Pathology of the Breast

Dr. Jimenez, MD

Special thanks to my colleague Dr. V.O. Speights

Robbins and Cotran, Pathologic Basis of Disease 9th edition

Chapter 23 (pages 1043-1071)

Objectives• After this presentation, the student will be able to

Recognize the normal anatomy and common pathologic changes in the breast

Recognize and assess the different risk factors for developing invasive breast carcinoma

Identify the different diagnostic approaches to breast cancer

Understand the clinical presentation, pathologic findings, workup, treatment and prognosis of the different histological types of breast cancer

• Know the different information which is needed to adequately treat breast cancer including special studies (estrogen receptors, progesterone receptors, HER-2/neu, multigene panels, adjuvant online and sentinel node biopsies).

• Understand the basics of breast cancer treatment principles

Breast anatomy / Histology

I. Disorders of development

II. Clinical presentations of breast disease

III. Inflammatory disorders

IV. Benign epithelial lesions

V. Carcinoma of breast

VI. Types of breast carcinoma

VII. Stromal tumors

Breast anatomy

Main component #1: Ducts

P63: Nuclear stain

Calponin

SMMHC

Myoepithelial cell markers:

- p63, nuclear stain - MMHC (Smooth Muscle Myosin Heavy chain), cytoplasmic and membranous- Calponin, cytoplasmic stain - SMA (Smooth muscle actin), cytoplasmic stain - Others: S-100, CD-10, CK5/6

Main component #2: Lobules

I. Disorders of Development

Disorders of Development

1. Milk line remnants:Supernumerary nipples

2. Accessory Axillary Breast Tissue

3. Congenital nipple inversion

Supernumerary nipples

Doctor is it possible to have 3 breasts?

Painful premenstrual enlargement

Accessory Axillary Breast Tissue

Congenital nipple inversion

II. Clinical presentation of breast disease

Clinical presentation of breast disease

Pain: mastalgia or mastodynia. 10% of breast cancers present with pain

Palpable mass: most common palpable include cysts, fibroadenomas and invasive carcinomas

Nipple discharge: less common finding, worrisome for carcinomaGalactorrhea: pituitary adenoma, hypothyroidism, anovulatory syndromes, medicine Bloody discharge: think LARGE DUCT PAPILLOMA (Others include cysts) Thick, white nipple secretions: duct ectasia

Clinical presentation of breast disease

Mammogram screening:

Introduced in 1980. Regular screening, annually starting at 40 years old Currently the most common means to detect breast cancerSensitivity and specificity of mammography increase with ageApproximately 10% of invasive carcinomas are not detected by mammography

Clinical presentation of breast disease

The principal mammographic signs of breast carcinoma are:

• Densities

• Calcifications: associated with benign or malignant lesions (DCIS)

Other radiology diagnostic tests

MRI:

Very sensitive.

Disadvantage it is sooo!!! sensitive that may false-positive, high recall biopsy rates. Not good for screening.

May be useful for high risk women .

Biopsy methods:

Needle-core biopsy (most common)

Fine needle aspiration (cysts)

Excisional/incisional biopsy

Lesson:

ALWAYS CORRELATE RADIOLOGY WITH PATHOLOGY

III. Inflammatory disorders

III. Inflammatory disorders

- Acute mastitis

- Fat necrosis

- Lymphocytic mastopathy

- Duct ectasia

- Granulomatous mastitis

- Other miscellaneous benign conditions

Inflammatory disorders:

Acute mastitis (Bacterial infection due to Staph Aureus or less commonly due to Strep). Most common on the first month of breast feeding. Treatment: AB

Inflammatory disorders: Fat necrosis (trauma)

Inflammatory disorders: Lymphocytic mastopathy (sclerosing lymphocytic lobulitis)

Patients present with single or multiple hard palpable masses or mammographic densities. Consists of atrophic ducts and lobules, surrounded by a prominent lymphocytic infiltrate. Most common in women type 1 DM Important because of differentiating it from breast cancer

Inflammatory disorders: Duct ectasia

Palpable periareolar mass, associated with thick, white nipple secretions and occasionally with skin retraction.

Chronic inflammation and fibrosis around a large duct Important because it can mimic cancer

Robbins 9th edition, figure 23-5

Inflammatory disorders: Granulomatous mastitis

Uncommon disease Systemic granulomatous disease (sarcoidosis) Fungal infection/ AFB infection: Immunocompromised patients

Other miscellaneous Benign conditions

IV. BENIG EPITHELIAL LESIONS

IV. BENIGN EPITHELIAL LESIONS

- Fibrocystic change

- Epithelial hyperplasia (usual and atypical)Usual ductal hyperplasia

Atypical Ductal hyperplasia (ADH)

- Intraductal Papilloma

- Sclerosing adenosis

- Radial scar (complex sclerosing lesion)

- Gynecomastia

Fibrocystic change

Cysts: Due to dilation of lobules. Blue in color (blue-dome cysts)

They are NOT associated with an increased risk of breast cancer

Fibrocystic change

Epithelial hyperplasia (ductal hyperplasia)

For a medical student important because: No definitive mass or symptoms Epithelial hyperplasia includes lobular , ductal, myoepithelial hyperplasia (and they can all be with or without

atypia). The majority are NOT precursors of cancer

Intraductal papilloma

Two types: Large duct and Small duct 80% of large duct papillomas produce a nipple dischargeClinically nipple discharge, palpable mass/ densities/calcifications on mammogram

Sclerosing adenosis

Increased number of acini that are distorted by dense stroma

Can mimic carcinoma presenting as a palpable mass, radiologic density or calcifications.

