Pathophysiology of breast cancer

PATHOPHYSIOLOGY OF BREAST CANCERPresented by-Priyanka Padhi

Contents

1. What is Cancer ?

2. Types of Cancer

3. What is Breast cancer ?

4. Eitiology

5. Types of Breast cancer

6. Histopathology

7. Inherited Genes

8. Conclusion

9. References

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body

Normal cells

Cancer cells

BRAIN CANCER

THYROID CANCER

BREAST CANCER

PANCREATIC CANCER

MELANOMA CANCER

Types of Cancer

LUNG CANCER

LIVER CANCER

KIDNEY CANCER

COLORECTAL

LEUKEMIA

SKINCANCER

OVARIAN CANCER

NON HODGKIN LYMPHOMA

ESOPHAGEAL

CERVICAL

BLADDER CANCER

UTERINE

Types of Cancer

Breast Cancer Breast cancer starts when the cells in the breast

begin to grow out of control and then after formation of tumor occurs.

The tumor is malignant (cancerous) if the cells can grow into invade surrounding tissues or spread (metastasize) to distant areas of the body.

Breast cancer can spread through the lymph system. Lymph system includes lymph nodes, lymph vessels, lymph fluid found throughout the body.

Lymph nodes are small, bean shaped having collections of immune system cells that are connected by lymph vessels.

Lymph vessels are like small veins, except that they carry a clear fluid called lymph away from the breast.

Breast cancer cells can enter lymph vessels and begin to grow in lymph nodes like axillary nodes and supraclavicular and infraclavicular lymph nodes (internal mammary lymph nodes).

Breast CancerIn

Everyday News

Etiology Mainly the etiology of the breast cancer is multifactorial and

involves diet, reproductive factors and related hormonal imbalances.

High risk of breast cancer mainly in affluent societies having western lifestyle, characteristics by a high calorific diet rich in animal fat and proteins with lack of exercises.

Reproductive lifestyle Breast cancer occurs more frequently among women who have

an early menarche remain nulliparous. If parous having few children with a late age at first delivery Late age at menopause. Lack of breast feeding.Exogenous hormone Two major types of hormonal compounds have been evaluated

in relation to breast cancer i.e. oral contraceptives and menopausal replacement therapy.

Mainly progestogen-estrogen complex contraceptives and therapy affects more than the individuals.

Incidence of female breast cancer by age in selected populations 1988-1993. From M. Parkin et al. {2189}.Source: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Nutrition High intakes of fruit, vegetables are probably associated with a

slightly reduced risk. High body mass. High calorific intake, no expenditure, total animal saturated fat

intake. Consumption of more red meat.Alcohol More alcohol consumption. Hormone use or other factors potentially including genetic

polymorphism may modify the risk.

Breast cancer risk by increasing levels of circulating insulin-like growth factor (IGF-1) in women <50 years. Blue columns, IGF-1, orange columns, IGF-1 binding protein (IGFBP-3). From S.E. Hankinson et al. {1127}.Source: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Insulin, IGF-I, bioavailable sex steroids, and breast cancer.Source: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Etiological factors involved in the development of breast cancer.

Endogenous hormones improves risk of breast cancer prediction

Endogenous Hormone Rise more steeply with age before

menopause than after, when ovarian synthesis of estrogens and progesterone ceases and ovarian androgen production gradually diminishes.

Depends on breast tissue exposure to estrogens, increases breast cell proliferation and inhibition of apoptosis.

Higher among postmenopausal women who have elevated plasma levels of testosterone and androstenedione, reduced levels of sex hormone- binding globulin (SHBG) and increased levels of oestrogene, oestradiol.

According to estrogen plus progestogen hypothesis postulated that, compared to exposure to estrogen alone, risk of breast cancer is more having elevated plasma and tissue levels of estrogen in combination with progestogens.

Nuclear explosions

Tuberculosis

Localization Breast carcinoma arises from the mammary epithelium mostly

from the Terminal duct lobular unit (TDLU). Higher frequency of invasive breast cancer in the left breast

with reported to left to right ratio of approximately 1.07 to 1. 40 to 50 % occurs in upper outer quadrant of the breast.

Clinical features Breast abnormalities should be evaluated by triple assessment

including clinical examination, imaging (mammography & ultrasound) tissue sampling by either fine needle aspiration cytology or needle cone biopsy.

