Breast lumps pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]

Overview

Breast development is influenced by different hormones such as estrogen, progesterone, prolactin, and estradiol. The pathophysiology of breast lumps depends on the histological subtypes. Histological findings of breast lumps are different from each other which lead to diagnosis. It is thought that breast lumps are the result of hormonal events and genetic mutations. Estrogen and progesterone may increase risk of benign proliferative disease to 74% and benign breast lesion in post-menopausal women receiving estrogen with or without progesteron for more than 8 years raise by 1.7 fold. Gene mutations are classified into 3 categories based on cancer risk such as BRCA1, BRCA2, TP53 considered as high risk mutations, Homozygous ataxia-telangiectasia, somatic mutation in CHEK2, BRIP1, PALB2 moderate risk mutations, and low risk genes mutation are not determined yet.

Pathophysiology

Physiology

• Mammary gland development, maturation, and differentiation is controlled by hormones through their action on epithelial and stromal cells:
  • Estrogen: Development of ductal tissue
  • Progesterone: Ductal branching and lobulo-alveolar development
  • Prolactin: Milk protein production
  • Estradiol and progesterone: Breast development at puberty
  • Estrogen and progesterone: Cell proliferation during luteal phase

Histological changes of breast

Histological changes of breast undergo continuous changes throughout the life:

• Fibrocystic disease
  • Histological apperance change from predominance of ducts, lobules to fibrous change, and cyst formation
  • Fibrocystic changes are not associated with breast cancer

• Specific changes during the period of times:
  • Early reproductive ages
    • Stromal hyperplasia, unilateral or bilateral macromastia
  • Middle reproductive ages
    • Substantial changes in glandular breast tissue result in adenosis
    • Stromal hyperplasia may result into ill-defined fullness areas called lumpy-bumpy consistency or firm areas which may require biopsy
    • No ductal changes
  • Late reproductive period
    • Hyperplastic glandular tissue with sclerosing adenosis or lobular hyperplasia
      • Hyperplastic glandular lesions may require biopsy
    • Hyperplastic ductal tissue

• Diagnostic subtypes and histologic subtypes are described according to their relative risk for cancer as below:

Diagnostic Subtypes

Diagnostic Subtypes	Breast cancer relative risk
Non-proliferative disease	1.17
Proliferative disease without atypia	1.76
Benign breast disease	2.07
Atypical hyperplasia	3.93

Histologic Subtypes

Histological subtypes	Relative risk|Breast cancer relative risk
Adenosis	2.00
Atypical ductal hyperplasia	3.28
Atypical lobular hyperplasia	3.92
Cysts	1.55
Fibroadenoma	1.41
Papilloma	2.06

Histological findings of breast lumps

Breast lumps	Histological findings
Atypical hyperplasia	Clonal neoplastic proliferations is present.
Atypical ductal hyperplasia (ADH)	Localized intraductal proliferations,having some microscopic features of ductal carcinoma in situ (DCIS), usually associated with calcification, duct spaces consist of complex proliferation of monotonous luminal-type cells by creating bridging feature. Differentiation of ADH from DCIS : ADH has less cytological atypia than DCIS. Distribution in severe ADH is restricted to less than 3 contiguous ducts and less than 0.2 cm in size.
Lobular neoplasia	Associated to decrease expression or missing expression of E-cadherine, lobular neoplasia is considered to be as incidental findings in during microcalcification evaluation.
Atypical lobular hyperplasia (ALH)	ALH is containing monomorphic cells and distend into lobular acini and adjacent terminal ducts. Differentiation between ALH and lobular carcinoma in situ (LCIS) associated with quantitative degrees about lobules and architecture feature.
Apocrine proliferative lesions	Apocrine atypia is described by a 3-fold variation in nuclear size or by cribriform structures with nuclear atypia, associated with sclerosing adenosis or complex sclerosing lesion.
Columnar cell lesions (CCL)	CCL has heterogeneous set of lesions distinguished by reduplication and microcystic changes in lobular acini, elevated estrogen receptor expression, increased proliferative rate, associated with sclerosing adenosis, clacification and pleomorphic appearnace.
Papillary lesions	Arborescent fibrovascular stalk lined to the myoepithelium are present.
Radical scars and complex sclerosing lesions	Radial scars are tumor like lesions with stellate nidus of dense elastotic collagen, surrounding with epithelial elements and sclerosing adenosis. Complex sclerosing lesions are kind of radial scars larger than 1 cm which has distorted glandular tissue.
Fibroadenoma	Consist of disposed compressed glands within collagenous stroma. Complex fibroadenomas: containing sclerosing adenosis, calcifications, papillary hyperplasia.
Phyllodes tumor	Prominent and hypercellular stromal feature expanded to epithelial of tumor. Classified to benign, borderline, and malignant on the basis of stromal mitotic rate, cytology and degree of stromal overgrowth.
Pseudoangiomatous Stromal Hyperplasia	Composed of dense collagen, slit like spaces resulting from fibroblast proliferation resembling blood vessels in the stroma between lobular units.
Sclerosing adenosis	Increase in lobular acini number, enriched in myoepithelial cells.