It does have myoepithelial cells

Figure 23-8, Robbins 9th edition

Radial scar: Looks like a tumor on radiology (stellate appearance). Mimics malignancy. Entrapped glands and ducts.

Gynecomastia

Result of an imbalance between estrogens (which stimulate breast tissue) and androgens, which counteract these effects.

Possible in the following scenarios:• Liver cirrhosis• Older men (testicular androgen

production goes down)• Alcohol, marijuana, heroin,

antiretroviral therapy, anabolic steroids • Testicular tumors

Incidence and Epidemiology

• Average at diagnosis: 61 years (white), 56 (Hispanic), 46 (African American)

• African American has the highest mortality rate (unequal access? More aggressive tumors?)

• 4-7 times higher in US (changing in developing countries due to western social lifestyles)

Risk Factors (Pages 1052-1054)

1. Germline mutations: BRCA 1 and BRCA 2

NOTE: 90 % of breast cancer are sporadicBRCA testing $3500

1. First degree relatives with breast cancer

2. Race/ethnicity (BRCA1 and BRCA 2 prevalent in Ashkenazi Jewish population)

1 in 40 Ashkenazi Jewish women has a BRCA gene mutation

1. Age: Peaks 70-80

2. Age at menarche and late menopause

3. Age at first live birth ( older than 35)

4. Benign breast diseases

5. Exogenous estrogen (menopausal hormonal therapy, oral contraceptives still ??)

6. Breast density: very dense breast tissue 4-6 risk

7. Radiation exposure: atomic bomb exposure. Radiation due to HL

8. Carcinoma of the contralateral breast or endometrium

9. Diet

10. Obesity

11. Exercise

12. Environmental toxins

The longer the women breastfeed, the greater the reduction in risk

Angelina Jolie's Disclosure of Prophylactic Bilateral Mastectomy: A Positive Example for Women with BRCA Mutations?

By Charlotte BathJune 25, 2013, Volume 4, Issue 10 Angelina Jolie, in a New York Times article

entitled “My Medical Choice,”1 disclosed that having a BRCA1 mutation and an estimated 87% risk of breast cancer, “I decided to be proactive and minimize the risk as much I could. I made a decision to have a preventive double mastectomy.” She was writing about it, she explained, “because I hope that other women can benefit from my experience.”The many media reports about Ms. Jolie’s choice mean that many women have undoubtedly learned about her experience, but the impact remains uncertain. Some commentators have applauded Ms. Jolie’s decision to speak out about the issue, while others have expressed concern that it could lead to an increase in women seeking unnecessary treatment.

BRCA Testing

Consider the following groups:

• Ashkenazi Jews

• People with family history of breast carcinoma, especially at young age

• Other neoplasm associated

• BRCA1 are commonly poorly differentiated and have “medullary features”

Types of breast cancer

In-situ carcinoma (preservation of myoepithelial cells): DCIS

LCIS

Invasive carcinoma Invasive ductal *****

Invasive lobular

DCIS (Ductal carcinoma In-Situ)

In-situ means myoepithelial cells present, tumor is within ducts (not in the stroma)

Frequently associated with calcifications

May treat with Tamoxifen (antiestrogenic agent).

Might have some estrogenic effects in some organs.

Current treatment: Surgery with radiation

Risk factors for recurrence• Positive margins after surgery• High nuclear grade and necrosis• Extensive disease

Paget disease of nipple

Rare: 1-4% of cases

Erythematous eruption with a scale crust

Mistaken for eczema frequently

A palpable mass (underling cancer) is present in 50-60% of women

LCIS (Lobular carcinoma in-situ)

Uniform population of cells that are E-Cadherin: Negative

Usually not associated with Ca or nodules (incidentally found)

Risk factor for lobular invasive

Treatment: still controversial, ? Tamoxifen only

INVASIVE BREAST CANCER

Invasive ductal carcinoma

Usually a stellate shaped mass

Most common site: Upper outer quadrant

Arises from ductal cells

E-Cadherin: POSITIVE

Invasive lobular carcinoma

Single file infiltrate

May not be palpable

May be more extensive than suspected clinically

Other special types of breast cancer

Medullary: Well circumscribed, lymphocytic infiltrate.

If medullary features, investigate more. BRCA?

Colloid: tumor cells in a pool of mucin. Good prognosis

Tubular carcinoma: Low grade, good prognosis

Medullary carcinoma

Mucinous (colloid) carcinoma

Tubular carcinoma

Prognosis and predictive factors1. Invasive carcinoma vs In-situ carcinoma: In-situ has a better prognosis

2. Distant metastasis

3. Lymph node metastasis: Axillary lymph node status is the MOST important prognostic factor for invasive carcinoma in the absence of distant metastases.

