Patho5-2_Breast [Dr. Yanez]

Dr. Soccorro Cruz-Yanez

Dr. Soccorro Cruz-Yanez

PATHOLOGY

PATHOLOGY

January 3, 2012

January 3, 2012

 In humans, paired mammaIn humans, paired mammary glands rest on the pery glands rest on the pectoralisctoralis muscle on the upper chest wall

muscle on the upper chest wall



  The breasts are composed of specialized epithelium and  The breasts are composed of specialized epithelium and stroma that may give rise to both benign and malignant stroma that may give rise to both benign and malignant lesions.

lesions.



 Histologically, the Histologically, the following are following are present:present:

o

o  Lobe  Lobe – – 10 in one whole breast 10 in one whole breast o

o  Lobule  Lobule – – Many per lobe Many per lobe o

o  Acinus/Alveolus  Acinus/Alveolus – – Many (5-10) per lobule Many (5-10) per lobule

 Functional secretory unit Functional secretory unit of the of the breastbreast

 The pathology of the breast is related to the origin ofThe pathology of the breast is related to the origin of the functional anatomy of the particular area.

the functional anatomy of the particular area.

o

o  Ducts  Ducts – – Intra or interlobular leading to the lactiferous ducts Intra or interlobular leading to the lactiferous ducts

in the nipple and is the non-secretory that just conducts in the nipple and is the non-secretory that just conducts milk

milk



 66 – – 10 major ductal system, subdivided into lobules 10 major ductal system, subdivided into lobules



 Successive branching of the Successive branching of the large ducts evelarge ducts eventuallntually leads ty leads too the terminal duct lobular unit

the terminal duct lobular unit



 In adult women, the In adult women, the terminal duct branches terminal duct branches into a grapelikeinto a grapelike cluster of small acini to form a lobule

cluster of small acini to form a lobule



  Each ductal system typically occupies more than one  Each ductal system typically occupies more than one quadrant of the breast, and the systems extensively overlap quadrant of the breast, and the systems extensively overlap one another

one another



 Drains Drains to to lactiferous sinuseslactiferous sinuses

Fig. 1.

Fig. 1. Normal breast histology Normal breast histology

Notes: Notes:



 Functional unit of secretion of milk for nourishment of babyFunctional unit of secretion of milk for nourishment of baby



 Made up of several lobules of mammary breast drainingMade up of several lobules of mammary breast draining into the nipple

into the nipple



 Drainage of lymphatic channelsDrainage of lymphatic channels  – –  Disease of breast,  Disease of breast,

 particul

 particularly arly malignmalignancy, ancy, breast breast carcinocarcinoma: ma: 11st st   line of  line of metastasis is regional lymph node, particular

metastasis is regional lymph node, particular a x i l l aa x i l l ar y r y n o d en o d e

(80-90%), internal mammary group of chain of lymph node, (80-90%), internal mammary group of chain of lymph node,  particul

 particularly arly the the inner inner quadrant quadrant of of the the breasbreast, t, andand supraclavicular group of lymph node.

supraclavicular group of lymph node.



  Axillary  Axillary – – Most common site because tumor cells in the outer Most common site because tumor cells in the outer quadrant travels this drainage

quadrant travels this drainage



 Internal Internal MammaryMammary – – Where tumor cells in the Inner Quadrant Where tumor cells in the Inner Quadrant enter and travel to the intrathoracic artery

enter and travel to the intrathoracic artery



  Supraclavicular  Supraclavicular  – –  If this is affected, it indicates a more  If this is affected, it indicates a more advanced stage of a disease

advanced stage of a disease

Fig. 2.

Fig. 2. Lymphatic drainage of the breast Lymphatic drainage of the breast

Mammary Lobules Mammary Lobules

-

- The secretory The secretory units of units of the breastthe breast -

- Each lobule consists of a vaEach lobule consists of a variable number of acriable number of acini, or glands,ini, or glands, embedded within loose connective tissue and connecting to embedded within loose connective tissue and connecting to the intralobular duct

the intralobular duct -

- Each acinus Each acinus is lined bis lined by y two two types of types of cells,cells, 1. Epithelial

1. Epithelial 2. Myoepithelial 2. Myoepithelial 1.

1. Epithelial or Epithelial or ductal ductal cellscells (columnar, luminal location)(columnar, luminal location) -

- Luminal epithelial ceLuminal epithelial cells overlay lls overlay the myoepithelial the myoepithelial cells.cells. -

- Only the Only the lobular luminal cells alobular luminal cells are capable re capable of producingof producing milk.

milk. -

- Responsible Responsible for for secretionsecretion 2. Myoepithelial

2. Myoepithelial (investing, basal location) (investing, basal location) -

- Also Also known known asas Sentinel CellsSentinel Cells -

- When these When these cells are present, it indicates the cells are present, it indicates the presence ofpresence of a benign Lesion

a benign Lesion -

- Contractile myoepithelial cells Contractile myoepithelial cells containing containing myofilammyofilaments ents lielie in a meshlike pattern on the basement membrane.

in a meshlike pattern on the basement membrane. -

- These These cellscells assist in milk ejectionassist in milk ejection  during lactation and  during lactation and provide structural support to the lobules

provide structural support to the lobules

Fig. 3.

Fig. 3. Normal histology of breast acinus Normal histology of breast acinus 

 There There are are alsoalso 2 types of breast stroma2 types of breast stroma:: 1.

1. Interlobular Interlobular stromastroma  – –  Consists of dense fibrous  Consists of dense fibrous connective tissue admixed with adipose tissue.

connective tissue admixed with adipose tissue. 2.

