The histological workup for breast cancer diagnosis and treatment
The histological workup is the summary report of the pathologist. Essentially, the histological evaluation is the microscopic analysis of the chemical and cellular properties associated with a suspicious breast tumor. The pathologist will also confirm the size of the breast tumor where necessary for breast cancer staging purposes. The histological evaluation is essential to determine the most effective approaches to hormone and chemotherapy, where recommended.
Histology is basically 'the microscopic study of living tissues'. There are really four basic types of tissue in the body: epithelial tissue, muscle tissue, connective tissue, and nervous tissue. Breast cancer (breast carcinoma) is a malignant transformation of epithelial tissue ( usually 'glandular' tissue). Fat (adipose) and fibrous tissue are both 'connective' tissues, which may also form into suspicious lesions on mammography, and the exact nature of the suspected tumor can almost always be confirmed on histological evaluation.
When a suspicious breast lesion appears on mammography or
ultrasound, a biopsy sample will likely be taken from the lesion and sent
for histological evaluation by the pathologist. Various amounts of tissue
may be required, (requiring either a fine needle, core, or excisional biopsy)
but generally one tries to remove as little tissue as possible while remaining
confident that the sample is representative and taken from the right spot.
So, an initial biopsy sampling and analysis could be considered as an extension
of the breast cancer screening process, where breast cancer is either confirmed
positive or confirmed negative. (or, the lesion appears to be 'at risk' for
breast cancer, but is not yet malignant, resulting in a 'follow-up' screening
in a few months). Once breast cancer is confirmed by the pathologist, the
breast cancer staging process begins. At that time, and additional sampling
of breast tissue may be required for more extensive histological evaluation,
and the lymph nodes will also be sampled in some manner. In the image below,
breast carcinoma has metastasized to the lymph nodes. The 'dark' cells are
node, while the purplish 'duct-forming' areas, are breast cancer.
Histological grade of breast cancer
The pathologist will be able to tell if the breast cancer is still confined to the breast ducts, (DCIS) , or whether it has reached infiltrative or invasive status, (and whether or not the cancer has metastatized to the lymph nodes in the axilla, based on an additional sample from that region, but it could also be determined by a PET scan). The cancer 'stage' is largely a function of the invasive or non-invasive status of the breast cancer. The 'grade' of the breast cancer is related more to the actual microscopic character of the cells in the breast tumor. Based on a variety of cellular features, the histological analysis helps determine the 'type' of breast cancer ( unless it is a generic or NOS type cancer) and the grade. Histological classification of breast cancer into essentially grades I, II, and III, determines the urgency and aggressiveness of treatment, as the higher grades do tend to correspond to poorer survival rates and prognosis.
What the pathologist will be considering is the degree of tubule formation within the tumor (the number and differentiation of tubules), the motitic count (the rate and number of cell divisions) and nuclear pleomorphism (basically the appearance of the cells and cell nuclei, in increasing amounts of variation and 'bizarre randomness'). A combined score from the three observations determines the histological grade of the breast cancer. Statistically, the five year surival rate for grade I breast cancers over 80%. The prognosis for grade II and III breast cancers is somewhat less optimistic, with five year survival rates of about 64% and 50% respectively. The pathologist may also note the presence and amount of necrosis (cell and tissue death and decay), and calcifications. Necrosis tends to be another indicator of an agressive breast cancer.
The use of steroid receptors to predict breast cancer outcome and responsiveness to therapy has been used for many years now. The usual method for measuring the presence of steroid receptors in breast cancer tumors is now by immunohistochemistry. There are no hard-and-fast rules for how to interpret the presence of various hormone and hormone receptor levels, but certain generally tendencies can be observed.
Estrogen and Progesterone receptors
The most important hormonal indicators to idenfity are the positive presence of oestrogen and progresterone receptors. Breast cancers which overexpress high amounts of oestrogen and progesterone receptors are likely to be more responsive to endocrine therapy treatment. Estrogen and progesterone receptors levels are detected in the nucleus of maligant cancer cells only, by the application of a protein-based stain.
