BREAST PATHOLOGY
INFILTRATING DUCTAL CARCINOMA
70-80% of breast cancers. Haphazard proliferation of malignant cells which are no longer confined to the ductal/TDLU space and invade throughout the breast tissue Invasion of lymphatics and blood vessels results in regional lymph node- and distant hematogenous metastases Usually associated with DCIS and rarely with LCIS Most IDCs produce a desmoplastic response (sclerotic stroma), which is a tissue response to invasive tumor and causes the tumor to form a hard palpable mass and have a gritty consistency and resistance when a needle biopsy is performed Heterogeneous microscopic appearance from well-formed tubules to solid sheets of poorly differentiated cells. Lymphovascular invasion is common 2/3 are ER/PR positive; 1/3 overexpress HER2/NEU
BREAST CANCER RISK FACTORS
ABSOLUTE LIFE-TIME RISK: Overall risk: 1 in 8 women in US will develop breast cancer (by age 90) No risk factors: 3% AGE: Breast cancer is rare in women <25 years of age 77% of women with breast cancer are >50 years of age Average age at diagnosis: 64 years MENSTRUAL HISTORY: Age at menarche <11 years: 4% Age at menopause >55 years: 5-6% PREGNANCY: Never pregnant: 10% First live birth <20 years of age (protective): 1.65% First live birth 20-35 years: 5-6% First live birth >35 years: 6-10%
ATYPICAL DUCTAL HYPERPLASIA
ATYPICAL DUCTAL HYPERPLASIA Duct filled with a mixed population of cells, which are more columnar and oriented towards the basement membrane at the periphery and more rounded in the central portion Cribriform pattern: some of the peripheral spaces are irregular and slitlike, some are round and regular, but do not look quite like the "cookie-cutter " spaces typical of DCIS.
ATYPICAL LOBULAR HYPERPLASIA
ATYPICAL LOBULAR HYPERPLASIA Monomorphic small, round, loosely cohesive cells partially fill a lobule The cells are morphologically identical to the cells of lobular carcinoma in situ, but the extent of involvement is not sufficient for the diagnosis of LCIS (not as many cells)
DNA CONTENT:
Analysis by flow cytometry Image analysis of tissue sections Aneuploid tumors have a worse prognosis
APOCRINE METAPLASIA IN FIBROCYSTIC CHANGE
Apocrine metaplasia is common in fibrocystic change. The epithelial cells are tall and columnar with abundant granular eosinophilic cytoplasm and uniform nuclei. Microcalcifications formed from inspissated secretions are often present and are seen in a mammogram.
FIBROADENOMA
Appears in young women Peak incidence at 20-30 years Often multiple and bilateral Well-circumscribed lesion Solid , rubbery, mobile mass Overgrowth of the intralobular stroma compresses and stretches the TDLU acini The stroma produces growth factors that stimulate the proliferation of the non-neoplastic epithelial component Enlarges with hormonal stimulation May shrink at menopause No increased risk of carcinoma
PHYLLODES TUMOR
Arises from the intralobular stroma Can occur at any age, but most present in the sixth decade, 10 to 20 years later than the peak age for fibroadenomas Much less common than fibroadenomas May be small, 3-4 cm in diameter, but are often much larger, sometimes massive More cellular than fibroadenomas Projections of stroma into the ducts create the leaf-like pattern (the Greek word phyllodes means leaf-like) Phyllodes tumors are low-grade neoplasms 10-15% are malignant Criteria of malignancy: - Stromal hypercellularity and atypia; >5 mitoses/ HPF - Necrosis and bleeding - Heterogeneity of stroma Even benign phyllodes tumors have a tendency to recur and therefore excision with at least a 1 cm margin is recommended About 15% of malignant phyllodes tumors metastasize Increased numbers of chromosomal aberrations and overexpression of the homeobox transcription factor HOXB13 are associated with higher tumor grade and more aggressive clinical behavior.