2. Intralobular Intralobular stromastroma – – Envelopes the acini of the lobules Envelopes the acini of the lobules and consists of breast-specific hormonally responsive and consists of breast-specific hormonally responsive fibroblast-like cells admixed with scattered lymphocytes. fibroblast-like cells admixed with scattered lymphocytes. There is important cross-talk between breast epithelium There is important cross-talk between breast epithelium and stroma that promotes the normal structure and and stroma that promotes the normal structure and function of the breast.

function of the breast.

3 Normal phases of breast development: 3 Normal phases of breast development:

1. Active

1. Active – – Gland and Stroma ratio are equal (50:50) Gland and Stroma ratio are equal (50:50) 2. Lactating

2. Lactating -

- Mostly Mostly glandsglands -

- There are There are more glands than stroma due more glands than stroma due to an increaseto an increase in the secretion and proliferation of glands

in the secretion and proliferation of glands -

- This can This can be observed be observed in pregnancyin pregnancy

-- This enlargement isn‟t purely fatty but because there‟sThis enlargement isn‟t purely fatty but because there‟s an increase in the number of lobules. (>>>50/50)

an increase in the number of lobules. (>>>50/50) -

- Active production oActive production of milk, f milk, after preafter pregnancygnancy 3. Atrophic

3. Atrophic -

- Mostly Mostly stromastroma -

- More stroMore strome than me than glands (<<<50glands (<<<50/50)/50) -

- Seen in post menopausal feSeen in post menopausal female and pre-pubertal agemale and pre-pubertal age group

group

Fig. 4. Left

Fig. 4. Left: Active phase.: Active phase. Middle: Middle: Lactating phase.Lactating phase. Right: Right: Atrophic phase Atrophic phase

OO IES

OO IES

Histology

Histology

Lymphatic Drainage

Lymphatic Drainage

NORMAL ANATOMY OF THE BREAST

 Majority of diseases of the breast are in the female because of the active physiologic function of the organ.

  Some Anatomic Sites of Breast Lesions

o Lobule – Fibroadenoma, cyst, lobular carcinoma o Terminal duct – Hyperplasia, breast carcinoma o Lactiferous duct – Intraductal papilloma o Nipple – Paget‟s disease

o Nipple, Lactiferous duct – Nipple adenoma

Fig. 5. Sites of breast lesions

1. Pain (mastalgia/ mastodynia)

- Diffuse cyclic pain  –  No pathologic correlate; more on hormonal changes

- Noncyclie pain  –  Usually localized to one area of the breast (Causes: ruptured cysts, physical injury, infections, but most often no specific lesion is identified

- 95% of painful masses are benign

- Usually associated with hormonal cyclic changes  – Menstruation

- Associated with inflammatory condition to the breast, particularly with sign of tenderness

- 10% of breast cancers are painful

2. Mass (palpable or detected through mammography)

- Discrete palpable masses are common and must be distinguished from the normal nodularity or lumpiness of the breast.

- Non-palpable lesions called densities (lumpiness on breast) can be detected through mammography

- Invasive carcinomas, fibroadenomas, cysts

- At least 2 cm size breast mass to become palpable

- Most common in premenopausal women but the likelihood of a palpable mass being malignant increases with age (age directly proportional to malignancy)

3. Nipple Discharge/ Retraction - Less common finding

- Most worrisome when it is spontaneous and unilateral since it might be from an underlying carcinoma

- The risk of malignancy with discharge increases with age. 1. Milky discharge (galactorrhea)

- Not associated with malignancy

- Associated with elevated prolactin levels (eg. Pituitary adenoma), hypothyroidism, or endocrine anovulatory syndromes, oral contraceptives, TCA drugs, methyldopa, phenothiazines

2. Bloody or serous discharge

- Most commonly associated with benign conditions - The most common etiologies are solitary large duct

papillomas and cysts.

 A. Imaging

- Mammography (age 40 – screening mammography) i. Densities

Most neoplasms are radiol ogically denser than the intermingled normal breast tissue.

The average size of an invasive carcinoma detected by mammography (1.1cm) is less than half that of carcinomas detected by palpation (2.4cm)

ii. Calcification (Malignant – Heavy speckled type of whitish calcification that are group around)

They form on secretions, necrotic debris, or hyalinized stroma.

Ductal carcinoma in situ (DCIS)   is most commonly detected as mammographic calcifications, which are deposited in a linear, branching pattern as the carcinoma fills the ductal system.

- Ultrasound, MRI B. Biopsy

- Fine Needle Aspiration - Tissue biopsy

- Immunohistochemistry

1. Disorders of development (congenital maldevelopment) 2. Inflammatory conditions (mastitis)

3. Pathology of breast implants

4. Fibrocystic changes (hormonally related, not a real tumor) 5. Proliferative breast diseases

6. Tumors, either benign or malignant which originate from - Epithelial cells

- Stromal cells - Epithelial/stromal

 Due to persistence of epidermal thickening along the milk line, which extends from the axilla to the perineum

 2 or more nipples

 can occur in both males and females

 Heterotopic, hormone-responsive foci, which most commonly come to attention as a result of painful premenstrual enlargements

 Developmental anomaly

Fig. 6. Nipple lines from the axilla to the pubic region. Also known as „milk lines‟

 Breast epithelium outside of the breast proper (axillary area) might undergo lactational changes or give rise to tumors that appear to be outside the breast

 Nodular growth pattern at the axillary line

 Rudimentary protrusion of the lactiferous side

 Breast tissue in the axillary area – Clinically in apparent

 Fibroadenoma arising from accessory breast

 Carcinoma of the breast arising from the axillary area

Fig. 7. The most common location of an accessory breast is the axilla.

