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

It is thought that breast lumps is the result of hormonal events and genetic mutations. The pathophysiology of breast lumps depends on the histological subtypes.

Pathophysiology

Physiology

Mammary gland development, maturation, and differentiation is controlled by hormones through their action on epithelial and stromal cells:^[1]^[2]^[3]
- 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:^[4]

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^[5]
  - Stromal hyperplasia, unilateral or bilateral macromastia
- Middle reproductive ages^[6]
  - 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^[6]
  - 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:^[7]

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	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^[8]	Clonal neoplastic proliferations is present.
Atypical ductal hyperplasia (ADH)^[9]	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^[10]	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)^[11]	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^[12]	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)^[13]	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^[14]	Arborescent fibrovascular stalk lined to the myoepithelium are present.
Radical scars and complex sclerosing lesions^[15]	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^[16]	Consist of disposed compressed glands within collagenous stroma. Complex fibroadenomas: containing sclerosing adenosis, calcifications, papillary hyperplasia.
Phyllodes tumor^[17]	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^[18]	Composed of dense collagen, slit like spaces resulting from fibroblast proliferation resembling blood vessels in the stroma between lobular units.
Sclerosing adenosis^[19]	Increase in lobular acini number, enriched in myoepithelial cells.

Pathogenesis

It is understood that breast lumps are the result of hormonal events:^[20]
- 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%.^[21]
- Anti-estrogen drugs such as tamoxifen, decrease prevalence of breast lesions such as adenosis, cysts, hyperplasia, duct ectasia to 28%^[22]

Genetics

Breast lumps is associated with deletion of small segments of DNA (loss of heterozigosity).^[23]
The development of breast lumps is the result of multiple genetic mutations such as:

- High risk genes mutations:^[24]
  - 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:^[25]^[26]^[27]
  - Homozygous ataxia-telangiectasia (ATM)
  - Somatic mutations in CHEK2
  - BRIP1: BRCA1 modifier
  - PALB2: BRCA2 modifier
- Low risk genes mutations:^[28]
  - Clinical determination of these genes have not determined yet

