vary in size and shape with angulated “tear-drop” appearance. Glands lined by cells with prominent apical snounts and without a surrounding basement membrane. EMA+, S100-.
What entities are in the differential diagnosis of metaplastic carcinoma of the breast?
Comprising less than 1% of invasive carcinomas of the breast, metaplastic carcinomas are a heterogeneous group of malignant tumors in which part or all of the carcinomatous epithelium is transformed into a nonglandular (metaplastic) growth process. The differential diagnosis of metaplastic carcinomas depends on the degree of atypia observed in the tumor and includes exuberant scars, fibromatosis, nodular fasciitis, myofibroblastomas, pseudoangiomatous stromal hyperplasia, acute and chronic abscess with fat necrosis, malignant phyllodes tumor, and primary or metastatic sarcoma.
In breast: LG nuclear atypia + limited architectural atypia = __. LG nuclear atypia + architectural atypia = __. HG nuclear atypia +/- architectural atypia = __.
LG nuclear atypia + limited architectural atypia = ADH. LG nuclear atypia + architectural atypia = DCIS. HG nuclear atypia +/- architectural atypia = HG DCIS. Architectural atypia includes: cribriform spaces, trabecular bars, Roman arches, micropapillae, uniform solid growth.
How can DCIS and ADH in the breast be distinguished? Both lesions share many architectural and cytologic features, such as nuclear monomorphism, regular cell placement, punched out round regular spaces, and are oftentimes associated with microcalcifications. The difference lies in the extent of involvement of the ducts; specifically, ADH lesions occupy only part of the involved space, while LG DCIS occupies the entire duct space and often adjacent duct spaces as well. What size criteria are proposed by Page and by Tavassoli and Norris?
Page proposed that at least 2 spaces of uniformly present atypical cells should be seen in order to call a LG atypical epithelial lesion DCIS instead of ADH. Tavassoli and Norris proposed the 2 mm rule, namely, any LG atypical epithelial lesion smaller than 2 mm should be placed in the ADH category and larger than 2mm in the LG DCIS category.
How is microinvasion in the breast defined?
As per the cancer staging manual of the AJCC, microinvasion is defined as the extension of cancer cells beyond the basemnt membrane with no focus larger than 0.1 cm in diameter. When multiple foci of microinvasion are seen, their presence should be noted in the report, but only the measurement of the largest microinvasive focus should be documented. Foci of microinvasion are unusual in DCIS lesions smaller than 2.5 cm but are very common in larger such lesions.
What are the 4 major molecular subtypes of breast cancer?
Luminal A, luminal B, triple negative/basal-like, and HER2 type. Other less common molecular subtypes have also been described, including normal breast-like, apocrine molecular subtype, luminal ER-/AR+, and claudin-low type. Luminal A subtype (40-60% prevalence) is ER+ and/or PR+, HER2-, low Ki67. Luminal B subtype (10-20% prevalence) is ER+ and/or PR+, HER2+ (or HER2- with high Ki67). Triple negative/basal-like subtype (10-20% prevalence) is ER-, PR-, HER2-, CK5/6+ and/or HER1+. HER2 type (10-15% prevalence) is ER-, PR-, HER2+.
Adenoid cystic carcinoma in the breast. It has cribriform, solid, trabecular and basaloid patterns, two types of cavities and two types of cells. What are the two types of cavities and two types of cells?
True glandular lumina are lined by ductal epithelium (EMA+, keratin+, CD117+) and eosinophilic “cylinders” with basement membrane material are lined by basal / myoepithelial-type cells (p63+, S100+, smooth muscle actin+, vimentin+). Secretions in the true lumina are PAS+ diastase resistant, and cribriform spaces are Alcian blue+. All salivary gland tumors of the breast, including adenoid cystic carcinoma, are characteristically negative for ER, PR, and HER2 (triple negative), and express basal cell markers CK5/6, P-cadherin and p63.
Microscopic appearance of adenomyoepithelioma of the breast.