 Accessory Axillary Breast Tissue

Supernumerary Nipples Disease (Milkline remnants)

Disorders of Development

PATHOLOGY OF THE BREAST

Laboratory Diagnosis of Breast Cancer

Clinical Presentation of Breast Disease

ANATOMIC SITES OF BREAST LESIONS

Note:

Breast tissuealways  extends to the axilla, and when it does form an actual protuberance, it can be called an accessory breast. Breasts are modified apocrine sweat glands embryologically.

 Particularly occurs in women with large or pendulous breasts

 Congenital or acquired

 Failure of the nipple to evert during development

 It is common and may be unilateral

 Congenitally inverted nipples usually correct spontaneously during pregnancy, or can sometimes be everted by simple traction

 One of the cardinal signs of breast CA

 Majority caused by inflammation (fat necrosis, ductal ectasia, piercings-acquired)

Fig. 8. Inverted nipple

 Abnormal enlarged breast

 May be unilateral or bilateral

 Symmetrical enlargement

 May be due to variations in body habitus or to an unusual tissue response to hormones

Fig. 9. Macromastia

 Inflammatory diseases of the breast are uncommon.

 Women usually present with an erythematous, swollen painful breast

 Inflammatory Disorder: 1. Acute Mastitis 2. Periductal Mastitis 3. Mammary Duct Ectasia 4. Fat Necrosis

5. Granulomatous mastitis 6. Lymphocytic Mastitis 7. Silicone Breast Implants Note:

 Periductal mastitis, mammary duct ectasia and fat

n e c r o s i s    may be mistakenly clinically seen as malignancy due to same clinical presentation like scarring and nipple inversion.

 Be sure to know the difference among the inflammatory disorders, like how acute mastitis morphologically differ from lymphocytic mastitis.

 Almost all cases of acute mastitis occur during the first month of breastfeeding.

 Difficulty during lactation

  Associated with breaks, cracking in the skin, lactation (mechanical trauma due to sucking of the baby)  –  Breast is vulnerable to bacterial infection

 Big, swollen, erythematous painful breasts with pus, fever

 Predominant inflammatory cells: Neutrophils inside the ducts and stroma

 S. aureus  (more common) from skin & strep: Usual etiologic

agents

 Staph infection

o Localized area of suppurative inflammation o Redness, tenderness, pain and fever o Single/multiple abscesses

 Strep infection

o Seat of inflammation is diffuse throughout the parenchyma

Fig. 10. Left: Gross – There is erythema and edema. Right: Histological Hallmark – Presence of many pigmented neutrophilic infiltration(yellow arrow) inside the ducts.

 Also known as Recurrent Subareolar Abscess, Squamous Metaplasia of lactiferous ducts, Zuska Disease

 Subareolar location

 Seat of inflammation is around the duct

 Presents with a painful, erythematous, subareolar mass that clinically appears to be an infectious process.

 Recurrences are common

 More than 90% of the afflicted are smokers

o  Vitamin A deficiency associated with smoking or toxic

substances in tobacco smoke alter the differentiation of the ductal epithelium

  This condition is not associated with lactation, a specific reproductive history, or age.

  May be mistaken clinically for carcinoma due to fibrosis, scarring, induration and nipple inversion.

  Can present clinically as a malignant lesion because of presentation

 Many women with this condition have an inverted nipple, most likely as a secondary effect of the underlying inflammation

 Location is very important: Centrally beneath the nipple Histology

- Squamous metaplasia of lactiferous duct (normally cuboidal lining)

- Keratin trapping and duct dilatation Rupture of duct

- Chronic and granulomatous inflammation  –  Develops once keratin spills into the surrounding preductal tissue

- The inflammation is PERI-ductal, not Intraductal that is why you would see the inflammatory cells surround the ducts.

Fig. 11. The key hist ologic feature is keratinizing squamous metaplasia of the n ipple ducts; it also shows lymphocytic infiltration around the dilated ducts(upper left).

Note:

Remember! DILATED, LYMPHOCYTE around the ducts and METAPLASIA.

 Plasma cell Mastitis

 Ductesia: Dilated ducts

 Presents with a history of difficulty of lactation

 Usually occur in 5th or 6th decade of life, multiparous women

 Not associated with cigarette smoking   (vs. Periductal mastitis)

  Malignant clinical presentation: Irregular firm induration periareolar mass ,thick white nipple discharge, nipple/ skin retraction (due to fibrosis that is why nipple retracted)

 Principal significance of this disorder is that it produces an irregular palpable mass that mimics the mammographic appearance of carcinoma

Mammary Duct Ectasia

Periductal Mastitis

 Acute Mastitis

Inflammatory Conditions

Macromastia

Nipple Inversion

Histology:

- Dilated ducts filled with granular, necrotic debris - Necrotic, atrophic lining

- Periductal & interductal chronic granulomatous inflammation: (+) Lymphocytes, macrophages

- Squamous metaplasia of nipple ducts is absent.

Fig. 12. Mammary Duct Ectasia, dilated ducts can be seen and atrophic lining. Some fibrosis is appreciated.

 History of trauma, prior surgery or radiation therapy or those with big pendulous breasts

 Can present as a painless palpable mass, skin thickening or retraction, a mammographic density, or mammographic calcifications

 Clinically simulate malignancy due to firm fibrosis occurring at late stages of fat necrosis

 The major clinical significance of this condition is its possible confusion with breast cancer.

Histology:

- Early: Central focus of fat, necrosis, surrounded by lipid, macrophages, inflammatory cells

- Late: Fibrosis, calcification

Fig. 13. Fat necrosis, some calcification are seen and necrosis of fat cells which looks like ghost cell.