MOLECULAR CLASSIFICATION FOR INVASIVE CARCINOMAS OF "NO SPECIAL TYPE" (NST) Basal like
BASAL-LIKE 15% of NST ductal carcinomas ER-, PR-, and HER2-negative (triple negative) Gene expression resembles basally located myoepithelial cells Positive basal cytokeratins (5, 6, 14, or 17) Many carcinomas in women with BRCA1 mutations are of this type In the US more common in African American women and in women < 45 years old High grade, aggressive cancers with a high proliferation rate Frequent metastases to viscera and brain, but not to axillary lymph nodes Poor prognosis 15-20% are chemosensitive with a complete response to chemotherapy Immune checkpoint inhibitors are being investigated for metastatic triple-negative tumors HER2 positive Please see slide #93
BREAST CANCER RISK FACTORS
BREAST FEEDING: Protective effect: overall 2.6% The longer a woman breast-feeds, the greater the reduction in the risk. The lower incidence in developing countries may be partly explained by longer nursing of infants. FAMILY HISTORY: Risk increases with the number of first-degree relatives with breast cancer: 4-30% 13% of women with breast cancer have one affected first-degree relative; 1% have two or more BUT most cancers occur in women without family history AND >87% of women with a family history will not develop breast cancer GENETICS: BCRA1 and BCRA2: 6->90% Li-Fraumeni syndrome (germ-line mutation in Tp53) Cowden disease (germ-line mutation in PTEN) Ataxia-telangiectasia (defective DNA repair)
INTRADUCTAL PAPILLOMA
Bloody discharge from nipple, rarely nipple retraction. Small subareolar mass, usually only a few mm in diameter, rarely over 1 cm. Usually found in one of the principal lactiferous ducts. Composed of papillary projections lined by a double layer of benign epithelial cells. Solitary papillomas are almost invariably benign Note: Intraductal papillomatosis (multiple small papillomas in small ducts and ductules) is associated with a small increase in cancer risk (1.5-2 x)
BREAST CANCER RISK FACTORS, extrinsic
CARCINOMA OF THE CONTRALATERAL BREAST OR ENDOMETRIUM: Common hormonal risk factors in these cancers DIET: Diet high in saturated fat appears to be linked to higher risk of HER2/neu negative breast cancer. OBESITY: Decreased incidence in obese women <40 years of age Association with anovulatory cycles and lower progesterone levels late in the cycle Increased risk in postmenopausal obese women: 3.6-10% Estrogen synthesis in fat implicated ALCOHOL: Moderate or heavy alcohol consumption increases risk slightly: 3.6-4.6% LACK OF EXERCISE: Decreased risk of breast cancer in premenopausal women who exercise; possibly attributable to lower BMI and hormone levels
PROLIFERATIVE CHANGE: SCLEROSING ADENOSIS
Clinically and grossly sclerosing adenosis may mimic breast cancer. It has a firm, rubbery consistency. This lesion has pronounced epithelial hyperplasia and fibrosis with almost back-to-back glands. Note compression of acini (lower right) to almost solid cords. These may be difficult to tell apart from invasive cancer.
PAGET DISEASE OF THE NIPPLE
DCIS that infiltrates the epidermis of the nipple. Nipple erythema, ulceration, and eczematoid changes.
COMPLEX RADIAL SCLEROSING LESION (AKA RADIAL SCAR)
DIFFICULT LESION: Can look deceptively like an infiltrating ductal carcinoma both in a mammogram (A) and in the gross specimen (B) Epithelium lining the entrapped ducts surrounded with the fibrotic stroma is without atypia (C).