HER-2; human epidermal growth factor receptor 2
Human epidermal growth factor receptor 2 (or HER2, or Her-2/neu/c-erb B2) has been an important aspect of breast cancer histology since about 1987. It has been shown that high levels of either HER2 gene amplification or protein expression tends to result in a poorer breast cancer prognosis. A monoclonal antibody therapy was developed to counter the effects of HER2, (trasuzumab), and its use has been shown to reduce rates of recurrence and mortality in HER2 postive early stage breast cancers.
In the image above, the brown stain is attaching to HER-2 receptors, which would indicate a fairly "positive" result for HER-2/neu. Consequently, treatment for this particular breast cancer would likely benefit from the use of herceptin.
Epidermal growth factor receptor
The epidermal growth factor receptor (EGFR or HER1) is a type 1 tyrosine kinase receptor that is expressed in normal breast tissue. Generally speaking, higher than expected levels of EGFR are accompanied by low levels of estrogen receptors, and other poor prognostic features. EGFR tends to be associated with grade III breast tumors.
Basal breast tumor markers.
Some breast tumors may express high levels of proteins that are not normally associated with epithelial cells (like duct-lining cells most commonly associated with breast cancer) but are rather derived from basal or myepithelial cells. There are a number of proteins associated with basal and myoepithelial gene expression, including cytokeratins 5 and 6, and 14, P-cadherin, and p63. Most of these tumors also have a corresponding low expression of ER, PgR, and HER2, and are considered to have a higher risk of metastasis. (especially to the lung)
Markers of breast cancer 'proliferation'
An antigen calls Ki-67 is expressed in the nucleus of neoplastic cells in all phases of a cell cycle, and is therefore thought to be a useful marker for high levels of proliferation. Notable changes in Ki-67 expression following a neoadjuvant treatment by endocrine therapy has been shown to be a useful predictor of long term outcome in some cases. If one can 'inhibit' new cell growth , Ki-67 levels will also decrease, and this tends to predict a good response to chemotherapy. Other proliferation markers in use in some breast cancer research centers include p21, p27, cyclin E, and cyclin D1.
However, in practical terms it is still the presence of estrogen and progesterone receptors which remain the most reliable and useful predictive marker for the staging and management of breast cancer. Epidermal growth factor receptors, Ki-67, and Topoisomerase II alpha have high potential as prognostic markers of breast cancer, while other markers such as P53, cyclin E, cyclin D1, p21, p27, Bcl2, bax, bcl-x, and survivin are still in an experimental phase,with limited clinical applicability.
Molecular and genetic aspects could be included in histological grading in the near future
In the future, (and in some cases presently) microarray-based high-throughput technologies might be employed to look more closely at the molecular characteristics of breast cancers. Certain genetic/molecular features have been associated with an increased proclivity to mestastatize. Certainly, the more you know about the tumor, the more fine-tuned can be the treatment, and it is possible that in the near future these genetic and molecular features of a breast tumor might be included in the determination of histological breast cancer grade.
- Pritt, B., Ashikaga, T., Oppenheimer, RG., Weaver, DL. Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. Modern Pathology (2004) 17, 905910
- Pain JA, Ebbs SR, Hern RPA, et al. Assessment of breast cancer size: a comparison of methods. Eur J Surg Oncol (1992);18:4448.
- Nichols HB, Trentham-Dietz A, Love RR, Hampton JM, Hoang Anh PT, Allred DC, Mohsin SK, Newcomb PA: Differences in breast cancer risk factors by tumor marker subtypes among premenopausal Vietnamese and Chinese women.Cancer Epidemiol Biomarkers Prev (2005) , 14(1):41-47
- Akiyama F, Iwase H: Triple negative breast cancer: clinicopathological characteristics and treatment strategies.Breast Cancer (2009) , 16(4):252-3.
