Breast Flashcards
BRCA
BRCA 1 and 2 account for 80-90% of breast malignancies that can be attributed to single gene mutations and approx 3% of all breast cancers.
BRCA 1
think of this as female centric – triple -ve breast, ovarian, fallopian tube)
Ch 17q21
* More common than type 2
* Increased risk of breast, ovary (more so than BRCA2), pancreatic, CRC, fallopian carcinoma, primary peritoneal serous carcinoma
* 72% breast Ca and 44% ovarian Ca risk.
* Triple -ve is common with medullary breast Ca the most common subtype in BRCA 1
* Also get fallopian tube, pancreas, colonic cancers
* Associated with male breast (less so than BRCA 2), prostate and higher rates of fallopian tube than BRCA 2
BRCA 2
(male centric)
Ch 13q12-13
* Male carriers have a higher risk of male breast cancer with BRCA 2
* Increased risk of prostate in men (20x increased risk)
* Increased risk of breast, ovary and various GI cancers.
* 69% breast Ca and 17% ovarian Ca risk.
* Increased risk of fallopian (less so than BRCA1), pancreatic (5%), colonic, gallbladder, pharyngeal
* BRCA2 mutation carriers are at increased risk for skin cancer, compared with BRCA1 carriers, in particular for basal cell carcinoma, also melanoma.
* Association with FA - Biallelic germline mutations cause a rare form of Fanconi anaemia
* Fanconi anemia (FA) is a rare genetic disorder that primarily affects the bone marrow, leading to a decrease in the production of all types of blood cells. It is a form of inherited bone marrow failure syndrome
BRCA associated Ovarian serous carcinoma peritoneal spread:
The nodular pattern of disease and presence of disease in the gastrohepatic ligament are associated with significantly higher odds of BRCA mutant disease.
Pattern of peritoneal disease:
* presence of peritoneal disease in gastrohepatic ligament
* mesenteric involvement and supradiaphragmatic lymphadenopathy at CT are significantly associated with BRCA mutation status at univariate analysis and multiple regression.
Risk factors for Breast Cancer (Robbins):
> 4.0 RR:
* Female
* Increasing age
* Germline mutations of high penetrance (BRCA)
* Strong family hx (>1 FIRST DEGREE RELATIVE, young age, multiple cancers)
* Personal hx of breast ca
* HIGH BREAST DENSITY
2.1-4.0 RR:
* Germline mutation of moderate penetrance
* High dose radiation to the chest at a young age
* Family hx (1 1st degree relative)
1.1-2.0 RR:
* Early menarche (<12 yrs)
* Late menopause (>55 yrs)
* Late first pregnancy (>35 yrs)
* Nulliparity
* Absence of breast feeding
* HRT/exogenous hormone therapy
* Postmenopausal obesity
* Physical inactivity
* High EtOH consumption.
Triple negative breast cancer:
- 15% of breast cancers
- Most common genetic mutation PIK3CA (9%), TP53 (70-80%)
- Histological type medullary features, metaplastic
- Typically seen in young women, women of African heritage, BRCA1 mutation carriers.
- Approx 30% will have a complete response to chemotherapy.
- Mets to bone, viscera and brain most commonly
- Relapse seen within 8 yrs, lat recurrence is rare. Survival with mets is rare
- Immunotherapy: Some TNBCs express programmed death-ligand 1 (PD-L1), which has led to the investigation of immune checkpoint inhibitors, such as pembrolizumab and atezolizumab
Male Breast Cancer:
- Uncommon in men and very uncommon in younger men
- Average age of 70
- 1 in 4 will have BRCA 1 mutation
- Other RFs include Klinefelter syndrome, cirrhosis, chronic EtOH
- Classic description Is eccentric but near the nipple.
- Almost always IDC-NOS subtype. Men don’t get ILC/LCIS
- On mammo and US it looks like cancer.
- Microcalcs alone are uncommon in men. When seen they are usually coarse and associated with a mass. Seen in 25% of male breast Ca
- No increased risk with gynaecomastia following gender re-assignment.
Gynaecomastia:
Deep to the nipple. Not eccentric.
* Non-neoplastic enlargement of the epithelial and stroma elements in a man’s breast
* Occurs physiologically in adolescents affecting around 50% of adolescent boys and men over 65.
* Between the ages of 13-65 it is considered pathology and associated with a number of conditions including spironolactone, antipsychotics, marijuana, EtOH cirrhosis, testicular cancer.
* Kleinfelter syndrome, or in association with functioning testicular neoplasms such as Leydig and Sertoli.
** 3 patterns;**
* Nodular – flame shaped behind the nipple. Radiating bands posteriorly blending into fat. Breast often tender.
* Dendritic – Resembles a branching tree.
* Chronic fibrotic pattern
* Diffuse glandular – looks like a woman’s breast. Seen in men receiving oestrogen treatment.
Invasive Ductal Carcinoma (IDC):
type of breast cancer that starts in the milk ducts of the breast and moves into nearby tissue
Mass like opacity with spiculated margins. May have central calcifications.