PROGNOSIS OF BREAST CANCER
DISTANT METASTASES Favored sites: lungs, bones, liver, adrenals, brain and meninges. 4. TUMOR SIZE The second most important prognostic factor and independent from lymph node status. Node-negative carcinomas <1 cm in diameter have a prognosis approaching that of women without breast cancer. 10-year survival rate without further treatment is circa 90%. 5. LOCALLY ADVANCED DISEASE 6. LYMPHOVASCULAR INVASION (LVI): Strongly associated with the presence of lymph node metastases Higher incidence in African American and younger women The presence of tumor cells in lymphatics of the dermis is associated with the clinical appearance of inflammatory cancer and a very poor prognosis (3-year survival rate of 3-10%) 60% are ER negative and 40-50% overexpress HER2/neu
BREAST CANCER RISK FACTORS
ESTROGEN EXPOSURE: confusion reigns! Postmenopausal hormone replacement therapy appears to slightly increases the risk of breast cancer in current users but might not increase the risk of death: 3.6-10% ER and PR together increase the risk more than estrogen alone The latest studies suggest that estrogen alone has a protective effect ER-positive carcinomas are increased in this group Oral contraceptives are unlikely to increase the risk of breast cancer Reducing endogenous estrogens by oophorectomy decreases the risk of developing breast cancer by up to 75% RADIATION EXPOSURE: Women exposed to therapeutic radiation or radiation after atom bomb exposure have a higher rate of breast cancer Risk increases with younger age and higher radiation doses Women <30 years of age undergoing mantle radiation for Hodgkin disease have a 20%-30% risk of developing breast cancer 10-30 years after treatment Mammography is unlikely to increase the risk of breast cancer
LOBULAR NEOPLASIA
Encompasses LCIS and Atypical Lobular Hyperplasia ALH) LCIS and ALH are often difficult to distinguish from each other* May be multifocal and and/or bilateral Women with LCIS have a 20-25 % chance of developing DCIS or invasive lobular or ductal breast cancer in the first 15 years after the diagnosis of LCIS; the risk is 8 - 10 times higher than in women in the general population Invasive carcinomas in patients with LCIS may be ductal or lobular and may not be at the same site or in the same breast
GYNECOMASTIA OF THE MALE BREAST
Enlargement of the male breast is the only benign lesion seen with any frequency in the male breast. Presents as a button-like subareolar unilateral or bilateral. Enlargement Microscopically, there is an increase in dense collagenous connective tissue associated with epithelial hyperplasia of the duct lining Lobule formation is almost never observed. Results from an absolute or relative estrogen excess May occur at puberty, or in the very aged, or at any time during adult life when there is hyperestrinism In older males, may stem from a relative increase in estrogens as testicular androgen production falls. Analogous to fibrocystic change in a female breast Causes: Cirrhosis of liver (most important cause) Liver cannot metabolize estrogen, which accumulates in he blood Estrogen-producing tumors (Leydig cell or Sertoli cell tumors) Klinefelter syndrome (XXY karyotype) Therapeutic and street drugs: Digitalis, antiretroviral therapy, anabolic steroids, alcohol, marijuana, heroin
MOLECULAR SUBTYPE: HER2 overexpression
HER2 (human epidermal growth factor receptor 2 (c-erb B2 or neu) Transmembrane glycoprotein involved in cell growth control Acts as a coreceptor for multiple growth factors Overexpressed in 20-30% of breast carcinomas In >90% of cases overexpression is associated with amplification of the gene on 17q21 Detected by evaluating protein content by immunohistochemistry or by determining gene copy number by using FISH Overexpression is associated with a poorly differentiated tumor, high proliferation rate, often brain metastases and poor prognosis Variable response to hormonal or anthracycline chemotherapy regimens Evaluation of HER2 is most important to determine response to therapy targeted to this protein by trastuzumab (Herceptin) a humanized monoclonal antibody to HER2 developed to target tumor cells
PRIMARY STROMAL TUMORS
INTRALOBULAR STROMA: Fibroadenoma - the most common benign breast tumor Phyllodes tumor - less common INTERLOBULAR STROMA: Lipoma Fibromatosis Myofibroblastoma; consists of benign myofibroblasts The only breast tumor that is equally common in males and females Angiosarcoma: The most common stromal malignancy, but comprises <0.05% of malignant breast tumors Sporadic: Most occur in young women (mean age 35) High grade lesions with a poor prognosis Treatment associated: Radiation exposure or lymphedema post axillary lymph node excision Rhabdomyosarcoma, liposarcoma, leiomyosarcoma, osteosarcoma, chondrosarcoma; all rare
SENTINEL LYMPH NODE SAMPLING
Important in staging of breast cancer. Technetium along with blue dye, is injected near the tumor and flows to the local lymph nodes. Surgeons use the gamma probe to identify the first lymph node(s) which drain(s) the tumor, the "sentinel lymph node". This node is excised and sent to pathology, where it is analyzed for the presence of metastatic tumor.
