PREMALIGNANT CONDITION OF BREAST AND RISK ASSESSMENT IN BREAST CARCINOMA

​

By

Professor. Pranab.Kumar. Bhattacharya

Professor and Head Department of Pathology School of Tropical Medicine 108 CR Avenue Kolkata-73

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DEFINATION

A premalignant lesion can be **defined as one that is not itself malignant, but has a greater probability of becoming malignant than normal tissue.

​

TDLU

BC usually arise in a multi-step fashion through a series of intermediate lesion, each of which has a greater chance of becoming malignant than the preceding one �

Mamographic screening�

has led to increase detection of premalignant breast disease. �

In situ carcinomas and

Atypical hyperplasia are �not the only abnormalities thought to be precancerous , but

Some commonly associated benign lesion also appears to be associated with increased cancer risk

​

​

HOW TO KNOW ?

• Animal Experiment
• Review of human H.P. material
• Genetic analysis

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�Animal Experiment�

• Mouse mammary tumor model.
• Murine mammary tumor virus (MuMTV)
• Normal epithelium
• HANs
• carcinoma.

​

Review of human �H.P. material�Provide indirect evidence by

• Identifying morphological feature of benign lesion that are shared with carcinoma.
• Identifying morphological transition between benign and malignant lesion.
• Comparing incidence of benign changes in cancerous and non-cancerous breasts.
• Comparing incidence of benign changes in populations with different risk of developing breast cancer.
• Following up patients with putative premalignant lesions

Genetic Analysis�genetic changes between malignant and other lesion�

Sharing of

It is assumed that the various steps in the development of cancer are characterized by the acquisition of irreversible genetic changes. If the lesions are precancerous, they will show some genetic change with the cancer in to which they evolve. If the lesion exhibit genetic change not found in cancer, it is highly unlikely to be a precursor of the particular type of tumor

FIBROCYSTIC CHANGES

FIBROADENOMA AND VARIENT

ADENOMA

SCLEROSING LESION

DUCT PAPILLOMA AND RELATED CONDITION

PROLIFERATIVE BREAST LESIONS

• Sclerosing adenosis
• Microglandular adenosis
• RS
• CSL

• DUCTAL

HUT

ADH

DCIS

• LOBULAR

ALH

LCIS

Cyst formation

Apocrine metaplasia

Fibrosis

Epithelial hyperplasia

Calcification

Chronic inflammation

Fibroadenomatoid change

Adenosis (BDA)

FIBROADENOMA�HAMARTOMA�PHYLLOID TUMOR

Tubular adenoma

Lactating adenoma

Apocrine adenoma

Duct Papilloma

Nipple Adenoma

Ductal adenoma

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PROLIFERATIVE BREAST DISEASE

• DUCTAL
• DCIS
• ADH
• HUT

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• LOBULAR
• LCIS
• ALH

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DCIS

Proliferation of epithelial cells that have undergone malignant transformation but remain at their site of origin , confined by a basement membrane.

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• Page’s Criteria for DCIS are:

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• Uniform (Monomorphic) population of cells.
• Smooth geometric spaces between cells or Micropapillary formation with even cellular placement. (may be tufts, fronds, bridge, solid , cribriform pattern).
• Ovoid to rounded hyperchromatic nuclei.

​

• Full feature should be present at least 2 duct space
• Some suggest that DCIS should involve at least 2 mm area.
• Any lesion failing short of this would be classified as ADH

​

• DCIS with microinvasion is defined by foci of tumor cells less than 0.1 cm in diameter invading the stroma.

Grading

Nuclear characteristics is a better predictor of behaviour than architecture .

• Based on cytological characteristics:
• Grade 1: Small, uniform cell unassociated with necrosis. Classic solid, Cribriform, Micropapillary form fall in this category.
• Grade 3 : Large, Pleomorphic cell associated with necrosis. Classic Comedocarcinoma fall in this category.
• Grade 2 : Showing intermediate feature.

​

MIN/DIN classification

• DIN ( ductal intraepithelial neoplasia.)
• 1a. corresponds to HUT
• 1b. flat epithelial atypia
• 1c. ADH & small grade 1 DCIS
• 2. Large grade 1 DCIS & grade 2 DCIS
• 3. Grade 3 DCIS.
• LIN- LIN1, LIN2, LIN3.
• MIN for the proliferative lesion.