Pathogenesis

• It is understood that breast lumps are the result of hormonal events:
  • Prevalence of benign breast lesion in post-menopausal women receiving estrogen with or without progesteron for more than 8 years raise by 1.7 fold.
  • Estrogen and progesterone increase rate of benign proliferative breast disease to 74%.
  • Anti-estrogen drugs such as tamoxifen, decrease prevalence of breast lesions such as adenosis, cysts, hyperplasia, duct ectasia to 28%.

• Although estrogen receptors (ER) and progesterone-receptor (PR) attributed to weak prognosis, they may predict patients' response to endocrine therapy.
  • Assessment of presence of ER and PR are required in invasive breast cancers.
  • ER-positive result is present in 70% of breast cancers and PR-positive result is present in 60% of breast cancers.
• HER2/neu is a proto-oncogene which involves in breast regulatory pathways such as proliferation, cell motility and invasion.
  • In 10% to 34% of breast cancers, overexpression and amplification of HER2 is reported.
  • In 90% of cases, overexpression, amplification, and surface membrane protein expressions of HER2/neu may be seen.

Genetics

• Breast lumps is associated with deletion of small segments of DNA (loss of heterozigosity).
• The development of breast lumps is the result of multiple genetic mutations such as:
  • High risk genes mutations:
    • BRCA1
    • BRCA2
    • TP53 resulting in Li-Fraumeni syndrome
    • PTEN resulting in Cowden syndrome
    • STK11 resulting in Peutz-Jegher’s syndrome, Neurofibromatosis (NF1) and (CDH-1) E-Cadherin
  • Moderate risk genes mutations:
    • Homozygous ataxia-telangiectasia (ATM)
    • Somatic mutations in CHEK2
    • BRIP1: BRCA1 modifier
    • PALB2: BRCA2 modifier
  • Low risk genes mutations:
    • Clinical determination of these genes have not determined yet

Associated Conditions

• There are no other associated conditions with breast lumps.

Gross pathology

Gross findings	Gross pathology
Fibrotic capsule and infiltrated the surrounding tissue Gray-white color and moderately increased consistency	Gross feature of fibroadenoma Source: Netha Hussain , from Wikimedia Commons
Stellate area of cancer 2cm in diameter Felt as a hard mobile mass Histology as a moderately well differentiated duct carcinoma	Gross image of breast cancer Source: John Hayman , from Wikimedia Commons

Microscopic Pathology

Pathologic findings	Microscopic image
Phyllodes tumor is a tumor of the intralobular breast stroma and it may be benign or malignant with large slit-like spaces. It is a type of fibroepithelial tumor.	Histopathologic image of Phyllodes tumor Source: Nephron, from Wikimedia Commons
Sclerosing adenosis microscopic pathology has increased numbers of small breast acini with collapsed lumens, fibrosis surrounds the acini, considered as benign lesion with increased risk of breast cancer.	Histopathologic image of sclerosing adenosis Source: Nephron, from Wikimedia Commons
ADH, based on a molecular basis, is a low-grade DCIS with localized proliferation.	Histopathologic image of atypical ductal hyperplasia Source: Nephron, from Wikimedia Commons

References

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