AME is biphasic, composed of cuboidal to columnar, epithelial-lined tubules surrounded by myoepithelial cells. A spectrum of histologic patterns, however, has been observed among various examples of these tumors and even in different areas of individual tumors. These variations are based on the distribution of proliferating glandular and myoepithelial cells, the extent of spindle or polygonal configuration of myoepithelial cells, the prominence of papillary component, and the degree of fibrosis. Most AMEs have papillary configuration and, therefore, have been considered a variant of intraductal papilloma or a morphologic evolution from intraductal papilloma. Myoepithelial cells forming nests or sheets frequently display a spindle to myoid appearance at places with clear cytoplasm. This solid proliferation may displace, compress, or obliterate the epithelial gland, resulting in a zone nearly devoid of glands. The myoid areas may exhibit myoepithelial cells with pink to amphophilic cytoplasm or a plasmacytoid appearance with dense, hyaline-like, glassy eosinophilic cytoplasm and eccentric nuclei. Myxochondroid matrices may be produced by the myoepithelial cells. Epithelial cells tend to have hyperchromatic nuclei and dense eosinophilic to amphophilic cytoplasm, when compared with myoepithelial cells.
What entities are in the differential diagnosis of adenomyoepithelioma of the breast?
Papilloma with prominent myoepithelial cells (the cases with only myoepithelial cells lining the papillae and forming the basal layer below the epithelial elements and without nests, nodules, or an increased proportion of myoepithelial cells are categorized as such). Nipple adenoma (favored by the presence of florid ductal hyperplasia and the pseudoinfiltrative pattern of stromal sclerosis entrapping glandular epithelium without an entrapped fibrous tissue or supporting fibrovascular cores). Clear cell carcinoma (can confirm AME by positive IHC for both epithelial and myoepithelial cell types). Metaplastic tumors associated with papilloma. The adenosis variant of AME has an infiltrative growth pattern that resembles microglandular adenosis (the latter is characterized by an absence of myoepithelial layer and S100 positivity). If the AME predominantly displays a spindle cell component, it may morphologically be mistaken for myoid hamartoma or leiomyoma (AMEs will have strong positivity for S100 and p63, and are negative for actin and cytokeratin). Lesions composed exclusively of benign myoepithelial cells suggest myoepithelioma (do thorough sampling to identify a luminal epithelial component). Adenoid cystic carcinoma (ACC has infiltrative borders, cribriform architecture, and the myoepithelial cells of ACC tend to be smaller, more hyperchromatic, basaloid appearing, and have much less cytoplasm than do those of an AME). Pleomorphic adenoma (hyaline matrix with chondroid areas and distinct encapsulation are more prominent in PA).
Signet ring cells in the stomach. The differential diagnosis includes ___.
Lymphoma with artifactual signet ring cells due to cytoplasmic shrinkage (CD45 is usually positive in lymphoma). Metastases from breast or lung (clinical history, plus the use of appropriate immunostains such as TTF1 or GCDFP-15 is helpful). Reactive epithelial atypia associated with radiation treatment or chemotherapy. Xanthoma.
Peutz-Jeghers (hamartomatous) polyps overview.
Peutz-Jeghers polyps (hamartomatous polyps) are supported by broad bands of muscularis mucosa smooth muscle, which is thicker centrally, and resembles a Christmas tree at low power. The polyp has superficial columnar and goblet cells, but Paneth and endocrine cells at its base. Peutz-Jeghers polyps are large, pedunculated polyps of the gut almost always seen in association with Peutz-Jeghers syndrome. This rare autosomal dominant disorder is usually diagnosed at ages 20-30, with hamartomatous polyps in the small bowel (100%), stomach and colon (25%), and associated adenomatous lesions that may give rise to adenocarcinoma of the stomach, large or small bowel; adenoma malignum of the cervix, ovarian mucinous tumors, and carcinoma of the breast, lung and pancreas. The syndrome is also associated with sex-cord tumor with annular tubules (almost all patients) and melanotic pigmentation of the digits, genitalia, lips, oral mucosa, palms and soles. Peutz-Jeghers syndrome is caused by mutations in STK11/LKB1, a serine threonine kinase that may play a role in cell polarity.
A distinguishing features of lobular carcinoma is the loss of expression of E-cadherin, a protein involved in calcium-dependent cellular adhesion. What are 3 mechanisms of loss of the E-cadherin protein that are seen?
Mechanisms of loss of E-cadherin protein include mutations in the gene, which is located on chromosome 16q22.1, loss of heterozygosity of chromosome 16, and silencing of gene expression by promoter methylation.
What is the PTEN gene? In what tumors is it often mutated?