Types of Breast Carcinoma (Histopathology based)

Mammographic demonstration of the evolution of a poorly differentiated invasive ductal carcinoma, a circular tumor mass on the mammogram.A Non-specific density in the axillary tail of the right breast, undetected at screening. B 18 Months later: >30 mm ill defined, high density lobulated tumor, mammographicallymalignant. Metastatic lymph nodes are seen in the axilla. C Large section histology of the tumor.

Spectrum of histological diagnosis corresponding to mammographic circular/oval lesions.Source: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Source: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Types of Breast CancerEpithelial tumors

Myoepithelial lesions

Mesenchymaltumors

Fibroepithelialtumors

Tumors of the nipples

Malignantlymphoma

Metastatic tumors

Invasive breast carcinomaInvasive ductal carcinoma

Invasive lobular carcinomaTubular carcinoma Invasive cribriform carcinomaMedullary carcinomaMucinous carcinomaInvasive papillary carcinomaInvasive micropapillary carcinomaApocrine carcinomaMetaplastic carcinoma

Lobular NeoplasiaIntraductal proliferative lesionsMicroinvasive carcinomaIntraaductal papillary neoplasmsBenign epithelial proliferations Adenosis Radial scar / complex Sclerosing lesion

Mixed type carcinomaPleomorphic carcinomaCarcinoma with osteoclastic giant cellsCarcinoma with choriocarcinomatous featuresCarcinoma with melanotic features

Pure epithelial metaplastic carcinoma Squamous cell carcinoma Adenocarcinoma with spindle cell metaplasia Adenosquamous carcinoma Mucoepidermoid carcinomaMixed epithelial metaplastic carcinoma

Haemangioma

Angiomatosis

Haemangiopericytoma

Pseudoangiomatous stromal hyperplasia

Myofibroblastoma

Fibromatosis

Inflammatory myofibroblastic tumor

Lipoma

Granular cell tumor

Myoepitheliosis

Adenomyoepithelial adenosis

Adenomyoepithelioma

Malignant Myoepithelioma

Fibroadenoma

Phyllodes tumor Benign Borderline MalignantPeriductal stromal sarcoma

Mammary hamartoma

Nipple adenoma

SyringomatousAdenoma

Paget disease ofthe nipple

Diffuse large B-cells lymphoma

Burkitt lymphoma

Follicular lymphoma

Extranodal marginal-zone B-cell lymphoma of MALT type

Invasive breast carcinoma

[A] EPITHELIAL TUMORSInvasive breast carcinoma It is a group of malignant epithelial tumors characterized by

invasion of adjacent tissues and marked tendency to metastasize to distant sites.

Mainly adenocarcinomas. Derived from mammary parenchymal epithelium cells of TDLU

(terminal duct lobular unit).

1. Invasive ductal carcinomas Lack of regularity of structure. Predominantly solid or syncytial infiltration pattern with little

associated stroma. Glandular differentiation may be apparent as tubular structures

with central Lumina. Cytoplasm abundant and eosinophilic. Nuclei may be regular uniform or highly pleomorphic with

prominent. 80 % ductal carcinoma insitu present. Multiple nucleoli mitotic activity may be virtually absent or

extensive. Highly cellular fibroblastic proliferation, a scanty connective

tissue element, marked hyalinization. Foci of elastosis may be present Focal necrosis present.

Well differentiated infiltrating ductal carcinoma, Grade 1. A First screen. Inframammary lymph node and small (<5 mm), nonspecific density. B Secondscreen: 20 months later. The density has grown a little. C Third screen: after another 29 months. The 10 mm tumor is more obvious but still not palpable. Invasive ductal

carcinoma, not otherwisespecified. 84 year old patient, mastectomy specimen.Source: http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Invasive breast

carcinoma

Mixed infiltrating ductal and infiltrating lobular carcinoma. Two distinct morphologic patterns are seen in this tumor, ductal on the left and lobular on the right.

a. Mixed type carcinoma Both infiltrating ductal & lobular carcinoma

b. Pleomorphic carcinoma Proliferation of pleomorphic and bizarre tumor giant cells. 75% of the tumor cells in a background of adenocarcinoma with

spindle and squamous differentiation. Cavitation and necrosis occur in larger tumor

c. Carcinoma with osteoclastic giant cells Presence of osteoclastic giant cells in the stroma. The giant cells are generally associated with an inflammatory

fibroblastic, hyper vascular stroma, extravasated red blood cells, lymphocytes, monocytes along with mononucleated and binucleated histiocytes containing haemosiderin.