SMOKING*:
Increased risk in smokers and passive smokers Current smokers: 14-26% >35 cigarettes/day: 1 in 4 women get breast cancer Risk is highest for those, who started smoking in adolescence or pre-menarche Risk starts decreasing 20 years after smoking cessation
BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE CELL LYMPHOMA (BIA-ALCL)
Individuals with breast implants have a risk of developing breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) The risk varies from 1:1,000 to 1:30,000 in patients, who received textured implants Very rare; <10 patients/year are diagnosed with this condition Compare to >300,000 women, who receive breast implants in US/year In most cases, BIA-ALCL is found in the scar tissue and fluid near the implant. In some cases it can behave aggressively and spread throughout the body. Precise risks are difficult to determine due to lack of information about how many patients have received breast implants in the US and worldwide. In 2016, the World Health Organization designated breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) as a T-cell lymphoma.
BENIGN CONDITIONS
Inflammatory diseases (<1% of breast symptoms) Acute mastitis Periductal mastitis (aka. squamous metaplasia of lactiferous ducts, Zuska disease Duct ectasia Lymphocytic mastopathy (aka. Sclerosing lymphocytic lobulitis) Granulomatous mastitis Fat necrosis Fibrocystic change Sclerosing adenosis Blunt duct adenosis Intraductal papillomatosis Complex sclerosing lesion (aka. radial scar) Intraductal papilloma (nipple adenoma) Gynecomastia and cancer in a male breast Fibroadenoma Phyllodes tumor (up to 15% are malignant)
INTRADUCTAL PAPILLOMA
Intraductal papilloma. A central fibrovascular core extends from the wall of a duct. The papillae arborize within the lumen and are lined by myoepithelial and luminal cells.
PROGNOSIS OF BREAST CANCER TUMOR-NODES-METASTASIS (TNM) STAGING
MAJOR PROGNOSTIC FACTORS: 1. INVASIVE CARCINOMA VS. IN-SITU DISEASE 2. LYMPH NODE METASTASES Axillary lymph node status is the most important prognostic factor for invasive carcinoma in the absence of distant metastases. 10-year disease-free survival rate vs. number of positive nodes 0 70-80% 1-3 35-40% >10 10-15% The sentinel node is highly predictive of the status of the remaining nodes and can be identified by radiotracer and/or colored dye Macrometastases (>0.2 cm): proven prognostic importance Micrometastases (<0.2 cm): survival rate between node-negative and node-positive cancer
OTHER PROGNOSTIC FACTORS:
MOLECULAR SUBTYPE: Estrogen and progesterone receptor Immunohistochemistry to detect ER and PR receptors in the nucleus 50-85% of carcinomas express estrogen receptors; more common in postmenopausal women Hormone receptor-positive cancers have a better prognosis than hormone receptor-negative carcinomas Predict response to therapy: 80% of ER+/PR+ tumors respond to hormonal manipulation 40% with only one type of receptor respond <10% of ER-/PR-negative tumors respond
FIBROCYSTIC CHANGE normal to epithelial hyperplasia
Normal duct or acinus with a single basally located myoepithelial cell layer (cells with dark, compact nuclei and scant cytoplasm) and single luminal cell layer (cells with larger open nuclei, small nucleoli, and more abundant cytoplasm). Epithelial hyperplasia. The lumen is filled with a heterogeneous, mixed population of luminal and myoepithelial cell types. Irregular slit-like fenestrations are prominent at the periphery.
