Preface

Agam is a group of budding medicos, who are currently doing their under graduation in
various Medical Colleges across Tamil Nadu and Pondicherry. The group was initiated on 18th
November 2017, in the vision of uniting medicos for various social and professional causes.

We feel delighted to present you Agam Pathology notes prepared by Agam Divide and Rule
2020 Team to guide our fellow medicos to prepare for university examinations.

This is a reference work of 2017 batch medical students from various colleges. The team
took effort to refer many books and make them into simple notes. We are not the authors of the
following work. The images used in the documents are not copyrighted by us and is obtained from
various sources.

Dear readers, we request you to use this material as a reference note, or revision note, or
recall notes. Please do not learn the topics for the 1st time from this material, as this contain just the
required points, for revision.
Acknowledgement

On behalf of the team, Agam would like to thank all the doctors who taught us Pathology.
Agam would like to whole heartedly appreciate and thank everyone who contributed towards the
making of this material. A special thanks to Vignesh M, who took the responsibility of leading the
team. The following are the name list of the team who worked together, to bring out the material in
good form.

• Neelavathi S
• Mahalakshmi R
• Subhashree B
• Gauri Krishna R S
• Afrah Marzook
• Srudhi Pugazhendi
• Varshni R
• Yashwantha Elumalai Jagadeesan
• Vignesh. M
 THE BREAST
ESSAY
1. Breast cancer and its classification.

SHORT NOTES
1. CA breast – etiology
2. Paget disease of breast
3. Phyllodes tumor
4. Fibroadenoma breast
5. Risk factors of CA breast
6. Types of Breast CA
7. Fibrocystic disease of breast

SHORT ANSWERS
1. Comedo Carcinoma of breast.
2. Gynaecomastia

UPDATES

PATHOLOGY AGAM
ESSAY
1. BREAST CANCER
 Most common non skin malignancy in women
 Second most common cause of cancer death
 All breast malignancies are adenocarcinoma
 First arise in the ductal /lobular system as CIS.
 Based on the expression of estrogen receptor and HER2 it is divided into:
 ER positive and HER2 negative – mucinous, papillary, cribriform, lobular
 HER2 positive either ER positive or ER negative – apocrine, micropapillary
 ER negative and HER2 negative - medullary
 Risk factors
 First degree relative with Breast Cancer
 Radiation, Toxins, Smoking
 Germline mutation
 Prolonged exposure to Estrogen
 Benign Breast diseases
 Age: 70 to 80 years
 Diet, Reproductive pattern, Breast feed
ETIOLOGY
 Familial Breast Cancer
 Arises due to inheritance of an identifiable susceptibility gene.
 Major known susceptibility gene for familial breast cancer are BRCA1, BRCA2, Tp53,
CHEK 2.
 Mutation in BRCA 1 and 2 are highly associated with Breast Cancer
 BRCA1 and BRCA2 are part of large complex of proteins that are required to repair
double stranded DNA through a process called Homologus recombination
 Sporadic Breast Cancer – Major risk factor is
 Hormonal exposure
 Gender, Age at menarche and menopause
 Reproductive history, Breast feeding
 Exogenous steroids
 Environmental risk factors
 Radiation exposure
 Exposure to chemical with estrogen like effects

AGAM PATHOLOGY
MOLECULAR CARCINOGENESIS

ER+ & HER2- HER2+ ER- & HER2-

Germline mutation BRCA 2 Germline mutation TP53 Germline mutation BRCA1

P1K3CA mutation HER2 amplification TP53 mutation

Precursor Lesions: Precursor Lesion: No precursor

 Flat Epithelial Atypia  Atypical Apocrine Adenosis lesion identified
 Atypical Ductal Hyperplasia
DCIS DCIS
DCIS
Invasive Cancer Invasive Cancer
Invasive Cancer HER2 enriched Basal Like
Luminal

CLASSIFICATION OF BREAST CARCINOMA

 Non-invasive carcinoma
 Ductal carcinoma in situ (DCIS)
 lobular carcinoma in situ (LCIS)
 Invasive carcinoma
 Invasive carcinoma of no special type
 Specific histological type invasive carcinoma
 Stromal tumours
 Intralobular
 Fibroadenoma;
 Phyllodes tumor
 Interlobular
 Lipoma
 Sarcoma