Invasive ductal carcinoma: pleomorphic carcinoma. A Poorly differentiated cells without distinctive architecture often lead to misinterpretation of thelesion as a sarcoma. B Immunostain for keratin (AE1/AE3 and LP34) confirms the epithelial nature of the process.Source: http://www.iarc.fr/en/publications/pdfs-online/pat- gen/bb4/bb4-chap1.pdf

Invasive carcinomas with stromal osteoclastic giant cells often have vascular stromal tissue with hemosiderin pigment accumulation giving them a brown macroscopic appearance.


Giant cells uniform expression of CD68, negative for S100 protein, actin, cytokeratin, EMA, estrogen, progesterone receptor.

Strongly positive for acid phosphate, non specific esterase, lysozyme but negative for alkaline phosphatase.

Tumor associated macrophages (TAM) are capable of differentiating into multi nucleated cells which can affect bone resorption in metastases.

d. Carcinoma with choriocarcinomatous features Elevated levels of serum human β- chorionic gonadotrophin (β-

HCG) Carcinoma found 60% in β-HCG positive cells.

e. Carcinoma with melanotic features Mammary parenchymal tumor represent combinations of ductal

carcinoma and malignant melanoma. Melanin pigmentation of carcinoma cells can occur when breast

cancer invade the skin and involve the dermo-epidermal junction.

Melanocytic differentiation from breast carcinomas with prominent cytoplasmic lipofuscin deposition.

2. Invasive lobular carcinoma An invasive carcinoma usually associated with lobular

carcinoma insitu is composed of non cohesive cells individually dispersed or arranged in single file linear pattern in a fibrous stroma.

A Invasive ductal carcinoma with stromal osteoclastic giant cells and hemosiderin-laden macrophages. B The invasive ductal carcinoma is low grade.Multinucleated giant cells are evident in the stroma.

Carcinoma with choriocarcinomatous features. A,B Multinucleated tumor cells with smudged nuclei extend their irregular, elongated cytoplasmic processes around clusters of monocytic tumor cells, mimicking the biphasic growth pattern of choriocarcinoma. B Note the abnormal mitotic figures in this high grade carcinoma.


Mammography of invasive lobular carcinoma. A Architectural distortion in the axillary tail, corresponding to a palpable area of thickening. B Magnification view of the architectural axillary distortion.

In situ and invasive lobular carcinoma.The larger cells on the left and lower part of the field are invasive tumor cells.

A Invasive ductal carcinoma with stromal osteoclastic giant cells and hemosiderin-laden macrophages. B The invasive ductal carcinoma is low grade.Multinucleated giant cells are evident in the stroma.

Carcinoma with choriocarcinomatous features. A,B Multinucleated tumor cells with smudged nuclei extend their irregular, elongated cytoplasmic processes around clusters of monocytic tumor cells, mimicking the biphasic growth pattern of choriocarcinoma. B Note the abnormal mitotic figures in this high grade carcinoma.

Mammography of invasive lobular carcinoma. A Architectural distortion in the axillary tail, corresponding to a palpable area of thickening. B Magnification view of the architectural axillary distortion.

In situ and invasive lobular carcinoma.The larger cells on the left and lower part of the field are invasive tumor cells.

A Invasive lobular carcinoma. B Loss of E-cadherin expression is typical of lobular carcinoma cells. Note immunoreactivity of entrapped normal lobules.C Large number of signet ring cells and intracytoplasmic Lumina (targeted secretion).

Loss of E-cadherin expression is typical. Tumor cells arranged in globular

aggregates of atleast 20 cells.

Analysis of E-Cadherin expression may help to divide these cases between ductal and lobular tumors.

Tubular carcinoma. Specimen X-ray.Source:

http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

Tubular breast carcinoma 3. Tubular carcinoma

A special types of breast carcinoma with a particularly favourable prognosis composed of distinct well differentiated tubular structure with open Lumina lined by a single layer of epithelial cells.