Phosphatase and tensin homolog (PTEN) gene is on chromosome band 10q23.31. In addition to its role as a tumor suppressor, it has important roles in embryogenesis and maintenance of physiologic functions in many organ systems and is constitutively expressed in normal tissues. It is one of the most frequently inactivated genes in sporadic cancer. Sporadic mutations of PTEN occur frequently in many tumors such as glioblastoma, breast carcinoma, endometrial carcinoma, thyroid neoplasms, skin neoplasms, and advanced prostate cancer.
Pleomorphic lobular carcinoma has morphologic and immunophenotypic characteristics that overlap between classical invasive lobular carcinoma and invasive ductal carcinoma. What genetic mutations do PLC have in common with classical ILC and with IDC?
Molecular studies have demonstrated that PLC and ILC share several molecular features such as alterations in the gene CDH1 on chromosome band 16q22 that results in changes in E-cadherin protein function, as well as recurrent genomic changes affecting 1q+, 11q−, 16p+, and 16q− and genomic amplifications in the region of 8q24, 11q13, 12q13, 17q12, and 20q13. The aggressive biology of pleomorphic lobular carcinoma relates to the acquisition of genetic alterations typical of high-grade ductal carcinoma, such as overexpression of HER2/neu and c-myc, p53 positivity, and amplification of 8q24, 12q13, and 20q13.
How do lobular and ductal breast cancers stain differently with p120 and β-catenin immunostains?
In lobular neoplasms, p120 yields a diffuse cytoplasmic immunostaining pattern. Conversely, ductal neoplasms retain the dominant membrane immunostaining pattern of p120 catenin. The presence of weak membranous positivity for p120 may be observed in a small subset of ductal carcinoma cases, which could lead to misinterpretation as a lobular phenotype. Complete lack of β-catenin membranous expression is associated with lobular histologic type, while expression of β-catenin is observed in virtually all cases of ductal carcinoma, both in situ and invasive.
__% of all women with breast cancer and __% of Ashkenazi Jewish women with breast cancer have a BRCA mutation. The lifetime risk of breast cancer in women is __% and the lifetime risk in BRCA1 or BRCA2 is __%.
5% of all women with breast cancer and 25% of Ashkenazi Jewish women with breast cancer have a BRCA mutation. The lifetime risk of breast cancer in women is 10% and the lifetime risk in BRCA1 or BRCA2 is 70%.
Three BRCA mutations appear with high frequency in persons of Ashkenazi Jewish descent, together accounting for over 90% of the BRCA mutations in this population. What are they?
A two base pair deletion in codon 23 (185delAG) in BRCA1, a 5832insC mutation in BRCA1, and a 6174delT mutation in BRCA2.
What tumors occur in Carney complex?
Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): acute mastitis.
For bone tumors, metastases are far more common than primary bone tumors in a ratio of __:1. The 5 most common primary sites are ___.
For bone tumors, metastases are far more common than primary bone tumors in a ratio of 25:1. The 5 most common primary sites are lung, breast, prostate, kidney, and thyroid. After lungs and liver, skeleton is 3rd most frequent site of metastatic disease.
What immunostains can be used to distinguish microglandular adenosis from tubular carcinoma of the breast?
MA is S100++, EMA-/+, ER/PR/HER2 -/-/-. TC is S100-, EMA++, ER/PR/HER2 +/+/-.
How do collagenous spherulosis, adenoid cystic carcinoma, cribriform DCIS, and invasive cribriform carcinoma stain with p63, SMMHC, calponin, and c-KIT?
CS: Positive at the periphery and surrounding lumens for the 3 MEC makers, c-KIT neg. ACC: Positive at the periphery and in the basaloid cells with p63, negative for the other 2 MEC markers, and c-KIT pos. Cribriform DCIS: Positive at the periphery only for the 3 MEC markers, c-KIT neg. ICC: Negative for all.
Paget disease (breast only??) almost always stains with what 2 stains?
Paget disease cells are almost always positive for CK7 and CAM5.2 (and are usually positive for HER2/neu).
Paget disease cells are almost always positive for CK7 and CAM5.2 and are usually positive for HER2/neu. Other positively staining markers with less frequency include CEA, EMA, p53, GCDFP-15, and mucicarmine. ER and PR are positive in less than half of cases. How does the immunoprofile for Toker cells compare?
Except for HER2/neu and mucicarmine negativity, Toker cells have the same immunoprofile as PD cells.