MAMMARY DUCT ECTASIA, AKA PLASMA CELL MASTITIS
Occurs in 50-60 year old, usually multiparous women Unlike periductal mastitis, it is not associated with cigarette smoking Clinically appears as a poorly defined palpable periareolar mass Skin retraction sometimes Often accompanied by thick, white nipple secretions
BREAST CANCER RISK FACTORS
RACE: Caucasian women have the highest rates of breast cancer The risk of developing an invasive carcinoma within the next 20 years at age 50: 1 in 15 for Caucasians 1 in 20 for African Americans 1 in 26 for Asian/Pacific Islanders 1 in 27 for Hispanics African-American women are diagnosed at a later stage and have an increased mortality rate Less access to health care Lower use of mammography Genetics play a role Higher incidence in AA women <40 years of age Higher nuclear grade Tumors more frequently lack hormone receptors Tumors have more frequent sporadic TP53 mutations.
CARCINOMA IN A MALE BREAST
Same histologic patterns as in females IDC most common Poor prognosis 50% have spread to regional nodes or have distant metastases at the time of diagnosis Because of the small amount of breast tissue in a male, the tumor infiltrates the overlying skin and the underlying thoracic wall early Note the many dystrophic calcifications in this papillary tumor.
PROLIFERATION OF ATYPICAL CELLS IN TDLU RESULTS IN ATYPICAL HYPERPLASIA AND CARCINOMA-IN-SITU
TWO TYPES OF ATYPICAL HYPERPLASIA: Atypical ductal hyperplasia (ADH) Some but not all features of DCIS Not palpable Not visible on mammogram unless calcifications are present Atypical lobular hyperplasia (ALH) Not palpable Not visible on mammogram Invariably an incidental finding in a breast biopsy TWO MAJOR TYPES OF CARCINOMA-IN-SITU: Ductal carcinoma-in-situ (DCIS) Not palpable Usually contains calcifications and is visible on mammogram Lobular carcinoma-in-situ (LCIS) Not palpable Calcifications absent or small and therefore usually only found, if DCIS is also present RISK OF PROGRESSION OF CIS TO INVASIVE CARCINOMA: Variable, depending on risk factors, generally 25-30%
HISTOLOGIC SUBTYPE:
The 30-year survival rate of women with special types of invasive carcinomas (tubular, mucinous, medullary, lobular, and papillary) is >60% compared with < 20% for women with invasive ductal cacinoma of no special type (NST) 3. TUMOR GRADE = The degree of tumor differentiation and growth rate Evaluation of nuclear grade, tubule formation, and mitotic rate each on a scale 1-3 and then adding the scores together. Sum = 3,4,5: Grade I (well-differentiated) Sum = 6,7: Grade II (moderately-differentiated) Sum = 8,9: Grade III (poorly differentiated) 10-year survival by Scarff Bloom Richardson grade: I 85% II 60%
TUBULAR CARCINOMA
Tubular carcinoma: 2% of all invasive carcinomas Accounts for about 20% detected by mammography Very well-differentiated cells form tubular structures Desmoplastic response is present Good prognosis Left: Tubular carcinoma and micropapillary intraductal carcinoma (= DCIS). Right: Tubular carcinoma is composed of well-formed angulated tubules lined by a single layer of cells with small uniform nuclei.
PROLIFERATION RATE:
Tumors with high proliferation rates have a worse prognosis Analysis by flow cytometry (as the S-phase fraction) Thymidine labeling index Mitotic counts Immunohistochemical detection of cellular proteins (e.g., cyclins, Ki-67) produced during the cell cycle Overexpression of cyclin E leads to resistance to chemotherapy
WHAT NEEDS TO HAPPEN FOR A SUCCESSFUL DEVELOPMENT OF CANCER?