Presence of open tubules composed of a single layer of epithelial cells enclosing a clear lumen.

Myoepithelial cells are absent but some tubules may have an incomplete surrounding layer of basement membrane component.

Apical snout is present.

Tubular carcinoma. A There is a haphazard distribution of rounded and angulated tubules with open lumens, lined by only a single layer of epithelial cells separated by abundant reactive, fibroblastic stroma. B The neoplastic cells lining the tear-drop shaped tubules lack significant atypia.


Invasive cribriform carcinoma. The haphazard distribution of irregularly shaped and angulated invasive areas is in contrast with the rounded configuration of the ducts with cribriform DCIS on the left side of the field.

4. Invasive cribriform carcinomaGrows in cribriform pattern

5. Medullary carcinoma Poorly differentiated cells arranged in large sheets, with no

glandular structures scant stroma and a prominent lymphoplasmacytic infiltrate.

Syncytial, glandular or tubular structures absent, carcinoma cells are round with abundant cytoplasm and vesicular nuclei.

Medullary carcinoma. The tumour is composed of a syncytial sheet of large pleomorphic cells. There is no glandular differentiation. The adjacent stroma contains numerous plasma cells and mature lymphocytes.

Medullary carcinoma. Mammogram showing a typical rounded, dense tumor without calcifications.

Medullary carcinoma. Note multinucleated malignant cells with atypical mitoses.


6. Mucin producing carcinomasProduction of abundant extracellular or intracellular mucin, along with mucinous carcinoma, mucinous cystadenocarcinoma, columnar cell mucinous carcinoma and signet ring cell carcinoma. Carcinoma are various types of it.

Criteria for the differential diagnosis of mucin producing carcinomas.

Mucinous carcinoma. 38 year old patient, tumor excision.

Mucinous carcinoma. A Hypercellular variant with large clusters of densely packed malignant cells. B Hypocellular variant. Lakes of mucus are separated by fibrous septae. A few isolated or clusters of carcinoma cells are floating inthe mucus lakes.


7. Neuroendocrine tumorAlveolar structure on solid sheets of cells having tendency to produce peripheral palisading.

(a) Solid neuroendocrine carcinoma Densely cellular, solid nests, and trabecular of cells are found. Vary from spindle to plasmacytoid and larger clear cells

separated by delicate fibro vascular stroma.(b) Small cell/ oat cell carcinoma Tumors are composed of densely packed hyperchromatic cells

with scant cytoplasm and infiltration growth pattern. Nuclear streaming occur Lymphatic tumor emboli are frequently encountered.(c) Large cell neuroendocrine carcinoma Crowded large clusters of cells, abundant cytoplasm, nuclie with

vesicular to finely granular chromatin. Neuroendocrine differentiation.(d) Atypical carcinoid tumor Solid neuroendocrine carcinoma.

8. Invasive papillary carcinoma Delicate or blunt papillae, focal solid areas Cells show amphiphilic cytoplasm having apocrine features Nodular densities which may be multiple and are frequently

lobulated.

Neuroendocrine carcinoma. A Tumor cells are polarized around lumina; some cells show eosinophilic granules – carcinoid-like pattern. B IHC staining is positive for chromogranin.

Neuroendocrine carcinoma of the breast. Alveolar pattern with rounded solid nests of spindle cells invading a dense collagenous stroma.

Invasive papillary carcinoma. A Microfocus magnification image of a papillary carcinoma shows a low density rounded tumor. B Large section histology.C Ultrasonography shows a lobulated, well delineated lesion.Papillary carcinoma with

invasion. A Overview of an intraductal papillary carcinoma, present at the centre, with invasive carcinoma apparent in the upper right side of the lesion. B Higher magnification shows an infiltrating duct carcinoma pattern by the invasive component of the lesion while the in situ region is clearly papillary.


9. Invasive micro papillary carcinoma Carcinoma composed of small cluster of tumor cells lying with in

clear stromal spaces resembling dilated vascular channels. Hollow aggregates of malignant cells, appearance of tubules with

diminished or obliterated lumens rarely containing pyknotic nuclei.

Lymph node metastable and malignant cells in pleural fluid.