DCIS type :

• Comedocarcinoma
• Cribriform
• Clinging
• Solid
• Papillary
• Micropapillary
• Cystic hypersecretory
• Signet ring cell
• Apocrine DCIS [nuclear pattern, necrosis , architecture, and extent of lesion are the criteria to classify it to DCIS or apocrine atypia.]
• Endocrine DCIS,
• Spindle cell type DCIS.

DCIS

Comedocarcinoma : solid sheets of Pleomorphic cells with high grade nuclei and central necrosis. Necrotic cell membrane commonly calcify, peri ductal fibrosis and chronic inflammation are common.

Cribriform : intraepithelial space are evenly distributed.

DCIS

Cystic, hypercecretory type

Apocrine variety

DCIS

Papillary DCIS. grows in to spaces and commonly lined by fibrovascular core, typically lacking normal myoepithelial layer. There is loss of nuclear polarity, marked hyperchromasia.

Micropapillary form Some of the papillae lack a central fibrovascular core

“Clinging type.” One or two layers of atypical cells line dilated glandular structures containing granular intraluminal material in which ghosts of tumor cells are identified. The cell may be highly Pleomorphic or with individual cell necrosis or may be smaller and more regular.

Solid DCIS

• Completely fill the space by small cell

DCIS

DCIS : Risk

• DCIS- 24-28% develops ca in 6-10 years in different studies, mostly in ipsilateral breast.
• In ca breast, infiltrating and in situ carcinoma are often found side by side and usually exhibit identical cytologic characteristics.
• In follow up study after excision it was found that 50% recurrence include an invasive components.
• DCIS shows gains of 1q, 6q, 8q, 17q, 19q, 20p, 20q and Xq & loss of 13 13q, 16q, 17p, and 22q. These alteration are similar to those identified in invasive carcinoma.
• 80% of DCIS share their LOH (loss of heterozygosity) pattern with the accompanying invasive ca. LOH on 7p, 16q, 17p and 17q found in 25-30% of DCIS.
• C-erb2 amplified in 20% invasive ca. C-erb2 derived protein identified in 60-80% of HNG- DCIS, lower % in LNG- DCIS.
• P53 expression has been demonstrated in HNG_DCIS. TP53 mutation in DCIS is associated with invasive ca, but not in normal breast. This support that DCIS is a precursor of carcinoma.

The duct in the center of the field shows epithelial proliferation with protrusions and rigid arches. The cells are uniform, irregularly arranged with crowding and overlapping. These latter features, together with the involvement of only this one duct, led to a diagnosis of atypical hyperplasia.

ADH

ADH : Exhibit some but not all of the morphological feature of DCIS . Any lesion failing short of Page’s criteria would be classified as ADH

ADH : Risk

​

• ADH found in 62% of malignant biopsy compared to 4% in normal breast.
• Follow up study shows 0-10.3% incidence of BC.
• Page found RR 1.9 in proliferative disease, 5.3 if associated with atypia.
• Cystic breast disease- 1.7 times > chances of developing ca, 2.5 times if associated atypia present, severe atypia - > 5 times risk.
• With positive F/H- 2.7 times risk, 11 times if associated with atypia.
• LOH - 16q & 17p found in Inv. DC and DCIS, also found in ADH with similar frequency.
• LOH- 11q13 - 27.3 % found in DCIS, 9% in ADH.

HUT�( Hyperplasia of Usual type/Epitheliosis/ Papillomatosis/ Non atypical hyperplasia) ; Proliferative disease without atypia.

​

Epithelial hyperplasia is defined by the presence of > 2 cell layer. The proliferative epithelium often include both luminal and myoepithelial cells, fills and distend ducts and lobule.

​

• Mild Hyperplasia: Cell up to 4 layer.
• Moderate : > 4 cell layer, lumen still present. Bridging present.
• Florid : Lumen distended and obliterated. Distinction between moderate and florid is subjective.

​

• Can involve terminal duct, peripheral small duct, or large duct.

​

• HUT are polyclonal, Polymorphic cell population, but ADH are monoclonal uniform cell population.

Moderate epithelial hyperplasia

The proliferating epithelial cells are polymorphic, Intercellular space are irregular

Florid epithelial hyperplasia.

Note the oval shape of the nuclei and the parallel arrangement, resulting in a “streaming” effect.

HUT : Risk

• HUT associated with 1.5-2 times increased RR of developing BC.
• The risk of developing BC in Anglo American is 89/100,000/year, the incidence of HUT among them is 24%, compared to American Indian the Ca risk is 24 and incidence of hut is 2% only.
• LOH in different loci range from 0-15%.
• LOH at 17q – 13% in HUT [ 25-55% in DCIS & ADH ]
• Some HUT is clonal neoplastic proliferation.