1. Loss of apoptosis 2. Genomic instability 3. Loss of growth inhibition 4. Self-sufficient growth 5. Limitless replication 6. Angiogenesis 7. Loss of basement membrane integrity 8. Invasion is required for full malignant transformation
INFILTRATING LOBULAR CARCINOMA (ILC)
10-15% of breast cancers 2/3 have an adjacent LCIS More often bilateral and multicentric than ductal carcinomas; over 30% of patients with bilateral breast cancer have ILC or LCIS in one or both breasts ILC has few calcifications and this increases false negatives in a mammogram Nearly all are ER/PR + and rarely overexpress HER2 Immunohistochemical stains indicate luminal A category (see #) Mutations in CDH1 gene inhibit normal function of E-cadherin, Similar pattern of infiltration as in diffuse type gastric carcinomas (linitis plastica), which also has mutations in CDH1 Typical metastatic pattern: serosal surfaces, CSF, GI-tract, ovary, uterus and bone marrow
PROLIFERATIVE CHANGE: SCLEROSING ADENOSIS
A 45-year-old female presented with an abnormal screening mammogram, and subsequent diagnostic mammogram and ultrasound appearance were nonconclusive. MRI was recommended for further evaluation and showed a Type 3 enhancing kinetic curve (not shown) highly suggestive of malignancy. A core needle biopsy was performed and revealed sclerosing adenosis. Diagnosis of sclerosing adenosis can be difficult with a mammogram, ultrasound, and MRI, and tissue diagnosis may be required for definitive diagnosis.
FIBROCYSTIC CHANGE
A term encompassing a wide range of benign changes to the TDLU Common; found in 60-80% of autopsy samples A consequence of an exaggeration and distortion of the cyclic breast changes, which occur during a menstrual cycle Estrogen and oral contraceptives (OCs) do not increase the risk for fibrocystic change OCs may decrease the risk Histologic diagnosis should always be accompanied by a full description of the components: Microcysts Stromal fibrosis Adenosis = increase in number of acini in TDLU Sclerosing adenosis = Adenosis and intralobular fibrosis Epithelial hyperplasia/papillomatosis = benign increase of cells within the TDLU
BREAST CANCER INCIDENCE, EPIDEMIOLOGY, AND ETIOLOGY
KEY CONCEPTS Breast cancer is the most common non-skin malignancy in women and the second most common cause of cancer deaths. The most important risk factors are estrogenic stimulation and age. All cancers arise by the accumulation of DNA alterations and epigenetic changes. 25-30% of breast cancers are familial, related to inheritance of genetic variants that increase breast cancer risk. High-risk genes associated with familial breast cancer include several involved with DNA repair and genomic stability, most notably BRCA1, BRCA2, and TP53. Breast cancers cluster into three major molecular groups, luminal (ER-positive), HER2, and triple negative, each with distinctive biologic and clinical features. Luminal cancers are further divided into two groups, A and B, based on proliferation rate. HER2 cancers are defined by overexpression of the HER2 receptor, usually due to HER2 gene amplification, and respond well to HER2 inhibitors. Triple negative breast cancers (TNBCs) lack ER and HER2 expression, are often associated with defects in DNA repair or genomic stability (e.g., due to silencing of BRCA1 or TP53 mutation), and carry a relatively poor prognosis
MOLECULAR CLASSIFICATION FOR INVASIVE CARCINOMAS OF "NO SPECIAL TYPE" (NST)
LUMINAL A 50% to 65% of NST cancers The largest group ER-PR-positive and HER2 negative Includes germline BRCA2 mutation carriers The gene signature is dominated by the dozens of genes under the control of ER Increased transcription of genes that are thought to be characteristic of normal luminal cells Keratin 8 and 18 positive The majority are well- or moderately differentiated (grade 1 or 2), and most occur in post-menopausal women Tumors are generally slow growing and respond well to hormonal treatments Only a small number will respond to standard chemotherapy
MOLECULAR CLASSIFICATION FOR INVASIVE CARCINOMAS OF "NO SPECIAL TYPE" (NST) LUMINAL B
LUMINAL B 20% of NST cancers ER- positive and often overexpress HER2 PR-positive or negative Higher grade (mainly 2 and 3) and a higher proliferation rate than luminal A Patients are younger than in the Luminal A group Includes germline TP53 mutation carriers Comprise a major group of ER-positive cancers that are more likely to have lymph node metastases May respond to chemotherapy
DCIS, CRIBRIFORM TYPE
Lattice-like pattern with punched-out "cookie-cutter" holes Stiff "Roman arches" Monotonous cell population (one cell type only) No myoepithelial cells
PHYLLODES TUMOR gross morphology
Left: Benign phyllodes tumor. The tumor is fibrotic and well demarcated. Right: Malignant phyllodes tumor with foci of necrosis and hemorrhage.