Associated Conditions

Gross pathology

Microscopic Pathology

References

↑ Going JJ, Anderson TJ, Battersby S, MacIntyre CC (1988). "Proliferative and secretory activity in human breast during natural and artificial menstrual cycles". Am J Pathol. 130 (1): 193–204. PMC 1880536. PMID 3337211.
↑ Hughes LE, Mansel RE, Webster DJ (1987). "Aberrations of normal development and involution (ANDI): a new perspective on pathogenesis and nomenclature of benign breast disorders". Lancet. 2 (8571): 1316–9. PMID 2890912.
↑ Santen RJ. Benign Breast Disease in Women. [Updated 2018 May 25]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278994/
↑ Love, Susan M.; Sue Gelman, Rebecca; silen, William (1982). "Fibrocystic Disease of the Breast — A Nondisease?". New England Journal of Medicine. 307 (16): 1010–1014. doi:10.1056/NEJM198210143071611. ISSN 0028-4793.
↑ Pearlman MD, Griffin JL (2010). "Benign breast disease". Obstet Gynecol. 116 (3): 747–58. doi:10.1097/AOG.0b013e3181ee9fc7. PMID 20733462.
↑ ^6.0 ^6.1 Huh SJ, Oh H, Peterson MA, Almendro V, Hu R, Bowden M; et al. (2016). "The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women". Cancer Res. 76 (7): 1926–34. doi:10.1158/0008-5472.CAN-15-1927. PMC 4873436. PMID 26941287.
↑ Dyrstad SW, Yan Y, Fowler AM, Colditz GA (2015). "Breast cancer risk associated with benign breast disease: systematic review and meta-analysis". Breast Cancer Res Treat. 149 (3): 569–75. doi:10.1007/s10549-014-3254-6. PMID 25636589.
↑ Lakhani SR, Collins N, Stratton MR, Sloane JP (1995). "Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p". J Clin Pathol. 48 (7): 611–5. PMC 502709. PMID 7560165.
↑ Ely KA, Carter BA, Jensen RA, Simpson JF, Page DL (2001). "Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting". Am J Surg Pathol. 25 (8): 1017–21. PMID 11474285.
↑ Page DL, Dupont WD, Rogers LW, Rados MS (1985). "Atypical hyperplastic lesions of the female breast. A long-term follow-up study". Cancer. 55 (11): 2698–708. PMID 2986821.
↑ Middleton LP, Sneige N, Coyne R, Shen Y, Dong W, Dempsey P; et al. (2014). "Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting". Cancer Med. 3 (3): 492–9. doi:10.1002/cam4.223. PMC 4101740. PMID 24639339.
↑ Guray M, Sahin AA (2006). "Benign breast diseases: classification, diagnosis, and management". Oncologist. 11 (5): 435–49. doi:10.1634/theoncologist.11-5-435. PMID 16720843.
↑ Schnitt SJ, Vincent-Salomon A (2003). "Columnar cell lesions of the breast". Adv Anat Pathol. 10 (3): 113–24. PMID 12717115.
↑ Muttarak M, Lerttumnongtum P, Chaiwun B, Peh WC (2008). "Spectrum of papillary lesions of the breast: clinical, imaging, and pathologic correlation". AJR Am J Roentgenol. 191 (3): 700–7. doi:10.2214/AJR.07.3483. PMID 18716096.
↑ Krishnamurthy S, Bevers T, Kuerer H, Yang WT (2012). "Multidisciplinary considerations in the management of high-risk breast lesions". AJR Am J Roentgenol. 198 (2): W132–40. doi:10.2214/AJR.11.7799. PMID 22268202.
↑ Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K; et al. (2005). "Benign breast disease and the risk of breast cancer". N Engl J Med. 353 (3): 229–37. doi:10.1056/NEJMoa044383. PMID 16034008.
↑ Karim RZ, Gerega SK, Yang YH, Spillane A, Carmalt H, Scolyer RA; et al. (2009). "Phyllodes tumours of the breast: a clinicopathological analysis of 65 cases from a single institution". Breast. 18 (3): 165–70. doi:10.1016/j.breast.2009.03.001. PMID 19329316.
↑ Hoda SA, Rosen PP (2004). "Observations on the pathologic diagnosis of selected unusual lesions in needle core biopsies of breast". Breast J. 10 (6): 522–7. doi:10.1111/j.1075-122X.2004.21412.x. PMID 15569209.
↑ Ferrara A (2011). "Benign breast disease". Radiol Technol. 82 (5): 447M–62M. PMID 21572066.
↑ Rohan TE, Miller AB (1999). "Hormone replacement therapy and risk of benign proliferative epithelial disorders of the breast". Eur J Cancer Prev. 8 (2): 123–30. PMID 10335458.
↑ Rohan TE, Negassa A, Chlebowski RT, Lasser NL, McTiernan A, Schenken RS; et al. (2008). "Estrogen plus progestin and risk of benign proliferative breast disease". Cancer Epidemiol Biomarkers Prev. 17 (9): 2337–43. doi:10.1158/1055-9965.EPI-08-0380. PMC 2584343. PMID 18725513.
↑ Tan-Chiu E, Wang J, Costantino JP, Paik S, Butch C, Wickerham DL; et al. (2003). "Effects of tamoxifen on benign breast disease in women at high risk for breast cancer". J Natl Cancer Inst. 95 (4): 302–7. PMID 12591986.
↑ O'Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC (1998). "Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci". J Natl Cancer Inst. 90 (9): 697–703. PMID 9586667.
↑ Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E; et al. (2007). "Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening". J Med Genet. 44 (8): 481–4. doi:10.1136/jmg.2007.049346. PMC 2597938. PMID 17369502.
↑ Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R; et al. (2006). "Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles". Nat Genet. 38 (11): 1239–41. doi:10.1038/ng1902. PMID 17033622.
↑ Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Avery-Kiejda KA, Talseth-Palmer B; et al. (2011). "BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer". Breast Cancer Res Treat. 127 (3): 853–9. doi:10.1007/s10549-011-1443-0. PMID 21409391.
↑ Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A; et al. (2005). "Cancer risks and mortality in heterozygous ATM mutation carriers". J Natl Cancer Inst. 97 (11): 813–22. doi:10.1093/jnci/dji141. PMID 15928302.
↑ Lalloo F, Evans DG (2012). "Familial breast cancer". Clin Genet. 82 (2): 105–14. doi:10.1111/j.1399-0004.2012.01859.x. PMID 22356477.