10.Apocrine carcinoma A carcinoma showing cytological and immunohistochemical

features of apocrine cells in more than 90% of the tumor cells. Type A cell have intensely eosinophilic cytoplasm acid-Schiff

positive after diastase digestion. Type B cells shows abundant cytoplasm fine empty vacuoles are

seen, resemble histiocytes and sebaceous cells.

Invasive micro papillary carcinoma. Tumor cell clusters with irregular central spaces proliferate within empty stromal spaces. Some clusters have reversed polarity with an “inside out” morphology.

Apocrine carcinoma. Note abundant eosinophilic cytoplasm and vesicular nuclei.

Apocrine carcinoma, superficially resembling a granular cell tumor.

Apocrine carcinoma. Immunostaining shows intense positivity for GCDFP-15.


11. Metaplastic carcinomaHeterogeneous group of neoplasms intimate admixture of adenocarcinoma with dominant areas of spindle cells, squamous, mesenchymal differentiation.

(a) Pure epithelial metaplastic carcinomas (1) Squamous cell carcinoma- Breast carcinoma entirely composed of metaplastic squamous cells may be keratinizing , non keratinizing or spindled.(2) Adenocarcinoma with spindle cell metaplasia- Abundant spindle cell transformation. Glandular in nature.(3) Adenosquamous carcinoma- Areas of well developed tubule or gland formation having solid nests of squamous differentiation. (4) Low grade squamous carcinoma- Small glandular structures and solid cords of

epithelial cells haphazardly arranged.(b) Mixed Epithelial/ mesenchymal metaplastic carcinomaCarcinoma with osseous metaplasia, chondroid metaplasia, carcinosarcoma (1) Lipid Rich Carcinoma- Approximately 90% of neoplastic cell containing cytoplasmic neutral lipid.(2) Secretory carcinoma- Secretion of abundant intra and extra cellular (milk like) secretory material.

Low grade Adenosquamous carcinoma / infiltrating syringomatous adenoma. A highly infiltrative growth pattern is responsible for the high frequency of local recurrence associated with many lesions.

A Metaplastic carcinoma with chondroid differentiation, 77 year old patient, mastectomy. B Carcinoma with mesenchymal (benign osseous and chondroid) differentiation. Typically, these carcinomas have a well delineated pushing margin. Areas of osseous and/or chondroid differentiation are variably scattered in an otherwise typical infiltrating ductal carcinoma. C Carcinomawith mesenchymal (benign osseous and chondroid) differentiation. The adenocarcinoma is admixed, in part, with chondroid matrix containing lacunar spaces and rare chondrocytes.

Secretory carcinoma. The tumor cells have abundant pink eosinophilic cytoplasm.


Low grade Adenosquamous carcinoma / infiltrating syringomatous adenoma. A highly infiltrative growth pattern is responsible for the high frequency of local recurrence associated with many lesions.

Oncocytic carcinoma. Note well circumscribed nodule and cells with abundant eosinophilic cytoplasm.

(3) Oncytic carcinoma- Oncytic cells.(4) Acinic cell carcinoma- occur parotid gland and acinic cell (serous).(5) Glycogen rich clear cell-cells containing glycogen

(f)Sebaceous carcinoma(g)Inflammatory carcinoma

Acinic cell carcinoma showing aggregates of cells with granular cytoplasm.

Acinic cell carcinoma showing aggregates of cells with granular cytoplasm.

Glycogen-rich carcinoma. A Cells with abundant clear cytoplasm and relatively uniform round nuclei grow in a solid pattern supported by branching vessels.

Source: http://www.iarc.fr/en/publications/ pdfs-online/pat-gen/bb4/bb4 chap1.pdf

Sebaceous carcinoma. The cells have abundant finely vacuolated cytoplasm and form rounded aggregates with a few amphophilic cells present in the periphery.

Inflammatory Carcinoma

12. Lobular NeoplasiaTerm refers to atypical epithelial proliferations originating in the terminal duct lobular unit (TDLU).

Early lobular neoplasia. A The few neoplastic lobular cells are hardly apparent on a quick examination of the TDLU. B Double immunostaining with E-cadherin (brown) and CK34BE12 (purple) unmasks the few neoplastic cells (purple) proliferating in this lobule. These early lesions are often missed on H&E stained sections.