FNAB OF A BREAST LUMP: LOBULAR CARCINOMA
Left: LCIS consists of a neoplastic proliferation of cells in the terminal breast ducts and acini. The cells are small and round. Though these lesions are low grade, there is a 20-25% risk for development of invasive carcinoma in the same or the opposite breast, but not necessarily of the same histologic type. Right: Invasive lobular carcinoma with the classic pattern. This tumor arises in the terminal ductules of the breast. About 5 to 10% of breast cancers are of this type. There is about a 20-25 % chance that the opposite breast will also be involved. Multicentricity in the same breast is common. At high magnification, the characteristic single file strands of infiltrating lobular carcinoma cells are seen in the fibrous stroma. Pleomorphism is not great.
MOLECULAR CLASSIFICATION FOR INVASIVE DUCTAL CARCINOMAS OF "NO SPECIAL TYPE" (NST) CAUTION: SCIENTIFIC FACTS ARE EVOLVING
Major patterns of gene expression in the NST group have been identified by gene expression profiling The molecular classes correlate with prognosis and response to therapy Luminal A: ER-PR-positive and HER2-negative Luminal B: ER-positive, often overexpress HER2, PR-positive or negative HER2 enriched: ER-PR-negative and overexpress HER2 Basal-like: ER-, PR-, and HER2-negative (triple negative), AR+ (luminal?) ER-, PR-, HER2-, and AR-negative (quadruple negative) It gets complicated: Some triple negative (ER-, PR-, and HER2-negative) cancers had a better prognosis than expected and turned out to be androgen receptor (AR) positive. AR+ tumors should theoretically respond to AR-targeted therapies AR- tumors were more often found in younger African American women, had enrichment of immune genes (IL12**, CCR5***), and a B-cell response, a shorter time to progression, and the worst overall survival There is no targeted therapy currently available for quadruple negative breast cancer
GRANULOMATOUS MASTITIS
Manifestation of systemic granulomatous diseases: Granulomatosis with polyangiitis Sarcoidosis Tuberculosis Inflammatory or infectious disorders localized to the breast: Mycobacterial and fungal infections Localized infections by mycobacteria or fungi are very rare Most common in immunocompromised patients or adjacent to foreign objects such as breast prostheses or nipple piercings. Granulomatous lobular mastitis and cystic neutrophilic granulomatous mastitis May be a manifestations of the same disease Uncommon disease that occurs only in parous women. Granulomas are closely associated with lobules and may contain lipid vacuoles surrounded by neutrophils. Often caused by lipophilic Corynebacteria . Treatment includes antibiotics and sometimes steroids.
MEDULLARY CARCINOMA
Medullary carcinoma: 2% of all breast carcinomas Most common in postmenopausal women Clinically may be mistaken for fibroadenoma Prominent mononuclear inflammatory infiltrates Little desmoplastic response Women with BRCA1 mutations get this Tumors lack hormone receptors Tumors do not overexpress HER2/NEU
DISORDERS OF DEVELOPMENT
Milk Line Remnants Supernumerary nipples or breasts (heterotopic foci) result from the persistence of epidermal thickenings along the milk line Can be found from the axilla to the perineum May present as a painful swelling prior to menstruation Disorders of normally situated breasts rarely arise in the heterotopic foci Accessory Axillary Breast Tissue In some women the normal ductal system extends into the subcutaneous tissue of the chest wall or the axillary fossa (the axillary tail of Spence) May not be removed by a prophylactic mastectomy and thus the procedure does not completely eliminate the risk of breast cancer Congenital Nipple Inversion The failure of the nipple to evert during development is common May be unilateral Corrects spontaneously during pregnancy or can sometimes be everted by simple traction In contrast, an acquired nipple retraction may indicate the presence of an invasive cancer or an inflammatory nipple disease
COLLOID CARCINOMA
Mucoid (colloid ) carcinoma: 2% of breast cancers Occurs in postmenopausal women Tumor cells secrete mucin into the stroma resulting in a soft, slimy texture Better survival than in ductal carcinoma of the same size