LOBULAR NEOPLASIA : ALH & LCIS

All type of carcinoma are thought to originate from TDLU, so the term ‘Ductal’ or ‘Lobular’ do not imply a site or cell type of origin.

​

• Lobular neoplasia is defined as a uniform population of characteristic cells within acini of TDLUs. This cell can fill, distend or distort TDLU. It can involve the adjacent duct in a pagetoid fashion or replace the normal epithelial cells.

​

• Cells :
• small, uniform, round, Resemble acinar epithelial cell .
• Nucleus are small , rounded, regular and lightly staine
• Cytoplasm scanty, indistinct nucleoli. Occasional cells shows intracytoplasmic lumina, these are mucin filled vacules,

​

• ALH & LCIS is best to classify as a single entity, as
• Distinction is arbitrary
• Cell type are identical.

LCIS

​

• Monomorphic small round cell with thin rim of clear cytoplasm and high NC ratio.
• Intracytoplasmic lumina are common.
• Regularly spaced noncohesive cells fill lumen with moderate distension.
• > half of acini in lobular unit have to be distended with no central lumina.
• Pagetoid spread to the interlobular ducts may be seen.

ALH : the criteria set are-��Cells are similar to LCIS with 1/> of the following feature

• Cells only slightly distend lobule.
• Central lumina still identified
• < half acini of the lobule distended
• Other cell type- spindle cell/ WBC may be found within lumen.

LCIS

Typical pattern of involvement of terminal duct–lobular unit by lobular carcinoma in situ.

Involvement of duct by lobular carcinoma in situ.

LCIS

Marked expansion of a lobular unit by lobular carcinoma in situ. A few small spaces are still present in the smaller focus.

The lobular architecture is retained. The acini are distended and distorted by a monomorphic population of cells with loss of cohesion. The lumina are completely obliterated.

The incomplete obliteration of acinar lumina is apparent. The acini show less distention and distortion than in lobular carcinoma in situ.

ALH

LCIS/ALH : Risk

• Up to 2/3 rd cases of LCIS develop Inv.ca by 15-20 years. The risk is bilateral unlike DCIS.
• The risk of invasive carcinoma is half in ALH (4-5 times R.Risk) than LCIS(8-10 times R.Risk).
• E-cadherin : commonly found in inv. Ca & LCIS but not in ALH.
• LOH- in ILC found on 17p(8%), 17q (50%), &16q [30%]. The LOH are also found in LCIS. LOH in 50% of LCIS are associated with ILC.
• 56% of ILC show E-cadherin gene mutation, other ca type does not show. This mutation also found in LCIS .
• Is this LCIS & ALH separate entity? : Study found equal frequency of genetic material loss of 16p, 16q, 17p and 22q, & gain from 6q. This suggest both are different stages of the same disease

SCLEROSING LESIONS

• Sclerosing adenosis
• RS
• CSL
• Microglandular adenosis

Sclerosing Adenosis [SA] : �[ Adenosis tumor/ nodular sclerosing adenosis]

• The number of acini per terminal duct increased to at least twice. The normal lobular arrangement are maintained. The acini are compressed and distorted in centre and dilated at periphery.
• Myoepithelial cell layers are usually prominent. Usually 2 layer of acinar cell are seen but epithelial and myoepithelial cells may proliferate separately.
• Low power : multiple nodular area with overall retention of lobular architecture.
• Diffuse form : several small discrete lobular collections may be seen.
• Nodular form : Distorted lobules are fused together in an ‘organoid ‘ configuration to forma a definite mass lesion.

SA.

At low power, distorted lobules may give the appearance of distinct nodule

Sclerosing Adenosis

the acini of lobular unit proliferate to produce an infiltrative growth pattern, which may be mistaken for Inv.Ca. But-lobular architecture is retained.

Proliferation involve both luminal and myoepithelial cells. ( IHC/CK stain better)

Early cellular and late sclerosing phase of proliferation.

SA

• increased RR 1.7 times, which increased to 6.7 if associated with ADH.
• No adequate molecular genetic data.