 Non-bacterial etiology

  Idiopathic

 Non-caseous type of TB

 Associated with systemic granulomatous disease, mycobacteria, fungal infection, immunocompromized, foreign body, hypersensitivity reaction associated with lactation

 Causes include systemic granulomatous diseases that occasionally involve the breast, and granulomatous infections caused by mycobacteria or fungi

 Most common in immunocompromised patients or adjacent to foreign objects such as breast prostheses or nipple piercings

 Granulomatous Lobular Mastitis   is an uncommon breast-limited disease that only occurs in parous women

 The granulomatous inflammation is confined to the lobules, suggesting that it is caused by a hypersensitivity reaction to antigens expressed by lobular epithelium during lactation.

Fig. 14. Granulomatous mastitis, giantcells are seen and can be mistaken for TB therefore differentiated with an AFB stain.

 Also known as  Lymphocytic Mastitis/Lymphocytic Mastopathy/ Sclerosing Lymphocytic Lobulitis

 Diabetic Mastopathy

 Most common in women with Type 1 DM or autoimmune thyroid disease

 Non-Bacterial etiology

 Related to Inflammation

 A prominent lymphocytic infiltrate surrounds the epithelium and small blood vessels

 Destruction of mammary alveolus

 Single or multiple hard irregular palpable masses (The lesions are so hard that it can be difficult to obtain tissue with needle biopsy) Malignant clinical presentation

 The major clinical significance of this condition is its possible confusion with breast cancer.

 Microscopic findings:

o Collagenized stroma o Atrophic ducts and lobules o Thickened BM

o Prominent lymphocytic inflammatory infiltrates

Fig. 15. Lymphocytic Mastitis, plasma cell and lymphocyte can be seen.

  Histologic response to implants is chronic granulomatous inflammation, giant cell reaction and fibrosis

 Silicone gel seeps “bleeds” through intact silicone shells

 Silicone breast implant: Refractile, glassy, crystalline matter found in the connective tissue stroma, surrounded by chronic inflammatory process

 Leak and puncture get into the tissue, inside form a foreign body granulomatous inflammation

Fig. 16. Silicone Breast Implant, the white parts are silicone that has leaked.

 Most common breast disorder, 3rd-4th decade of life

 Non proliferative breast changes

 Not a tumor, not neoplasm, underlying pathology is hormonal (“lumpy bumpy”)

 Pathogenesis: Hyperestrenism

o  Ask patient is she had a history of estrogen therapy 

Increase proliferative activity

 Target cells are mammary lactiferous breast cell  –  Induce proliferative activity

 Produces hypernodularity

 Principal morphologic changes:

o Cyst

  Formation with apocrine metaplasia: From dilation and unfolding of lobules, change of columnar ductal cell Columnar apocrine cell

 Cysts are alarming when they are solitary and firm to palpation

  The diagnosis is confirmed by the disappearance of the cyst after fine needle aspiration of its contents.

Fibrocystic Changes

BENIGN EPITHELIAL LESIONS

Silicone Breast Implants

Pathology of Implants

Lymphocytic Mastitis

Granulomatous Mastitis

Fat Necrosis

o Fibrosis

  As cysts rupture, chronic inflammation and scarring fibrosis result Palpable firm breast

o Adenosis

 Increase in the number of acini per lobule

  The acini are line by columnar cells, which may appear benign or show atypical features (flat epithelial atypia)

 These atypical features may be the earliest recognizable precursor of epithelial neoplasia

o Ductal epithelial hyperplasia  (ducts affected have

increased proliferative activity.

 This is more worrisome due to the increased risk of malignancy.

Fig. 17. Fibrocystic Disease. There is adenosis beside the cysts. Without hyperplasia = no risk of malignancy. With hyperplasia, high incidence of malignancy

Fig. 18. Left: Blue dome cyst which appears to be like dome, brown to blue cyst due to leak with contamination of blood. Right: The encircled is the fibrocysts

surrounding the connective tissue and nodular upon palpation.

 No risk of carcinoma in the absence of proliferative breast disease

 No ductal hyperplasia, the risk of carcinomas zero

 Carcinoma increased 2 –_{5 times if with ductal epithelial}

hyperplasia.

  Typically more than one lesion is present, frequently in association with proliferative breast changes

  Characterized by proliferation of ductal epithelium and/or stroma without cytologic or architectural features suggestive of carcinoma in situ.

 2 cell layer rule is broken

 Solid cribiform proliferation

 Increased proliferation of the lining cells (>2 layers)

 2 cell rule is broken

 The lumen is practically non-existent

 The additional cells consist of both luminal and myoepithelial cell types that fill and distend ducts and lobules.

 Benign since myoepithelial cell is appreciated (since malignancy is associated with monoclonal proliferation which means, once it is already malignany; myoepithelial cell is not appreciated.)

 Usually an incidental finding

Fig. 19. Left: Normal ductal epithelium. Right: Ductal hyperplasia (more than 2 layers of cells)

 Increased number (to at least double the number) of distorted and compressed acini within the lobule, CT sclerosis within the mammary lobule

 The normal lobular arrangement is maintained

 Myoepithelial cells are usually prominent

 Firm with induration

  May be confused with Breast CA because of the CNT proliferation

 1-2 times increased risk of malignancy

Fig. 20 Sclerosing adenosis. There is connective tissue that grows inside the adenotic lobule

 Are clinically silent

 Composed of multiple branching fibrovascular cores, each having a connective tissue axis lined by luminal and myoepithelial cells

 Growth occurs within a dilated duct

 (+) Epithelial hyperplasia and apocrine metaplasia

 Large duct papillomas are usually solitary and situated in the lactiferous sinuses beneath the nipple

 Small duct papillomas are commonly multiple and located deeper within the ductal system

Note:

Number 1 commandment in pathology: NEVER diagnosis a malignant papilloma on a frozen section!! NEVER. – Dr. Yanez

Fig. 21. Hyperplastic proliferation of duct which is confined in the ductal lumen

 Associated with increased risk of malignancy

  Increase mitosis, pleomorphic, increase nucleus, irregular chromatin pattern

  Atypical hyperplasia is a cellular proliferation resembling carcinoma in situ but lacking sufficient qualitative or quantitative features for diagnosis as carcinoma.