Lobular neoplasia. A Aggregates of loosely cohesive neoplastic cells proliferate beneath the native epithelial cell lining (pagetoid growth pattern). B Typically, the neoplastic cells are E-cadherin negative. C Immunostain for CK34BE12 shows a polarized positive reaction in the cytoplasm.

Lobular neoplasia. CK5/6 immunohistochemistry demonstrating the pagetoid spread of tumor cells infiltrating the positively stained original epithelium, leading to a reticulated staining pattern.

Lobular neoplasia. A The acini are filledand moderately distended by neoplastic cells; theacinar outlines are retained. B Clover-leaf pattern.This is one of the classic patterns of LN, with theacini distended by neoplastic cells pulling awayfrom the intralobular segment of the terminal duct,creating a clover-leaf or necklace appearance.

Usual ductal hyperplasia. A Florid type. The peripheral distribution of irregularly sized spaces is acharacteristic of UDH readily apparent at low magnification.

Flat epithelial atypia. A terminal duct-lobular unit with distended acini and a floccular secretory luminal content. The spaces are lined by one to three layers of monotonous atypical cells.

Atypical ductal hyperplasia. A Two adjacent ducts showing partial cribriform involvement in a background of flat epithelial atypia. B Partial involvement of a duct by a cribriform proliferation of uniform, rounded cells in the setting of a flat epithelial atypia. Microcalcification is also present.

13.Intraductal proliferative lesionsLesions are diverse proliferations originating from the terminal duct lobular unit and confined to the mammary duct lobular system.Categories-

a. Usual ductal hyperplasia (UDH)Irregular peripheral fenestrations, stretched or twisted epithelial bridges, streaming, uneven distribution of nuclei.b. Atypical ductal hyperplasia (ADH)Monomorphic large cells, numerous.c. Ductal carcinoma in Situ (DCIS)Large cells, neurosis, nuclear grade.


14. Microinvasive Carcinoma Dominant lesion is non-invasive. Separate small, microscopic foci of infiltration into non-specialized

interlobular stroma.

Other lesions are specific to the nipple areolar complex.a.Adenosis Frequent, benign, proliferative process affects mainly the lobular

(acinar) component of the breast parenchyma. Distoration of the glands. Various types of adenosis are described below. Proliferation of acinar or tubular structure.

1. Sclerosing adenosis- Proliferation of acini with preservation of the luminal epithelial and peripheral myoepithelial cell layer along with basement membrane.2. Apocrine-Adenosis with apocrine metaplasia.

Micro invasive carcinoma. A A small focus of invasive carcinoma barely 0.8 mm in maximum extent is present adjacent to an aggregate of ducts displaying mainly flat epithelial atypia.

15. Intraductal papilloma Proliferation of epithelial and myoepithelial

cells overlying fibro vascular stalks creating an arborescent structure with in the lumen of a duct.

Types: (a) Central- Subareolar region (b) Peripheral-arising in TDLU.

16. Benign epithelial proliferations Mainly arises in the terminal duct lobular unit

(TDLU). Large ducts in the central region in the 90%

case.

Distribution of papilloma in breast.

Sclerosing adenosis. The myoepithelial cells are prominent with Immunostain for smoothmuscle actin.

Apocrine adenosis/sclerosing adenosis with apocrine metaplasia and focal atypia. B Immunostain for actin demonstrating myoepithelial cells around the tubules. C Typical apocrine metaplasia in Sclerosing adenosis, characterized by a three-fold nuclear size variation.Source: http://www.iarc.fr/en/publications/ pdfs-online/pat-gen/bb4/bb4 chap1.pdf

3. Blunt duct- Adenosis with variable distension of lumens showing columnar cell metaplasia.

4. Micro glandular- Diffuse haphazard proliferation of small round glands.

5. Adenomyoepithelial adenosis- Adenomyoepithelioma

(b) Radial scar/ complex Sclerosing lesion- Complex Sclerosing lesions, hyalinized and elastotic tissues.

(1) Tubular adenoma- Nodules formed by proliferation of tubular structures.

(2) Lactating adenoma- During lactation epithelial cells of tubular adenoma show extensive secretion and lesions

(3) Apocrine adenoma- Nodular adenosis with apocrine metaplasia.

(4) Ductal adenoma- Benign glandular proliferation

Blunt duct adenosis, typical morphology.