PATHOLOGY AGAM
SHORT NOTES:
1. CARCINOMA BREAST- ETIOLOGY
 Breast cancers are clonal proliferation of cells that arise from cells with multiple genetic
aberrations, acquisition of which is influenced by hormonal exposures and inherited
susceptibility gene.
 Hereditary or sporadic.
GENE MUTATIONS AND BREAST CANCER:
GENES % SINGLE RISK BY AGE CHANGES IN COMMENTS
GENE CANCER OF 70 YEARS SPORADIC CA
BRCA1(17q21) 52% (2% of all 40-90% Mutation are rare Breast carcinoma
Familial breast breast cancer) seen in are poorly
and ovarian Medullary carcinoma differentiated
cancer (1 in Metaplastic triple negative (basal
860) carcinoma like) TP53 mutation
present
BRCA2(13q12- 32% (1% of all 30-90% Rare mutation and Biallelic germline
13) breast cancer) loss of expression. mutation will cause
Familial breast Associated with Fanconi anaemia
and ovarian Ovarian tumour
cancer (1 in Male breast cancer
740) and prostate cancer
TP53(17p13.1) 3% (1% of all >90% Mutation in 20% TP53 is most
Li Fraumeni breast cancer) Most frequent in common mutation
syndrome (1 in triple negative in sporadic breast
20000) cancers cancers.
Associated with 53% ER-ve and HER-
Sarcoma, Leukemia 2 positive
Brain Tumour’s
CHEK-2 5%( 1% of all 10-20% Mutation in 5% May increase the
(22q12.1) breast cancer) Associated with risk of breast cancer
(1 in 100) Prostate cancer after radiation
Thyroid, kidney and exposure
colon cancer 70-80% ER+ve

AGAM PATHOLOGY
2. PAGET DISEASE
Rare manifestation of breast cancer

Malignant cells (Paget cell)

 extend from DCIS within ductal system via lactiferous sinus into nipple skin without
crossing the basement membrane
 Tumor cells disrupt the normal epithelial barrier allowing the extracellular fluid to seep
out of surface

MORPHOLOGY
 Gross:
 Unilateral
 Erythematous eruption with scale crust
 Microscopically: Paget cells - large spherical cells clear cytoplasm hyperchromatic nuclei
 Immunohistochemistry: ER negative overexpresses HER2

CLINICAL FEATURES
 Skin of nipple and areola shows ulceration
 Pruritus is common
 Palpable mass - underlying invasive Without palpable mass- underlying DCIS

PATHOLOGY AGAM
3. PHYLLODES TUMOUR
 Also known as cystosarcoma phyllodes.
 Large, fast growing masses that form from the periductal stromal cells of breast.
 Most commonly occurs after age 60 years.
 Associated with clonal acquired chromosomal changes like
 Gains in chromosome 1q (most common).
 Overexpression of homeobox transcription factor (HOX-B13) is associated with higher
tumour grade and more aggressive clinical behavior.
 High grade lesions also have epidermal growth receptor amplification.

MORPHOLOGY:
 Tumour vary in size from a few centimeters to massive lesion involving entire breast.
 Bulbous protrusions.
 Distinguished from fibroadenomas on the basis of higher cellularity, higher mitotic rate,
nuclear pleomorphism, stromal overgrowth and infiltrative borders.
 Most are low grade, intermediate and high grade often recur locally unless they are
treated with wide excision or mastectomy.
 Lymphatic spread is rare, axillary node dissection is contraindicated.
 Only stromal component metastasizes.

4. FIBROADENOMA BREAST
 Most common benign tumour of female breast, also known as breast mouse.
 They are frequently multiple and bilateral.
 Young women present with a palpable mass and older women with a mammographic
density or clustered calcifications.
 Epithelial component is hormonally responsive and increase in size due to lactational
changes during pregnancy.
 Many fibroadenomas are polyclonal hyperplasia of lobular stroma.
 Example: almost half of women receiving cyclosporine A after renal transplantation
develop multiple fibroadenomas that regress after cessation of treatment.
 Cysts larger than 0.3 cm, sclerosing Adenosis, epithelial calcifications, or papillary
apocrine changes.