 Atypia: Increase cells showing mitoses; pleomorphism, nucleoli is seen, irregular chromatin pattern.

 Histologic resemblance to ductal carcinoma in situ (DCIS)

  Shows hyperchromaticity, more rounded cells, N:C ratio disturbed, and loss of cellular polarity

 2 cell rule is broken

 It is distinguished from DCIS by being limited in extent and only partially filling ducts.

Fig. 22. Atypical Ductal Hyperplasia. No invasion of the stroma is seen. Atypical cells are appreciated.

 Atypical Ductal Hyperplasia (ADH)

Proliferative Disease With Atypia

Ductal Papilloma

Sclerosing Adenosis

Ductal Epithelial Hyperplasia

Proliferative Disease Without Atypia

Fibrocystic Change: Clinical Significance

 It is defined as a proliferation of cells identical to those of lobular carcinoma in situ (LCIS), but the cells do not fill or distend more than 50% of the acini within a lobule.

Fig. 23. Atypical Lobular Hyperplasia

 Increase risk of carcinoma is proportional to the type of PBD (Proliferative Breast Diseases) and presence of atypia

  No risk: Adenosis, cysts, apocrine metaplasia and mild epithelial hyperplasia

 No atypia = No risk of malignancy

 Type of Atypia: Mild, Moderate, Severe

 Slight increase: 1.5-2 times Sclerosing adenosis, moderate to florid epithelial hyperplasia, papillomas

 Moderate increase risk: 4-5 times ADH, ALH

 Stromal Tumors

 Recall: There are 2 types of stroma in the breast- intralobular and interlobular o Intralobular stroma:   Fibroadenoma  Phyllodes tumor o Interlobular stroma:   Lipomas   Angiosarcomas

 Pseudoangiomatous stromal hyperplasia

  Myofibroblastomas

 Fibrous tumors

 Most common benign tumor of female breast

 A new growth composed of fibrous and glandular tissue

  More common before 30 yrs of age [previous trans says before 20-30 yrs of age]

  Morphology

o  Spherical nodule, sharply circumscribed, freely movable,

palpable, soft, rubbery mass, small, demarcated, no fixation

o VS Malignant

 Irregular, thick, poorly demarcated border, firm gritty to stony hard

o Frequently occur in the upper outer quadrant o Size varies from 1cm to 10-15cm (giant!)

o Fibrous stromal and ductal epithelial proliferation

Fig. 24. Left: Gross – White circumscribed tumor in the middle. Right: Mammography showing calcification

Fig. 25. Proliferation of intralobular stroma: ducts are compressed.

 Also known as Cystosarcoma phylloides

 Epithelial stromal tumor, resembles fibroadenoma

 Large bulky tumor with bulbous protrusions

 Older population (mean age 45)

 High incidence of recurrence

  Benign(majority), Intermediate malignancy and Malignant categories

 Malignant counterpart with stromal atypia due to overgrowth and pleomorphism of the tumor

 closely resembles Fibroadenoma

 Phylloides Tumor is characterized by having MORE CELLS in the stroma and is a bulkier lesion than Fibroadenoma

 When the stroma becomes atypical, and the glands proliferate, then it becomes a Malignant Phylloides Tumor Gross

- Large , bulky , well circumscribed, cleft like spaces - Hemorrhage, necrosis , cysts

Histology

- Stromal hypercellularity - Not true sarcoma

- More fibroblastic cells within the connective tissue

- Benign glandular elements, often in canalicular slits with or without hyperplasia

Fig. 26. Left: Gross – Notice the well circumscribed, cleft-like spaces. Right: Histology –_{There is increased str omal cellularity, cytologic atypia, and stromal}

overgrowth giving rise to the typical leaflike structure.  Criteria of Malignancy:

o Stromal cell atypia

  Mitosis

  Pleomorphism

 Nuclear atypia

o Cellular stroma overrunning epithelial component o Infiltrative borders vs pushing borders

 Clinical Behavior

o Tendency for local recurrence

o Malignant PT, metastasis by hematogenous route

  Carcinoma of the breast is the most common non-skin malignancy in women

  The majority of carcinomas are estrogen-positive (ER) positive.

 Most common malignant tumor of female

 Affects 1 of 9 women in the U.S., especially those who live in urban populations

 Increases with increasing age

 More frequent in women of low parity with first child after 30

 In obesity because fat can be metabolized to estrogen

 With prior breast biopsies showing atypical hyperplasia

 With history of breast carcinoma

 In women with mother or sibling with breast cancer

  With mutations in BRCA1 or BRCA2 genes in hereditary breast Ca, mutation in the tumor suppressor gene, p53

 Gender: Rare (1%) in male

 Age: 61 yrs – Average age of diagnosis

Risk Factors

Incidence and Epidemiology 

Breast Carcinoma

Phyllodes Tumor 

Fibroadenoma

Benign Breast Tumors

Clinical Significance

 Age at Menarche

o Those <11 years of age have a 20% increased risk

compared to women who reach menarche when >14 years of age

o Late menopause also increases risk.