US Stavros criteria:
* Markedly hypoechoic
* Spiculation
* Angulated margins
* Shadowing
* Calcification
* Duct extension
* Branching pattern
* Microlobulation.
Benign features:
* Absence of malignant findings
* Internese hyperechogenicity
* Ellipsoid shape
* Gentle bi or trilobulation
* Thin echogenic pseudocapsule
Indeterminate features:
* Isoechogenicity
* Mild hypoechogenicity
* Normal sound transmission
* Enhanced transmission
* Heterogeneous echotexture
* Homogeneous echotexture.
Subtypes of IDC
Mucinous tumour:
Medullary subtype
Tubular subtype
Papillary carcinoma
Mucinous Tumour
- Round/lobulated well circumscribed mass.
- Uncommon. Has a better prognosis than IDC-NOS
- US: May mimic a cyst on US but with mixed solid cystic components - biopsy often yields gelatinous sample
- Mixed echogenicity with cystic and solid components
- Posterior acoustic enhancement is common
- Can be isoechoic to breast tissue at times
- Homogeneity is indicative of pure mucinous carcinoma
- One of the few T2 bright breast cancer
Medullary subtype
- Mass forming
- Well circumscribed
- Associated with BRCA1
- Although the majority of medullary carcinomas are not associated with germline BRCA1 mutations, hypermethylation of the BRCA1 promoter leading to downregulation of BRCA1 expression is observed in 67% of these tumors
Tubular subtype
- Spiculated, often without specific mass
- Indolent
- Best prognosis 98% 5 year survival
Papillary carcinoma
- Papillary carcinomas may manifest clinically as a palpable mass or nipple discharge
- NB: milky discharge is not suggestive of breast Ca, however unilateral spontaneous haemo/serous is
Galactorrhea is associated with elevated prolactin levels (e.g., by a pituitary adenoma), hypothyroidism, or endocrine anovulatory syndromes, and also occur in patients taking oral contraceptives, tricyclic antidepressants, methyldopa, or phenothiazines. - may be solitary or multiple
- Papillary carcinomas are usually well-circumscribed and often contain haemorrhagic and cystic areas.
- Approximately 50% of papillary carcinomas arise in the retro-areolar/subareolar region of the breast
- The most common mammographic pattern of invasive papillary carcinoma is a round, oval or lobulated mass. The mass margins are usually circumscribed but may be obscured or indistinct. Accompanying microcalcifications or a dilated ductal pattern may also be present.
US:
* hypoechoic and solid mass, often with posterior acoustic enhancement;
* alternatively, complex cystic and solid masses may be evident.
Galactography:
* ductography
* For patients presenting with nipple discharge, galactography may be helpful. Like intraductal papillomas, papillary carcinomas may be evident as:
* ductal obstruction,
* filling defects,
* or focal or diffuse ductal wall irregularity.
B-MRI:
* may have T2 bright cystic/haemorrhagic content
* fluid fluid levels
* enhancing septa and mural nodules
Basaloid subtype of Invasive Ductal Carcinoma (IDC)
Basaloid breast cancer is characterized by the expression of basal-like markers, which are proteins typically found in the basal cells of the breast.
Basal-like breast cancers often share characteristics with triple-negative breast cancer, meaning they lack the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).
Ductal Carcinoma In Situ (DCIS):
** Definition:**
Malignant clonal proliferation of epithelial cells limited to ducts and lobules (originating from ductal epithelium, not lobular).
Epidemiology and Associations:
* 15-30% of all breast cancers.
* Most detected on mammo with fine calcs more often than periductal fibrosis/architectural distortion.
* Bilateral in 10-20%
Pathogenesis/Organisms:
* Low grade DCIS progresses to IDC at a rate of 1% per year.
* Mastectomy is curative in 95%
* Excision followed by radiation has slightly higher recurrence.
* 1-3% of women with DCIS will die of breast cancer
Subtypes/Morphology:
* Comedocarcinoma – characterised by ducts and lobules dilated by sheets of high grade pleomorphic cells with zones of central necrosis.
* High grade subtype of DCIS; aggressive and 30% multicentric/multifocal
* Non-comedo – monomorphic population of cells of varying nuclear grades. Patterns include cribriform, solid, papillary, micropapillary
* Pagets disease of the nipple– DCIS of the nipple/areola
* rare.
* Seen in 1-4% of DCIS. Malignant cells extend from DCIS into nipple skin without crossing the basement membrane. Cells disrupt the epithelial barrier allowing extracellular fluid to seep out creating an erythematous eruption with scaly crust.
Complications:
* Recurrence
* Mets
* Progression to IDC
Clinical Presentation:
* Higher grade and more extensive DCIS associated with higher risk of progression to IDC.
* Treated with mastectomy, WLE/lumpectomy with post op RTx and tamoxifen
Breast lymphoma:
More commonly secondary involvement of NHL than primary.
When primary usually B cell lymphoma.
Rarer types of T-cell lymphoma associated with breast implants.