Metastatic tumors to the breast comprise ~1% of all tumors encountered in the breast. In adult women, what are the top 3 most common metastases to the breast?
Malignant melanoma, followed by lung and gynecologic cancers.
Does DCIS or LCIS arise more commonly in fibroadenoma? Does IDC or ILC arise more commonly in fibroadenoma?
DCIS and LCIS occur with equal frequency, but ILC is more common than IDC.
Phyllodes tumors of the breast have been categorized into 3 categories by the WHO (benign, borderline, malignant), based on histologic parameters, including stromal cellularity, nuclear atypia and degree of pleomorphism, mitotic activity, tumor margin/border, and stromal overgrowth. List these features for the 3 categories of PT.
Benign PT: modest cellularity, little nuclear pleomorphism, 1-3 mitoses/10 hpf, pushing margins, no stromal overgrowth. Borderline PT: modest cellularity, moderate nuclear pleomorphism, 4-9 mitoses/ 10 hpf, intermediate margins, heterogeneous stroma. Malignant PT: marked cellularity, marked nuclear pleomorphism, 10 or more mitoses/ 10 hpf, infiltrating margins, marked stromal overgrowth.
Separate out the triple negative breast cancer types into those that have favorable, comparable, and worse prognosis compare to that of similar-stage invasive ductal carcinoma.
Favorable: adenoid cystic carcinoma, medullary carcinoma. Comparable: metaplastic carcinoma, apocrine carcinoma. Worse: BRCA1-associated, basal-like, claudin-low.
What is alpha beta-Crystallin and its significance with basal-like breast carcinoma?
Alpha beta-Crystallin is one of many heat shock proteins that function as inhibitors of apoptosis by preventing accumulation of denatured proteins, thus prohibiting a signal for cell death and enabling survival. It impedes the proteolytic activation of caspase-3, a protease involved in the apoptotic cascade. Alpha beta-Crystallin is preferentially expressed in BLBCs and rarely in other molecular subtypes.
MammaPrint (Agendia, Amsterdam, the Netherlands). What is it used for? How does it work?
Based on a 70-gene set profile using an oligonucleotide array. A cDNA microarray-based test. Initially could be performed only on fresh frozen tissue of invasive breast cancer specimen but now FFPE tissue with RT-PCR can be used as well. The test helps in deciding whether the pt should receive adjuvant chemo by separating breast cancers by gene signatures into those with good vs poor prognosis. Pts with gene signature showing good prognosis will get hormone therapy (if the tumor is ER+). The poor prognosis signature consists of genes regulating cell cycle, invasion, angiogenesis, and metastasis. Pts with a gene signature showing poor prognosis will get chemo and hormone therapy (if the tumor is ER+). The test is offered for patients with tumors <5 cm, with LN-neg disease and low clinical stage (stage I or II). The advantage of MammaPrint is that the test can be performed on both ER+ and ER- tumors. However, the clinical utility of MammaPrint with ER- breast cancers is limited because only 0-4% of pts with ER- tumors are considered to have a good prognosis by the gene signature.
Oncotype Dx (Genomic Health Inc, Redwood City, California). What is it used for? How does it work?
An RT-PCR-based assay performed on FFPE tissue of invasive breast cancer specimen (but also recently approved for testing DCIS) which provides predictive and prognostic information in ER+, LN- tumors. It gives a recurrence score based on a 21-gene panel, with RS given from 0 to 100 and divided into 3 risk groups: low risk, <18; intermediate risk, 18-31; high risk, 31 or greater. The low RS pts get no chemo, the intermediate RS pts may or may not get chemo, and the high RS pts do get chemo.
HOXB13/IL17RB Ratio (AviaraDx Inc, Carlsbad, California). What is it used for? How does it work?
An assay that determines the risk of recurrence in women with LN neg, ER pos breast cancers who have received Tx with tamoxifen. The assay analyzes the ratio of homeobox B13 and interleukin 17 receptor gene expression using RT-PCR on FFPE tissue. To improve the assay, a numerical score called the molecular grade index was created by selecting 5 cell-cycle-related genes (BUB1B, CENPA, NEK2, RACGAP1, and RRM2) to be used concurrently with the H/I index to improve risk stratification. The combined MGI and H/I index stratifies pts into 3 risk groups: low risk, low for MGI and low or high H/I index; intermediate risk, high MGI and low H/I index; high risk, high for both MGI and H/I index.