 Age at First Live Birth

o Women with a first full-term pregnancy at <20 years old.

 Race / ethnicity: Highest among white americans

 Estrogen exposure – Hormonal Replacement Therapy 1.2 to 1.7 increase risk

 Oral Contraceptive use

 High breast radio density

 Radiation exposure

 Carcinoma of contra lateral breast Ca ( 1 % ) and ovarian Ca

  Diet:

o Increase risk: Alcohol, fat o Decrease risk: Caffeine o Post menopausal Obesity

 Exercise: Protective factor

 Breast feeding --. Lower risk

 Environmental Toxins (pesticides)

  Tobacco

 The major risk factors for the development of breast cancer are hormonal, radiation and genetic

 Breast cancers can therefore be divided into sporadic cases, probably related to hormonal exposure, and hereditary cases, associated with germline mutations.

 Hormonal factors

o Hyperestrenism, endogenous and exogenous

 Environmental factors

o  Radiation

o Diet: Fat, moderate alcohol consumption

 Increasing age

 Proliferative breast disease

 CA in contralateral breast

  Parity

o Decreased parity  Higher risk

o When the woman is pregnant, there‟s an interruption in

estrogen production there less risk for breast CA

  Obesity

 Genetic factors

o Gene line mutations in BRCA1 and BRCA2, p53,

 Autosomal inherited

o “sSngle gene” mutation of breast susceptible cancer

gene: BRCA1 and BRCA2, p53

o BRCA1 : 17q21

 Increase risk of developing ovarian CA

 Poorly differentiated , triple negative IHC

 (-) ER, Estrogen, Progesterone, HER2

 Poor prognosis, alternative hormonal treatment is not an option

o BRCA2: 13q12-13

 Associated carcinoma

  Ovarian(lesser extent), prostate, pancreatic stomach CA

 Poorly differentiated, more often ER positive.

 Amenable for hormonal treatment

o Germline mutation of p53 (17p13.1)

 Associated with Li-Fraumeni syndrome with sarcoma, lymphoma, leukemia, brain tumors

 Sporadic breast cancer

o Major risk factors related to hormone exposure o Usually post-menopausal and are ER +

o  Well-differentiated A. In situ Ca 15 – 30 % - Ductal Ca in situ 80 % - Lobular Ca in situ 20 % B. Invasive ( infiltrating ) Ca 70-85 % - Ductal ca 79 % - Lobular Ca 10 % - Tubular Ca 6 % - Colloid (Mucinous Ca ) 2 % - Medullary Ca 2 % - Papillary Ca 1 %

 Loss of stroma between acini

 “Swiss-Cheese” hyperplasia *

 Cribriforming **

 Cellular pleomorphism

 Cellular hyperchromasia

 Increased abnormal mitosis *

 “Roman bridges”***

 Necrosis *** (“COMEDO-carcinoma”) Note:

The asterisked items, are more suspicious than the non-asterisked items. Intraductal NECROSIS is the most suspicious feature of all.

 Also known as Intraductal Carcinoma

 Increase incidence due to mammographic screening

o  Among cancers detected mammographically, almost half

are DCIS

 Tumors confined within ducts  –  Malignant population of cells limited to ducts and lobules by the basement membrane

 Progression to invasive carcinoma

 Myoepithelial cells are preserved, but may be diminished in number

  DCIS is a clonal proliferation and usually involves only a single ductal system

 Tumor confined in the duct

 Presence of Roman Bridge

  Types:

a. ComedoCa

b. Noncomedo DCIS

c. Paget‟s disease of the nipple

 Characterized by solid sheets of pleomorphic cells with high-grade nuclei and central necrosis, calcification commonly detected on mammogram

 When the breast is squeezed, a paste like substance oozes out of the nipple

 NECROSIS in a hyperplastic duct is usually DCIS

 A. Comedocarcinoma (High-grade DCIS)

Invasive Breast Carcinoma

Features of Atypia

Histologic Types of Breast CA

Etiopathogenesis

 Consists of a monomorphic population of cells with nuclear grades ranging from low to high

 Solid without necrosis

 Morphologic variants:

o Cribriform DCIS o Solid DCIS o Papillary DCIS o Micropapillary DCIS

Fig. 27. Left: Roman Bridges. Right: DCIS comedo pattern.

 Rare manifestation of breast carcinoma

 Presents as a unilateral erythematous eruption with a scale crust, nipple appear fissured, ulcerated and oozing

 Pruritus is common, might be mistaken for eczema

  Ulceration and involvement of the external skin can be observed

o  Form of DCIS that extends from the nipple ducts into

contiguous skin of nipple.

 50-60 % associated with underlying invasive ductal CA

 Importance: Infiltration of the breast

 Presence of Paget cells in the epidermis

o Paget cells  –  Lymphatic, large, round cells with

perinuclear halo. Atypical, look like duct cells.