Breast implant associated anaplastic large cell lymphoma (BIA-ALCL) - associated with the Allergan Biocell Breast Implant
* See a bloody peri-implant effusion +/- a mass within the implant capsule.
More common with textured implants but can be seen with smooth.
* Late onset peri-implant effusion most common presentation
Burkitt lymphoma can be seen in younger breastfeeding women. Massive involvement of both breasts
Mets to the breast are rare, usually melanomas or ovarian cancers.
Invasive Lobular carcinoma:
Arises from the TLDU
Subtype with the clearest association of phenotype and genotype.
* Invasive lobular carcinoma is the most common special type of invasive breast cancer after invasive breast carcinoma of no special type
* have characteristic patterns of metastatic spread, often involving the peritoneum and retroperitoneum, the leptomeninges (carcinomatous meningitis), the gastrointestinal tract, and the ovaries and uterus.
* Males and females with heterozygous germline mutations in CDH1 also have a greatly increased risk of gastric signet ring cell carcinoma.
* Often fail to have a desmoplastic response
Most cases show biallelic loss of expression of CDH1 which encodes e-cadherin.
Specific biomarker is LOSS of e-cadherin (although 15% of invasive lobular carcinoma are positive fo E-cadherin)
These tumours are dyscohesive, infiltrate as single cells and sometimes fail to produce a desmoplastic response making it difficult to identify via palpation and on imaging.
These tumours are often multicentric and bilateral (10-15%) so MUST CHECK OTHER BREAST
Breast MRI usually recommended if histology shows lobular carcinoma due to propensity for multicentricity
Unique pattern of metastatic spread:
* Peritoneum and retroperitoneum
* Leptomeninges (carcinomatous meningitis)
* GIT
* Ovaries and uterus
Patients with heterozygous germline mutation in CDH1 are at increased risk of signet ring carcinoma of the stomach and lobular carcinoma.
Assoc with orbital mets
Imaging features:
* An ill-defined heterogenous infiltrating area of low echogenicity with disproportionate posterior shadowing is one of the sonographic characteristics of invasive lobular carcinoma.
Lobular carcinoma in situ (LCIS)
- Diagnosis of classic LCIS is usually an incidental finding in a breast biopsy performed for other indications, including screen detected calcifications or mass producing lesions
- LCIS involves the terminal duct lobular unit (TDLU), filling and distending acini
- 50% of the acini in a TDLU must be filled and expanded to qualify as LCIS; otherwise, called atypical lobular hyperplasia
- Loss of E-cadherin protein is the most common etiology (> 95%)
- Considered high risk lesion - Compared with the general population, women with LCIS have a 7 - 10 fold increase in breast cancer risk
- Excision is not recommended after incidental diagnosis of classic LCIS by percutaneous image guided core needle biopsy, as the risk of finding invasive carcinoma on excision is very low (< 5%)
- Surgical biopsy is recommended when core needle biopsy contains classic LCIS in addition to other high risk proliferative lesions (e.g., radial scar or ADH or there is discordance between histology and imaging)
- Management options for classic LCIS include active surveillance and chemoprevention with anti estrogens
Atypical lobular hyperplasia
- High risk lesion 4-5x relative risk of Ca, or 13-17% lifetime risk of cancer
- Cell identical to those of LCIS but the cells do not completely fill or distend the terminal lobular unit.
Multifocal vs Multicentric vs Synchronous:
Multifocal:
* Multiple primaries in the same quadrant.
* Less than 4-5 cm apart from one another
Multicentric:
* Multiple primaries in different quadrants.
* Multiple foci in unrelated sites/centres.
Synchronous:
* Bilateral breast cancer occurring within 6 months of each other.
* Seen in 2-3% of women with breast Ca.
* Risk of bilateral disease increased in infiltrating subtypes and multicentric disease.
Papilloma of the breast:
Invasive Breast Cancer Subtypes
Incidence of ER positive cancers increase with age, whereas ER negative and HER2 positive Ca remains constant regardless of age
Therefore ER negative HER2 positive Ca more common in younger pts
Breast Cancer Driver Mutations
The most common driver mutations involve the protooncogenes PIK3CA, HER2, MYC, and CCND1 (which encodes cyclin D1), and the tumor suppressor genes TP53 and (in familial cancers) BRCA1 and BRCA2
Lymphocytic Mastopathy/Diabetic mastopathy:
- Benign lesions presenting as single or multiple rock-hard palpable masses
- Multicentric or bilateral involvement is relatively frequent
- Collagenised stroma around atrophic ducts with prominent lymphocytic infiltrate.
- If associated with T1DM or Type 2 → Diabetic mastopathy
- If associated with autoimmune thyroid disease → lymphocytic mastopathy
- Self limiting, does not require treatment, but recurrences are frequent
- Ultrasound often reveals the most characteristic imaging findings of the disease: irregular hypoechoic masses with marked posterior acoustic shadowing.
- May be difficult to get tissue with needle biopsy due to dense collagenized stroma
- Mammo: ill defined massess of asymmetric densities
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