AGAM PATHOLOGY
MORPHOLOGY:
 Vary in size from less than 1cm to large tumours that replace most of the breast.
 Well circumscribed, rubbery, greyish white nodules that bulge above the surrounding
tissue.
 Delicate, myxoid stroma resembles normal intralobular stroma.
 Epithelium may be surrounded by stroma (pericanicular pattern) or compressed and
distorted by it (intracanicular pattern).
 In older women, stroma is densely hyalinised and the epithelium atrophied.

5. RISK FACTORS OF CA BREAST:

 Germline mutations: germline mutation in tumour suppressor gene.
 First degree relatives with breast cancer
 Race/ ethnicity
 Age: peaking at 70 to 80 years
 Age at menarche: menarche at age younger than 11 years
 Late menopause
 Age at first live birth
 Benign breast disease: breast biopsy revealing atypical hyperplasia or proliferative
changes increases the risk of invasive carcinoma.
 Estrogen exposure: menopausal hormonal therapy increases the risk of breast cancer.
 Breast density: very dense breasts have four to six fold increase in risk of ER+ve and
ER-ve cancer.
 Radiation exposure
 Carcinoma of contralateral breast or endometrium.
 Diet
 Obesity
 Exercise
 Breastfeeding
 Environmental toxins: organochlorine pesticides have estrogenic effects on human

PATHOLOGY AGAM
6. CLASSIFICATION OF CA BREAST
MOLECULAR CLASSIFICATION:
 Luminal A
 HER2 -ve
 ER +ve
 Best Prognosis
 PR +ve
 Luminal B
 BRCA2 +ve
 HER2 +ve
 Bad prognosis
 HER2
 HER2 +ve
 ER –ve
 PR –ve
 Poor prognosis
 Basal
 Triple negative
 Ck 5/6 +ve
 EGFR +ve
 BRCA1
 Worse prognosis
 Claudin Low Carcinoma
 Negative for ER, PR, HER2, Claudin 3, Claudin 4, Claudin 7 and E – Cadherin
 Young age onset
 Low expression of luminal genes
 Increased expression of lymphocyte and endothelial markers.
 Poor prognosis.
HISTOLOGIC TYPES OF CARCINOMA OF BREAST:
NON-INVASIVE CARCINOMA INVASIVE CARCINOMA
Invasive ductal carcinoma:
 Tubular carcinoma
Ductal carcinoma in situ (DCIS)  Mucinous carcinoma
 Medullary carcinoma
 Inflammatory carcinoma
Lobular carcinoma in situ (LCIS) Invasive lobular carcinoma
Paget disease of the nipple

AGAM PATHOLOGY
7. FIBROCYSTIC DISEASE OF BREAST:
 Nonproliferative breast changes
 LUMPY breast on palpation
 DENSE breast with cysts- radiological
 BENIGN lesion
 Not associated with an increased risk of breast cancer

MORPHOLOGY: Three principal morphological changes

Cysts:
 Small cysts formed by dilation of lobules coalesce to form larger cysts.
 Unopened cysts contain turbid, semi-translucent fluid of brown or blue colour (blue dome
cyst).
 Cysts lined either by flattened atrophic epithelium or by metaplastic apocrine cells.
 Metaplastic apocrine cells have abundant granular, eosinophilic and round nuclei.
 Calcification detected by mammography.
 Diagnosis is confirmed by the disappearance of the mass after fine-needle aspiration of its
content.

Fibrosis:
 Cyst ruptures releasing secretory material into the adjacent stroma.
 Chronic inflammation and fibrosis contribute to nodularity of breast.

Adenosis:
 Increase in the number acini per lobule.
 Normal feature in pregnant women.
 In non-pregnant women, Adenosis occur as focal change.
 Calcification are occasionally present within lumens
 Acini lined by columnar epithelium which may show nuclear atypia (fat epithelial atypia).
 Flat epithelial atypia - clonal proliferation associated with deletion of chromosome 16q.
 Other steps in cancer development are rate limiting.