Template:WH Template:WS

[pmid3337211-1] Going JJ, Anderson TJ, Battersby S, MacIntyre CC (1988). "Proliferative and secretory activity in human breast during natural and artificial menstrual cycles". Am J Pathol. 130 (1): 193–204. PMC 1880536. PMID 3337211.

[pmid2890912-2] Hughes LE, Mansel RE, Webster DJ (1987). "Aberrations of normal development and involution (ANDI): a new perspective on pathogenesis and nomenclature of benign breast disorders". Lancet. 2 (8571): 1316–9. PMID 2890912.

[3] Santen RJ. Benign Breast Disease in Women. [Updated 2018 May 25]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278994/

[LoveSue_Gelman1982-4] Love, Susan M.; Sue Gelman, Rebecca; silen, William (1982). "Fibrocystic Disease of the Breast — A Nondisease?". New England Journal of Medicine. 307 (16): 1010–1014. doi:10.1056/NEJM198210143071611. ISSN 0028-4793.

[pmid20733462-5] Pearlman MD, Griffin JL (2010). "Benign breast disease". Obstet Gynecol. 116 (3): 747–58. doi:10.1097/AOG.0b013e3181ee9fc7. PMID 20733462.

[pmid26941287-6] 6.0 ^6.1 Huh SJ, Oh H, Peterson MA, Almendro V, Hu R, Bowden M; et al. (2016). "The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women". Cancer Res. 76 (7): 1926–34. doi:10.1158/0008-5472.CAN-15-1927. PMC 4873436. PMID 26941287.

[pmid25636589-7] Dyrstad SW, Yan Y, Fowler AM, Colditz GA (2015). "Breast cancer risk associated with benign breast disease: systematic review and meta-analysis". Breast Cancer Res Treat. 149 (3): 569–75. doi:10.1007/s10549-014-3254-6. PMID 25636589.

[pmid7560165-8] Lakhani SR, Collins N, Stratton MR, Sloane JP (1995). "Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p". J Clin Pathol. 48 (7): 611–5. PMC 502709. PMID 7560165.

[pmid11474285-9] Ely KA, Carter BA, Jensen RA, Simpson JF, Page DL (2001). "Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting". Am J Surg Pathol. 25 (8): 1017–21. PMID 11474285.

[pmid2986821-10] Page DL, Dupont WD, Rogers LW, Rados MS (1985). "Atypical hyperplastic lesions of the female breast. A long-term follow-up study". Cancer. 55 (11): 2698–708. PMID 2986821.

[pmid24639339-11] Middleton LP, Sneige N, Coyne R, Shen Y, Dong W, Dempsey P; et al. (2014). "Most lobular carcinoma in situ and atypical lobular hyperplasia diagnosed on core needle biopsy can be managed clinically with radiologic follow-up in a multidisciplinary setting". Cancer Med. 3 (3): 492–9. doi:10.1002/cam4.223. PMC 4101740. PMID 24639339.

[pmid16720843-12] Guray M, Sahin AA (2006). "Benign breast diseases: classification, diagnosis, and management". Oncologist. 11 (5): 435–49. doi:10.1634/theoncologist.11-5-435. PMID 16720843.