Micro glandular adenosis. An extensive lesion that presented as a palpable mass; the characteristicopen lumens of the tubules and the colloid-like secretory material are apparent, providing clues to the nature of the process.

Adenomyoepithelial adenosis. A Prominent clear myoepithelial (ME) cells are evident around several ductules. B Both the clear and normal ME cells are intensely immunoreactivity for S-100 protein.

Tubular adenoma. A The fibrous capsule is present in the left upper corner. B Higher magnification displays epithelial and myoepithelial cell lining of the tubules.

Lactating adenoma. Epithelial cells show extensive secretory changes (A, B).

Ductal adenoma, characterized by a “polypoid “ protrusion into a distended

duct; a few papillary projections are evident (arrow).

[B] MYOEPITHELIAL LESIONS Dominant lesions on myoepithelial cells. Abundant eosinophilic cytoplasm proliferate around the

epithelial cells compressing the ductular lumens. Various types of this are tabulated below:

HISTOPATHOLOGY

1. Myoepitheliosis- Proliferation of spindle to cuboidal myoepithelial cells growing into and /or around small ducts and ductules.

2. Adenomyoepithelial adenosis-Diffuse proliferation of round or irregular tubular structures lined by cuboidal to columnar epithelium, apocrine metaplasia present. 3. Adenomyoepithelioma- Proliferation of layers of sheaths of ME cells around epithelial lined spaces spindle cell, tubular, lobulated growth pattern of the tumors.4. Malignant Myoepithelioma-Tumor composed purely of spindle shaped of myoepithelial cells with identifiable mitotic activity. Aggregation of collagen.

Myoepitheliosis, periductal type. A The myoepithelial cells with abundant eosinophilic cytoplasmproliferate around the epithelial cells compressing the ductular lumens. This change is often multifocal.B Immunostain for actin is positive in the myoepithelial cells, but negative in the epithelial-lined compressedductular spaces.

Adenomyoepithelioma, spindle cell type. A There is a solid proliferation of spindled myoepithelial cells surrounding irregular epithelial lined spaces.

Adenomyoepithelioma, adenosis type. A At least focally well delineated, these tumors superficially resemble a tubular adenoma.

Malignant myoepithelioma (myoepithelial carcinoma). A The lesion is composed of spindle cellslacking significant atypia or mitotic activity. B At the periphery of the same lesion, often a more epithelioid or plump cell population is evident emanating from the myoepithelial cell layer of the entrapped ductules.


[C] MESENCHYMAL TUMORS Benign and malignant mesenchymal tumor morphologically

similar to those occurring in the soft tissues as well as predominantly in the breast.

Different types are described.

HISTOPATHOLOGY

1. Haemangioma- Benign tumor or malformation of mature vessels.2. Angiomatosis- Excessive proliferation of well formed vascular channels affecting a large area in a contiguous fashion. 3. Haemangiopericytima- Circumscribed area of bland ovoid to spindled cells proliferating around branching and stag horn’ vessels.4. Pseudoangiomatous stromal hyperplasia- Benign lesion consisting of complex slit-like pseudovascular spaces, that are either acellular or lined by slender spindle shaped stromal cells.5. Myofibroblastoma- A benign spindle cell tumor of the mammary stroma composed of myfibroblasts.6. Fibromatosis- Lesion originates from fibroblasts and myofibroblasts within breast parenchyma.7. Inflammatory myofibroblastic tumor- Tumor composed of differentiated myofibroblastic spindle cells accompanied by numerous inflammatory cells.8. Lipoma- A tumor composed of mature fat cells without atypia.9. Granular cell tumor- Tumor of putative schwannian origin consisting cell with eosinophilic granular cytoplasm.

Perilobular haemangioma. Thin walled vessels lined by flattened endothelium are seen within the intralobular stroma.


[D] FIBROEPITHELIAL TUMORS Heterogeneous lesions combining an epithelial component and

a quantitatively predominant mesenchymal component. It has two types-1. Fibroadenoma- Admixture of stromal and epithelial proliferation, intracanalicular growth pattern due to compression of the ducts into clefts by the proliferating stromal cells, lobulated, bulging cut surface. 2. Phyllodes tumors- Double layered epithelial component arranged in clefts surrounded by an overgrowing hyper cellular mesenchymal component typically in leaf like structure.