 Progression to invasive carcinoma

Fig. 28. Paget cells

 Based on cyto-nuclear grade and differentiation , architectural growth pattern and necrosis

  Grading Classification:

o High grade DCIS – Grade 3

o Intermediate grade DCIS – Grade 2 o Low grade DCIS – Grade 1

o Increase grade – Increase necrosis o Low grade – More Solid

High grade DCIS Intermed

grade DCIS Low grade DCIS

Nuclei marked variation; Size > 2.5x; Coarse chrom, prom nucleoli,

mitosis, atypia Nuclear changes in between Round, uniform, monotonous, monomorphic, 1.5  –2x

size, few to absent nucleoli Severe loss of cell

orientaion

Polarity, cell orienta-tion maintained; Cribriform,

papillary Large comedo type of

necrosis

Punctate

necrosis Necrosis absent

DCIS (Low Grade)

- Duct filled by monolayer cells with few rigid round holes - Little nuclear variation

- No necrosis

- The cells show no orientation to the "holes" - Tumor cells confined by an intact BM

 Proliferation of terminal ducts, acinar lobules

 Bilateral in 50-70 %: Must do a contralateral mammography to check for malignancy

 Due to its bilaterally, do a mirror image biopsy

 Presence of signet ring cells containing mucin

 Slowly growing , many years before it infiltrates, in contrast to DCIS

  The best management may be judicious neglect, i.e., observation

o  Dra. Yanez said to disregard this, if detected, treat it

immediately

 If it does infiltrate, however, it is at least as bad as DCIS infiltrating, or probably WORSE, showing “Indian” files

  Always an incidental finding in a biopsy performed for another reason, as it is not associated with calcifications or a stromal reaction that would form a density

  More common in young women, 80% to 90% of cases occurring prior to menopause

  ALH, LCIS, and Invasive Lobular Carcinoma all consist of dyscohesive cells with oval or round nuclei and small nucleoli 

Fig. 29. LCIS: A whole lobule filled with monotonous cells of the same type can be called LCIS, or lobular carcinoma in situ.

  Also known as Invasive carcinoma, No Special Type (NST/Invasive Ductal Carcinoma)

 70 – 80 % of breast carcinoma

 Originates from ducts with invasion into stroma

 May have pronounced desmoplasia (Fibrosis)   Scirrhous carcinoma

 Most carcinomas induce a marked increase in dense, fibrous desmoplastic stroma, giving the tumor a hard consistency on palpation and replace fat, resulting in a mammographic density (scirrhous carcinoma)

Fig. 30. Infiltrating ductal Carcinoma  Graded according to:

o Degree of glandular differentiation o Degree of nuclear atypia

o Mitotic index (Scarff-Bloom-Richardson System)

 Graded according to pleomorphism, tubular production and mitosis:

o Well differentiated  –  Prominent tubule formation, small

round nuclei, and rare mitotic figures

o Moderately differentiated  –  May have tubules, but solid

clusters or single infiltrating cells are also present with a greater degree of nuclear pleomorphism and contain mitotic figures

o Poorly differentiated  –  Often invade as ragged nests or

solid sheets of cells with enlarged irregular nuclei and high proliferation rate and areas of tumor necrosis are common

 Within the center of the carcinoma, there are small pinpoint foci or streaks of chalky white elastotic stroma and occasionally small foci of calcification.

 There is a characteristic grating sound (similar to cutting a water chestnut) when cut or scraped.

Gross: Most are firm to hard with an irregular border

Classification of DCIS

C. Paget‟s Disease of the Nipple

B. Non-comedo DCIS

Inflitrating Ductal CA

 Bilaterality ( 5 – 10 % )

  Multicentric

 Diffusely invasive pattern

 Frequent metastasis to CSF, serosal surfaces, ovary , uterus and bone marrow

 Greater incidence of bilaterality

 Increasing incidence in postmenopausal women

 Multicentric: May involve all breast quadrants

  Usually present as a palpable mass or mammographic density

  ¼ have a diffusely invasive pattern without prominent desmoplasia

  Have a different pattern of metastasis than other breast cancers

o Metastasis tends to occur to the peritoneum and

retroperitoneum, the leptomeninges (carcinoma meningitis), GIT, and the ovaries and uterus

  In some cases, metastatic lobular carcinoma may be mistaken for signet ring carcinoma of the GIT, which it closely resembles

 Histologic hallmark: Pattern of single infiltrating tumor cells, often only one cell in width (in the form of a single file) or in loose clusters or sheets

Fig. 31. Indian File pattern: Like Indians dancing side by side in a single line

 Occurs in older women ( 6th decade)

 1% - 5 % of all breast Ca

 Large fleshy, well demarcated tumor

  Solid, sheets of large, pleomorphic cells with surrounding lympho-plasmacytic infiltrates

 Pushing, non infiltrative border

 Better prognosis – “Good carcinoma”

 Usually hormone receptor negative

Fig. 32. Medullary Carcinoma. Left: Gross. Right: Histology. Highly pleomorphic with lymphocytic infiltrates surrounding the tumor cells (important characteristic of

this carcinoma)  Characterized by:

o  Solid, syncytium-like sheets of large cells with vesicular,

pleomorphic nuclei, and prominent nucleoli, which compose more than 75% of the tumor mass

o Frequent mitotic figures

o Moderate to marked lymphoplasmacytic infiltrate

surrounding and within the tumor

o pushing(noninfiltrative) border

 All medullary carcinomas are poorly differentiated

 Tends to occur in older women (Median age is 71 yrs )

 Soft, well circumscribed , gelatinous consistency

  Better prognosis compared to NOS carcinoma - “Good carcinoma”

 Usually ER positive

 Unusual type of breast CA

Fig. 32. Left: Soft, well circumscribed, pale gray-blue gelatinous consistency. Right: The tumor cells are seen as clusters and small islands of cells within large lakes of

mucin that push into the adjacent stroma

 “Good carcinoma”

 Typically detected as irregular mammographic densities

 Occur in women in late 40s

 All are well-differentiated

 Excellent prognosis

 Consist exclusively of well-formed tubules and are sometimes mistaken for benign sclerosing lesions

 A myoepithelial cell layer is absent, and tumor cells are in direct contact with stroma

 Frequently associated with ALH, LCIS, or low grade DCIS

 Axillary metastases occur in fewer than 100% of cases unless multiple foci of invasion are present. This subtype is important to recognize because of its excellent prognosis

 Invasive carcinoma almost always presents as a palpable mass

  Palpable tumors are associated with axillary lymph node metastases in over 50% of patients

 Larger carcinomas may be fixed to the chest wall or cause dimpling of the skin

 When the tumor involves the central portion of the breast, retraction of the nipple may develop.