PATHOLOGY AGAM
SHORT ANSWERS
1. COMEDO CARCINOMA OF BREAST:
 A type of ductal carcinoma of breast.
 Considered as early stage of breast cancer.
 Occasionally produce vague nodularity.
 Detected on mammography as clustered or linear and branching areas of calcification.
 Defined by two features:
 Tumour cells with pleomorphic, high- grade nuclei.
 Area of central necrosis.

2. GYNECOMASTIA:
 Enlargement of breast in male.
 Present as button like sub-areolar enlargement and may be unilateral or bilateral.
 Occurs as a result of an imbalance between estrogens and androgens.
 It may appear during puberty or at any time during adult life when there is cause for
hyperestrinism.
 Drugs associated: Alcohol, marijuana, heroin, antiretroviral drug, anabolic steroids.
 It occurs as a part of Klinefelter syndrome and testicular neoplasm such as Leydig cell and
Sertoli cell tumors.
 Microscopically: increase in dense collagenous connective tissue associated with
epithelial hyperplasia of the duct lining with characteristic tapering micropapillae.
 Lobule formation is almost never observed.

AGAM PATHOLOGY
UPDATES
1. MAMMOGRAPHIC DENSITIES:
 Breast lesions that replace adipose tissue with radiodense tissue form mammographic
densities.
 Rounded densities are most commonly benign lesions such as fibroadenomas or cysts,
whereas invasive carcinomas generally form irregular masses.
 The average size of invasive carcinomas detected by mammography is about 1 cm
(significantly smaller than carcinomas detected by palpation), and only 15% will have
metastasized to regional lymph nodes at the time of detection.

2. MED12 MUTATIONS
 Both fibroadenoma and phyllodes tumor are driven by somatic mutations in MED12, a
component of a multiple protein complex called mediator that links RNA polymerase II to
specific DNA-binding transcription factors.
 Uterine leiomyoma (strongly a/w MED12 mutations) also arises from stromal cells within
an organ that is responsive to female sex hormones.
 By deranging mediator function, MED12 mutations alter the expression of sex hormone–
regulated genes that control the proliferation and survival of certain types of stromal
cells.
 In contrast, interlobular stroma is the source of the same types of tumors found in
connective tissue in other sites of the body (e.g., lipomas and angiosarcomas), as well as
tumors arising more commonly in the breast (e.g., myofibroblastoma and fibrous tumors),
and consist only of stromal cells.
 Benign-appearing phyllodes tumors that have only a slight propensity to recur often have
MED12 mutations and few other genetic changes. (In contrast, tumors that display
malignant behavior are more likely to have mutations in additional genes, such as TERT,
the gene that encodes telomerase)

3. FLAT EPITHELIAL ATYPIA

 It is a clonal process characterized by the presence of dilated acini and cysts lined by
epithelial cells that display mild cytologic atypia.
 It is associated with deletions of chromosome 16q and is the earliest morphologically
recognizable clonal lesion of the breast.
 It associated with lesions that increase the risk of cancer (e.g., atypical hyperplasia) but
has not been shown to increase risk in isolation.
PATHOLOGY AGAM
4. ONE LINERS
 Discharge a/w malignancy is most commonly due to ductal carcinoma in situ (DCIS)
 Lumpiness, or diffuse nodularity of the breast, usually is a manifestation of normal
glandular tissue. When pronounced, imaging studies may be needed to exclude the
presence of a discrete mass.
 Digital breast tomosynthesis (three-dimensional mammography) integrates additional
views of the breast and can detect subtle changes in breast parenchymal texture.
 Metaplastic carcinoma includes spindle cell carcinomas and matrix-producing carcinomas.
These carcinomas often have gene expression profiles resembling those of myoepithelial
cells.
 The most important familial factor conferring an increased risk for male breast cancer is
germline mutation of the BRCA2 tumor suppressor gene
 A lower risk of male breast cancer is conferred by germline mutations in BRCA1, PTEN,
TP53, and PALB2
 More than 90% of breast cancers in males are of luminal type, while TNBCs and HER2
cancers are very rare (<5%).

5. NEW TOPICS
 Pg-1060 Additional Prognostic Factors for Breast Cancer

AGAM PATHOLOGY
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