A Fibroadenoma showing lobulated, bulging cut surface. B Fibroadenoma with intracanalicular growth pattern.

Phyllodes tumor. A well circumscribed 6.5cm mass with a few clefts was histologically benign.

Benign Phyllodes tumor. A Leaf-like pattern and well defined interface with the surrounding normal tissue. B Higher magnification shows stromal cellularity.

Main histologic features of the 3 tiered grading subgroups for phyllodes tumors.Source: http://www.iarc.fr/en/publications/ pdfs-online/pat-gen/bb4/bb4 chap1.pdf


3. Mammary hamartomas- A well demarcated, generally encapsulated mass, composed of all components of breast tissues.

[E] Tumors of the nipplesThree types:

1. Nipple adenoma- Compact proliferation of small tubules lined by epithelial and myoepithelial cells with or without the proliferation of the epithelial component around the collecting ducts of the nipple.

2. Syringomatous adenoma- A non metastasizing locally recurrent invasive tumor of the nipple/ areolar region showing sweat duct differentiation.

3. Paget diseases of the nipple- Presence of malignant glandular epithelial cells with in the squamous epithelium of the nipple, is almost associated with underlying intraductal carcinoma, involving more than one lactiferous duct and distant ducts, deep in underlying breast.

Adenoma of the nipple. A compact aggregate of tubules replaces the nipple stroma.

Syringomatous adenoma of the nipple. A Irregular shaped glandular structures are present between smooth muscle bundles.

Paget disease of the nipple. A Atypical cells with clear cytoplasm admixed with those with dense cytoplasm.

[F] Malignant lymphoma and metastatic tumors

1. Malignant lymphoma- Diffuse large B cell lymphomas. Circumscribed mass, large pleomorphic neoplastic lymphoid cells present.2. Metastatic Tumor- When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original or primary tumor. This means, for example, that, if breast cancer metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells.

[G] Tumors of the Male BreastMuch less than women.There are three types of lesions are found-1. Gynecomastia- Non-neoplastic, enlargement of rudimentary duct system in male breast tissue with proliferation of epithelial and mesenchymal components.

2. Carcinoma- Rare malignant epithelial tumor.

3. Metastatic tumor- Almost all breast tumor which occur in women have also reported in men, albeit rarely.

Diffuse large B-cell lymphoma. A Medullary carcinoma-like appearance. B Circumscribed mass, composed of large pleomorphic neoplastic lymphoidcells.Source: http://www.iarc.fr/en/publications/

pdfs-online/pat-gen/bb4/bb4 chap1.pdf

BRCA1 & BRCA2The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 and BRCA2 genes. In normal cells, these genes help prevent cancer by making proteins that help keep the cells from growing abnormally. Mutated versions of these genes cannot stop abnormal growth, and that can lead to cancer.

In some families with BRCA1 mutations the lifetime risk of breast cancer is as high as 80%, but on average this risk seems to be in the range of 55% to 65%. For BRCA2 mutations the risk is lower, around 45%.

Inherited Genes

Today it has become national priorities to develop and organize a conceptual framework for future Research needs to cure and reduce breast cancer beyond medication pathway.For the prevention, the priority of research area accounts following factors:

Population- Statistics of population at high rate of risk. Lifestyle and dieting- Daily routine life style culture,

food habits and exercise are influential factors. Awareness- Effective communication to improvise

awareness at educational level, approaches in clinical practice as well as proper decision making for treatments at its initiation or continuation and understanding of preventive therapies.

Conclusion

Reference

https://biology.mit.edu/research/biochemistry_biophysicshttp://www.bu.edu/bmb/https://www.sciencedaily.com/news/matter_energy/biochemistry/https://www.sciencedaily.com/releases/2016/10/161019101202.htmhttps://www.sciencedaily.com/releases/2016/10/161019082535.htmhttps://www.ncbi.nlm.nih.gov/pubmed/11522269https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr268http://www.sciencedirect.com/science/article/pii/S0009912011027433http://www.sciencedirect.com/science/article/pii/S0009912000002010http://www.who.int/cancer/detection/breastcancer/en/https://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb4/bb4-chap1.pdf

-Thank you

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Healthcare

Pathophysiology of breast cancer