Radial scar

• 15-80 yrs. > in pre & perimenopausal age. Multiple , frequently bilateral.
• Characterized by a central nidus of entrapped glands in a hyaline stroma. Central tubular structure are compressed but 2 layers are maintained.
• Early: composed of a group of radiating ductules, surrounded by cellular CT, minimal elastosis. Later in large lesion – accumulation of dense sclerotic fibrous tissue in centre, > elastic tissue.
• Variable degree of epithelial hyperplasia are seen

RS

Flower head appearance. Relatively acellular centre with dilated duct at periphery

RS : Verhoeff-Van Gieson stain

RS and TC

Radial scar

Tubular Carcinoma

Tubular carcinoma shown for comparison. Note the angulated shape of the glands and the desmoplastic stroma in TC.

Complex sclerosing lesions

• Same to Radial scar, with
• Large size > 10 mm
• exhibit wide variety of morphological pattern. There may be foci of Sclerosing adenosis, Papilloma formation, or florid epithelial hyperplasia.

CSL

The central nidus with entrapped tubules in a densly fibrotic stroma surrounded by radiating arms of epithelium with cyst formation

RS/CSL- Risk

• 3% of RS ultimately diagonosed as InCa.
• High incidence of DCIS & LCIS and ADH in patient with RS.
• 17% RS contain foci of DCIS.
• RS are found more in carcinoma patient in same/ contra lateral breast.
• 1.8 times increased risk of developing inv. Ca. in RS patient.
• The risk is not related to the size of the lesion or number.

Microglandular adenosis

Proliferation of small, round, acinar structure – not lobulated, haphazardly arranged and appear to infiltrate fibrous stromal and adipose tissue. Basal myoepithelial cell components are absent. No stromal reaction seen, hyalinization- occasional.

• Gland contain PAS + secretion and periglandular reticulin deposition.

DD with TC:

• Tc have distinctive stellate configuration with central elastosis and fibrosis.
• TC- gland are irregular, angulated, branching.
• TC- cells are larger, > eosino. Cytoplasm, apical snouts
• Glandular secretion are rare

Risk: 25% had coexistant carcinoma, but inadequate data.

MGA

Haphazardly arranged tubules, containing eosinophillic PAS positive secretions, are lined by a single layer of cytologically benign luminal epithelium. This can be contrasted with the adjacent ducts and acini where a myoepithelial layer is apparent.

DUCT PAPILLOMA AND RELATED CONDITION

​

Intraductal Papilloma

​

A fronded fibrovascular core attached by a stalk to the duct wall. Frond are covered by 2 type of epithelial cell ; Outer cuboidal/ columnar secretory cells and Inner- myoepithelial cell layer.

• 35-55 years age group.
• 2 sub groups :
• Central lesion- arise from main duct – usually single, No increased risk of ca.
• Peripheral – Multiple, arise from TDLU. Increased RR of carcinoma.

Intraductal Papilloma

Nipple Adenoma

Ductal adenoma

Intraductal papilloma

Central fibrovascular core extends from wall

HP view

Risk

• There is controversy about increased risk in solitary papilloma, the risk is same as proliferative disease without atypia.
• Multiple papilloma are associated with increased malignancy. 1/3rd to 1/4th have associated ca, usually intraductal, cribriform, or papillary, with low to intermediate grade.
• Study shows 15% develop carcinoma in 4 - 9.5 years.

Nipple Adenoma

• Also known as florid papillomatosis, a variant of intraductal papilloma involving the terminal portion of the galactophorous duct.
• Usually unilateral in 4th or 5th decade. There is marked papillomatous change associated with distortion induced by dense stroma.
• Rarely measure 1-1.5 cm
• A cellular stroma accompanies the proliferative process, and at the periphery a pseudo infiltrative pattern of entrapped tubule can be seen.

​

• 3 pattern
• Sclerosing papillomatosis (with dense stroma)
• Papillomatosis ( without stroma)
• Adenosis (least common)

Nipple adenoma

Consists of diffuse, papillary ductal epithelial proliferation often intermingled with adenomatous area. The epithelium are 2 cell layer with a variable degree of secretary epithelial hyperplasia, mainly of usual type.

RISK

​

• Intraductal papillary carcinoma and ordinary inv.ductal ca can also occur in this location, some of them arise from nipple adenoma.
• Some cases are associated with carcinoma.
• Study found 14% had concurrent carcinoma. 1% case develop ca subsequently.

FIBROADENOMA AND VARIENT �

FIBROADENOMA�HAMARTOMA�PHYLLOID TUMOR

FIBROADENOMA�Proliferation of loose stromal connective tissue with glandular elements.