[pmid12717115-13] Schnitt SJ, Vincent-Salomon A (2003). "Columnar cell lesions of the breast". Adv Anat Pathol. 10 (3): 113–24. PMID 12717115.

[pmid18716096-14] Muttarak M, Lerttumnongtum P, Chaiwun B, Peh WC (2008). "Spectrum of papillary lesions of the breast: clinical, imaging, and pathologic correlation". AJR Am J Roentgenol. 191 (3): 700–7. doi:10.2214/AJR.07.3483. PMID 18716096.

[pmid22268202-15] Krishnamurthy S, Bevers T, Kuerer H, Yang WT (2012). "Multidisciplinary considerations in the management of high-risk breast lesions". AJR Am J Roentgenol. 198 (2): W132–40. doi:10.2214/AJR.11.7799. PMID 22268202.

[pmid16034008-16] Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K; et al. (2005). "Benign breast disease and the risk of breast cancer". N Engl J Med. 353 (3): 229–37. doi:10.1056/NEJMoa044383. PMID 16034008.

[pmid19329316-17] Karim RZ, Gerega SK, Yang YH, Spillane A, Carmalt H, Scolyer RA; et al. (2009). "Phyllodes tumours of the breast: a clinicopathological analysis of 65 cases from a single institution". Breast. 18 (3): 165–70. doi:10.1016/j.breast.2009.03.001. PMID 19329316.

[pmid15569209-18] Hoda SA, Rosen PP (2004). "Observations on the pathologic diagnosis of selected unusual lesions in needle core biopsies of breast". Breast J. 10 (6): 522–7. doi:10.1111/j.1075-122X.2004.21412.x. PMID 15569209.

[pmid21572066-19] Ferrara A (2011). "Benign breast disease". Radiol Technol. 82 (5): 447M–62M. PMID 21572066.

[pmid10335458-20] Rohan TE, Miller AB (1999). "Hormone replacement therapy and risk of benign proliferative epithelial disorders of the breast". Eur J Cancer Prev. 8 (2): 123–30. PMID 10335458.

[pmid18725513-21] Rohan TE, Negassa A, Chlebowski RT, Lasser NL, McTiernan A, Schenken RS; et al. (2008). "Estrogen plus progestin and risk of benign proliferative breast disease". Cancer Epidemiol Biomarkers Prev. 17 (9): 2337–43. doi:10.1158/1055-9965.EPI-08-0380. PMC 2584343. PMID 18725513.

[pmid12591986-22] Tan-Chiu E, Wang J, Costantino JP, Paik S, Butch C, Wickerham DL; et al. (2003). "Effects of tamoxifen on benign breast disease in women at high risk for breast cancer". J Natl Cancer Inst. 95 (4): 302–7. PMID 12591986.

[pmid9586667-23] O'Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC (1998). "Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci". J Natl Cancer Inst. 90 (9): 697–703. PMID 9586667.

[pmid17369502-24] Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E; et al. (2007). "Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening". J Med Genet. 44 (8): 481–4. doi:10.1136/jmg.2007.049346. PMC 2597938. PMID 17369502.

[pmid17033622-25] Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R; et al. (2006). "Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles". Nat Genet. 38 (11): 1239–41. doi:10.1038/ng1902. PMID 17033622.

[pmid21409391-26] Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Avery-Kiejda KA, Talseth-Palmer B; et al. (2011). "BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer". Breast Cancer Res Treat. 127 (3): 853–9. doi:10.1007/s10549-011-1443-0. PMID 21409391.

[pmid15928302-27] Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A; et al. (2005). "Cancer risks and mortality in heterozygous ATM mutation carriers". J Natl Cancer Inst. 97 (11): 813–22. doi:10.1093/jnci/dji141. PMID 15928302.

[pmid22356477-28] Lalloo F, Evans DG (2012). "Familial breast cancer". Clin Genet. 82 (2): 105–14. doi:10.1111/j.1399-0004.2012.01859.x. PMID 22356477.

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