4. Tumor Size <1cm vs >2cm

5. Locally advance disease

6. Inflammatory carcinoma

7. Lymphovascular invasion

More prognostic factors (from path report)

1. Molecular subtype (Tubular, mucinous, papillary, adenoid cystic) better PX.

2. Histologic grade

3. Proliferative rate

4. ER/PR status

5. Her2/neu expression

Stromal Tumors

Fibroadenoma

• Most common benign tumor of the female breast

• Young females (3rd decade)

• Gets larger with increase amounts of estrogen (pregnancy)

• Cyclosporin A, after renal transplant have a higher incidence and regress when you stop treatment

Phyllodes Tumor

• Greek “leaf-like”

• Arises from stroma

• Difference with fibroadenoma: higher cellularity, higher mitotic rate, nuclear pleomorphism, stromal overgrowth and infiltrative borders.

• Benign, borderline, malignant

Self review multiple choice questions

1. A 59-year old female who has been on estrogen (hormone replacement) therapy presents with a 1 cm stellate mass in the left breast. This was detected on mammography. The lesion is excised, and the margins of the surgical specimen are free of tumor. Microscopic examination confirms a neoplasm with varying amounts of fibrosis and a number of well-formed ductular structures. There is a very rare mitotic figure and no myoepithelial cell layer seen in the abnormal ductular epithelium. Which of the following is true of this tumor?

a. It probably has very large nuclei with very prominent nucleoli and a heavy lymphocytic infiltrate

b. It should be tested for estrogen and progesterone receptorsc. It has a large number of signet cellsd. It should be routinely tested for BRCA-1e. It is usually well circumscribed rather than stellate

2. A 49-year old female presents with an abnormal mammogram. A

biopsy shows sclerosing adenosis. Based on this information, which

is true about this patients risk for developing invasive breast cancer

over the next several years?

a. She has no significantly increased risk over the general population

b. There is an increased risk for both breasts

c. She has the same risk as a patient with atypical hyperplasia

d. She has an increased risk of developing lobular but not ductal carcinoma

e. She has an increased risk if she has been taking tamoxifen

3. A 52-year old female has a crusting of the nipple. Mammography

shows no focal lesions, however a biopsy of the nipple shows a

number of large intraepithelial malignant cells with abundant,

somewhat pale cytoplasm. Which of the following is true of this

process?

a. It is more commonly seen in males than females

b. It is inflammatory carcinoma

c. It is usually associated with an underlying infiltrating ductal carcinoma

d. It is most commonly associated with lobular carcinoma in-situ

e. Usually presents with a bloody nipple discharge

4. A 57-year old female has a biopsy showing a number of lobular units

which are filled and distended with monotonous cells. The lobular

architecture is intact. No frank invasion is noted. This process:

a. Is a marker of increased risk for subsequent development of malignancy

b. Usually has a cribriform pattern

c. Typically has comedo central necrosis

d. Has typical diagnostic features on mammography

e. Should be tested for Her-2/neu overexpression

5. A 55-year old female presents with an abnormal mammogram. Acore needle biopsy shows infiltrating duct carcinoma which is positivefor both estrogen and progesterone receptors. By mammographythe tumor measures 1.9 cm in the greatest dimension. She isotherwise in good health and there is no evidence of metastases.Which of the following is the most appropriate next step in thispatient’s management?

a. Assess her risk by the Gail Model.b. Radiation therapy directly to the sentinel lymph nodesc. Mastectomy or lumpectomy with margins negative for tumord. Hormone replacement therapy especially for patients who are post-

menopausale. Tamoxifen but no other treatment

Answers:

1. B

This description of an infiltrating duct carcinoma indicates a low-grade tumor. Medullary carcinoma is the entity which typically has large numbers of lymphocytes. Well differentiated neoplasms are typically seen in women taking exogenous hormone replacement therapy. The tumor should be tested for estrogen and progesterone receptors. Signet cells are typically associated with lobular carcinoma. There is no need for BRCA testing, and the neoplasm is typically stellate in appearance.

2. A

Although it causes very firm areas in the breast, it is associated with a slight but insignificantly increased risk of developing breast cancer.

3. C

It is associated with an infiltrating carcinoma in a number of cases. Inflammatory carcinoma refers to tumor cells in lymphatics, not in the squamous epithelium. A bloody nipple discharge is typically associated with an intraductal papilloma.

4. A

This is typical description of lobular carcinoma in situ. It is typically not seen mammographically and may not be palpable.

5. C

This is the treatment for invasive breast carcinoma. The lumpectomy would be followed by radiation therapy. Tamoxifen may have an active role as adjuvant treatment after appropriate surgery (plus or minus radiation) but is not the sole treatment for invasive carcinoma. Radiation therapy should be delivered to the tumor and not to the sentinel nodes. Hormone replacement therapy is contraindicated in an estrogen receptor positive patient and should be discontinued if a patient is currently taking it.