Morphological variety;

• Calcification/hyalinization
• Giant cell in stroma
• Stroma of adipose tissue, Sm ms., metaplastic cartilage.
• Myxoid
• Hemorrhagic infract
• Apocrine metaplasia
• Sclerosing adenosis
• Squomous metaplasia
• Lactational change
• Giant /Juvenile Fibroadenoma

Complex FA

​

FA with cyst >3 mm

​

Sclerosing adenosis

​

Epithelial calcification

​

Papillary apocrine change

FIBROADENOMA

FA, low power wiew

With apocrine metaplasia

FIBROADENOMA

RISK

​

• Complex FA [ FA with cyst/ sclerosing adenosis/ epithelial calcification] has increased RR of 3.1 and 3.7 if F/H of BC present.
• Epidemiologic study suggest app. 2 fold increase of RR in FA in some study, however most opinion is that non complex FA - has no increased risk.

ADENOMA

• Tubular adenoma- lined by a single layer of epithelial cells and an attnuated layer of myoepithelial cells
• Apocrine adenoma- consists of exclusively of apocrine cells.

• Lactational adenoma- proliferating cells are lined by actively secreting cuboidal cells.

Tubular adenoma

Lactational adenoma

Apocrine adenoma

Risk

• ATYPICAL APOCRINE ADENOMA :
• Relative risk- 5.5, > in women over 60, less in young age.
• Other date inadequate

FIBROCYSTIC CHANGES

This arise from TDLU. There is a combination of breast changes, which include

• Cyst formation
• Apocrine metaplasia
• Fibrosis
• Calcification
• Chronic inflammation
• Epithelial hyperplasia
• Fibroadenomatoid change
• Adenosis ( Blunt duct) [Sclerosing/Nodular /Microglandular adenosis included in the SL group in some text ]

Risk

Cystic breast disease- 1.7 times > chances of developing ca.(?)

Pure apocrine changes is currently regarded as carrying a low but significant risk of developing ca breast.(?)

ADENOSIS (Blunt duct adenosis.)- No risk

The acini are dilated with hypertrophy of both luminal and myoepithelium. The former shows columnar-cell metaplasia with apical snouting. The lobular architecture and specialized intralobular stroma are retained.

Terminology

• Adenosis :An increased number, or enlargement, of glandular components
• Epithelial hyperplasia (papillomatosis/epitheliosis): An increased number of epithelial cells within preexisting glandular components
• Cysts: Pathologically dilated sacs lined by epithelium and containing fluid
• Epithelial metaplasia: Change from one fully differentiated type of epithelium to another not normally found at that site
• Papilloma: A structure composed of fibrovascular cores covered by epithelium

​

Cyst formation�with Apocrine metaplasia

FC change

HAMARTOMA

​

• Predominate in perimenopausal age, clinically confused with FA and Phylloid tumor.

​

• composed of variable mixure of CT stroma and usually normal configuration breast lobule. Islands of adipose tissue found frequently, called ‘Adenolipoma’

​

• Entirely benign, do not recur after adequate excision.

PHYLLOID TUMOR

• Composed of 2 major elements.
• Clefts lined by epithelial cells. Consists of 2 layer- benign Epithelial and myoepithelial cells. Epithelial cell may show hyperplasia.
• Stroma are more cellular than Fibroadenoma. Stroma may be Benign, Boarderline or Malignant.

PHYLLOID TUMOR

• Malignant:
• Infiltrative margin
• Marked stromal overgrowth
• High cellularity and pleomorphism
• Mitotic counts > 10/10HPF.
• Benign:
• Minimal stromal overgrowth & cellularity
• Pushing margin
• Mitotic count < 10/10HPF
• Borderline: Feature in between.

PHYLLOID TUMOR

• Lipophylloid tumor: when stroma admix with mature adipose tissue foci.

​

• Neoplastic stromal components may be monomorphic or Pleomorphic, may appear like- Fibrosarcoma, MFH, Liposarcoma, may show metaplastic bone, cartilage etc.

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• IHC- CD34 & bcl-2 expression

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• Nearly all are PR+, 33% ER+

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• Metastasis by Phylloid tumor are rare & consists of only stromal elements, to Lung, Bone & CNS

PHYLLOID TUMOR

Phylloides tumor with adipose tissue differentiation of the neoplastic stromal component.

Flat epithelial atypia.

The spaces are dilated and lined by columnar epithelium showing scanty atypia.

AckNowledgment _: To my Sweetest Daughter Miss UPasna Bhattacharya

Dedication of this lecture- To my Diseased parents Late Bholanath Bhattacharya(1926-2009) and Late Mrs Bani Bhattacharya(1935-2006)

Acknowledgement-: To my only daughter

Miss Upasana Bhattacharya