 Lymphatics may become so involved as to block the local area of skin drainage and cause lymphedema and thickening of the skin

o  In such cases, tethering of the skin to the breast by

Cooper ligaments mimics the appearance of an orange peel: Peau d‟ orange

 The term inflammatory carcinoma is reserved for tumors that present with a swollen, erythematous breast

 Very aggressive! You‟ll be dead within months

 Involves dermal lymphatics

 Usually has a diffuse infiltrative pattern and typically does not form a discrete palpable mass

 Common presentation like mastitis

 Ulcerated, red, weeping, eczematoid, skin trophic changes

Fig. 34. Left: Inflammatory carcinoma with its classic Peau d‟orange appearance. Right: Lymphatic Invasion in axillary node

 Tender, big, no definite mass, dark, red, swollen, mottling effect, Peau d‟ orange

 Tumor embolization in lymphatic channel

 Advance axillary node metastatic is a high probability

 The clinical presentation is similar to that of carcinomas of NST, but the overall prognosis is better ( in Robbins, poor  prognosis because of lymph node metastases).

Invasive Papillary Carcinoma

Inflammatory Carcinoma

Invasive Infiltrating Carcinoma

Tubular Carcinoma

Mucinous (Colloid) CA

Medullary Carcinoma

Inflitrating Lobular CA

 Palpable firm mass

 Nipple discharge

 Nipple retraction

 Skin ulcers/ erosions – sign of far advanced cancer

 Skin dimpling , peau d‟ orange

 Axillary node palpable

 Fixation to chest wall

Fig. 35. Left: Palpable firm mass. Right: Nipple retraction

Fig. 36. Left: Skin ulceration. Right: Skin ulcerations with palpable axillary lymph nodes.

  Spread by lymphatic to regional axillary and internal mammary LN

 Hematogenous spread: Bone , liver , lungs ,

 SR dependent on stage

o  Size

o LN involvement (decrease LN involvement, increase

survival rate)

o Distant Metastasis

 Except in women who present with distant metastasis (<10%) or with inflammatory carcinoma (<5%) (in whom the prognosis is poor regardless of other findings), prognosis is determined by the pathologic examination of the primary carcinoma and the axillary lymph nodes

  Stage

o Size of primary tumor – Second most important factor; the

risk of axillary lymph node metastases increases with the size of the primary tumor

o  LN involvement  –  Axillary lymph node status is the most

important prognostic factor for invasive carcinoma in the absence of distant metastases.

 Negative node : 70 – 80 5 10 yrSR

 1 to 3 nodes positive : 35 – 40 %

 10 nodes positive : 10 – 15 %

o Distant metastasis – Once distant metastases are present,

cure is unlikely.

 Invasive carcinoma vs. in situ disease

o Breast cancer deaths associated with DCIS are due to the

subsequent development of invasive carcinoma or areas of invasion that were not detected at the time of diagnosis

 Histologic type

 Histologic grade

 ER/PR: Response to hormonal treatment

 Her2/neu  over-expression  –  Associated with poorer survival, predictor for response to trastuzumab treatment

o Well to moderately-differentiated tumors do not

overexpress HER2/neu, while poorly-differentiated tumors do

 Lymphovascular invasion – Poor prognosis

 Proliferative rate index:

o Mitotic rate

o IHC detection of cellular proteins seen in cell cycle

(cyclins, Ki-67 ,

 DNA content

 Gene expression profiling 

 Enlargement of the male breast

 May be unilateral or bilateral and presents as a button-like subareolar enlargement

 The lesion must be differentiated only from rare carcinomas of the male breast.

 May occur as a result of an imbalance between estrogen and androgen

 May be found at the time of puberty, in the very aged, or at any time during adult life when there is cause for hyperestrinism

  Associated with cirrhosis of the liver, since the liver is responsible for metabolizing estrogen

o  If you have a fibrotic or nonfunctioning liver, estrogen

levels increase and stimulates mammary gland to become proliferative.

 In older males, gynecomastia may occur owing to a relative increase in adrenal estrogens as the androgenic function of the testis fails

  Drugs such as alcohol, marijuana, heroin, antiretroviral therapy, anabolic steroids used by some athletes and body builders, and some psychoactive agents have also been associated with gynecomastia

 Marked micropapillary hyperplasia of the ductal linings occurs

Fig. 37. Gynecomastia

Histology: Proliferation of a dense collagenous connective tissue

 Rare occurrence (1% of males)

 More aggressive than of the females

 Risk factors are: First-degree relatives with breast cancer, decreased testicular function, exposure to exogenous estrogens, increasing age, infertility, obesity, prior benign breast disease, exposure to ionizing radiation, and residency in Western countries

 Usually present as a palpable subareolar mass, 2 to 3 cm in diameter, with nipple discharge as a common symptom.

 Ulceration through the skin is more common than in women.

 Distant metastases to the lungs, brain, bone, and liver are common

 Most cancers are treated locally with mastectomy and axillary node dissection.

1. Dra. Yanez’s Lecture and PPT

2. 2013B trans

3. Robbins and Cotrans

Breast Cancer Prognostic Factors

Biological Behavior of Breast Carcinoma

Clinical Features of Breast Carcinoma

REFERENCES

Carcinoma of the Male Breast

Gynecomastia