There are three major mechanisms by which hypercalcemia of malignancy can occur: osteolytic metastases with local release of cytokines (including osteoclast activating factors); tumor secretion of parathyroid hormone-related protein (PTHrP) (humoral hypercalcemia); and tumor production of 1,25-dihydroxyvitamin D (calcitriol). Additionally, some tumors cause ectopic secretion of PTH. List some malignancies that cause each of the three main types.
Osteolytic metastases: breast cancer, multiple myeloma, lymphoma, leukemia. Humoral hypercalcemia (PTHrP): squamous cell carcinoma, RCC, breast cancer, bladder carcinoma, ovarian carcinoma, non-Hodgkin lymphoma, CML, leukemia, lymphoma. Tumor production of calcitriol: lymphoma (Hodgkin, non-Hodgkin, lymphomatosis/granulomatosis), ovarian dysgerminoma.
In most cases of humoral hypercalcemia of malignancy, certain tumors secrete PTH-related protein (PTHrP), such as squamous cell carcinoma, breast cancer, and lymphomas. What normal epithelia secrete PTHrP?
Squamous epithelium and lactating breast epithelium.
On breast FNA, what lesions may show bland epithelial cells in a mucinous background, or even mucus alone?
Colloid carcinoma. Benign papillomas. Fibroadenoma with myxoid degeneration. Mucocele-like lesions.
Secretory breast carcinoma. Epidemiology. Gross appearance.
Secretory carcinoma is a distinct subtype of breast carcinoma, with characteristic histomorphology and generally favorable prognosis. Secretory carcinomas are one of the rarest types of breast carcinomas, accounting for <0.15% of all breast cancers. Although it was originally described as a juvenile breast carcinoma, the median age in women is 25. Although rare events of axillary LN or distant metastases have been documented, the prognosis is generally excellent. Grossly, the tumor is often a solitary, discrete, firm mass. The margins are usually well delineated but can be infiltrative.
Secretory breast carcinoma. Microscopic appearance.
Microscopically, it is arranged in microcystic, ductal, and solid patterns. Hyalinized fibrous tissue is frequently identified centrally, and papillary architecture is sometimes seen peripherally. An intraductal component is usually present; papillary and cribriform architecture are the most common. The tumor cells are polygonal, with vacuolated cytoplasm. The nuclei are small, round, and cytologically bland, with minimal atypia. Mitotic activity is low. The characteristic histomorphology is the presence of a large amount of intracellular and extracellular, eosinophilic secretions that are positive for PAS-D.
Secretory breast carcinoma. IHC.
The characteristic histomorphology is the presence of a large amount of intracellular and extracellular, eosinophilic secretions that are positive for PAS-D. Most tumors are positive for S100, alpha-lactalbumin, and E-cadherin, and negative for ER/PR/HER2, GCDFP-15/BRST-2, and mCEA. In addition, some secretory carcinomas demonstrate a basal-like immunoprofile (positivity for CK5/6, CK14, CK17, CD117, EGFR, and vimentin).
Secretory breast carcinoma. Characteristic molecular feature.
Recent studies have shown the characteristic molecular feature: a balanced translocation t(12;15), resulting in an ETS variant 6-neurotrophic tyrosine kinase receptor type 3 (ETV6-NTRK3) fusion gene encoding a chimeric tyrosine kinase.
Secretory breast carcinoma. DDx.
DDx includes benign lesions such as lactational change, lactational adenoma, juvenile papillomatosis with apocrine metaplasia, collagenous spherulosis, and cystic hypersecretory hyperplasia, as well as malignant lesions such as lipid or glycogen-rich carcinoma, mucinous carcinoma, acinic cell carcinoma, apocrine carcinoma, cystic hypersecretory carcinoma, and signet ring cell carcinoma.
Is the EML4-ALK fusion unique to non-small cell lung cancer?
No. This fusion has been detected, at lower frequency, in breast and colorectal adenocarcinomas, although its role in the pathogenesis of these tumors is unknown.
Tamoxifen is converted to its active metabolites 4-hydroxytamoxifen and endoxifen primarily by CYP___.
Tamoxifen is converted to its active metabolites 4-hydroxytamoxifen and endoxifen primarily by CYP2D6.