- Kakarala M, Rozek L, Cote M, Liyanage S, Brenner DE. Breast cancer histology and receptor status characterization in Asian Indian and Pakistani women in the U.S.--a SEER analysis. BMC Cancer.(May 2010) 11;10:191.
- Gathani T, Bull D, Green J, Reeves G, Beral V; Million Women Study Collaborators.Breast cancer histological classification: agreement between the Office for National Statistics and the National Health Service Breast Screening Programme. Breast Cancer Res. (2005);7(6):R1090-6.
- Champion HR, Wallace IW, Prescott RJ.Histology in breast cancer prognosis. Br J Cancer. (1972) Apr;26(2):129-38.
- Serpell, JW., Johnson, WR., Pre-operative histological diagnosis of breast cancer.Australian and New Zealand Journal of Surgery (June 1997) Volume 67, Issue 6, pages 325329.
- Potter J. D., Cerhan J. R., Sellers T. A., McGovern P. G., Drinkard C., Kushi L. R., Folsom A. R. Progesterone and estrogen receptors and mammary neoplasia in the Iowa Womens Health Study: how many kinds of breast cancer are there?. Cancer Epidemiol. Biomark. Prev.(1995), 3: 319-326.
- Huang W. Y., Newman B., Millikan R. C., Schell M. J., Hulka B. S., Moorman P. G. Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status. Am. J. Epidemiol.,(2000) 151: 703-714.
- Li CI, Malone KE, Daling JR. Differences in breast cancer hormone receptor status and histology by race and ethnicity among women 50 years of age and older.Cancer Epidemiol Biomarkers Prev. (2002) Jul;11(7):601-7.
- Scarff, R.W. and Torloni H. Histological typing of breast tumors., International histological classification of tumours, no. 2. Vol. 2. World Health Organization, Geneva, (1968) pp. 13-20.
- Elston, C.W.The assessment of histological differentiation in breast cancer. Aust N Z J Surg, (1984) 54, 11-5.
- Bloom, H.J. and Richardson W.W. Histological grading and prognosis in breast cancer. Br. J. Cancer,(1957) 11, 359-377.
- Pinder, S.E., Murray S., Ellis I.O., Trihia H., Elston C.W., Gelber R.D., Goldhirsch A., Lindtner J., Cortes-Funes H., Simoncini E., Byrne M.J., Golouh R., Rudenstam C.M., Castiglione-Gertsch M. and Gusterson B.A. (1998) The importance of the histologic grade of invasive breast carcinoma and response to chemotherapy. Cancer, 83, 1529-39.
- Varga, Z., Mallon, E.,
Histology and Immunophenotype of Invasive Lobular Breast Cancer. Daily Practice and Pitfalls .Breast Disease, (2009) volume 30, p. 15-19.
- Weigelt, B., Reis-Filho, JS., Histological and molecular types of breast cancer: is there a unifying taxonomy? Nature Reviews Clinical Oncology (December 2009) 6, 718-730
- Provenzano E, Hopper JL, Giles GG, Marr G, Venter DJ, Armes JE. Histological markers that predict clinical recurrence in ductal carcinoma in situ of the breast: an Australian population-based study. Pathology.(Jun. 2004) 36(3):221-9.
- Dublin EA, Millis RR, Smith P, Bobrow LG. Minimal breast cancer: evaluation of histology and biological marker expression. Br J Cancer. (July 1999) 80(10):1608-16.
- Walker, RA., Immunohistochemical markers as predictive tools for breast cancer. J Clin Pathol (2008);61:689-696
- Ross JS,. Symmans WF,. Pusztai L,et al. Standardizing slide-based assays in breast cancer: hormone receptors, HER2, and sentinel lymph nodes. Clin Cancer Res (2007);13:28315.
- Piccart-Gebhart MJ,. Procter M,Leyland-Jones B,et alTrastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med (2005);353:165972.
- Slamon DJ,Clark GM,. Wong SG,et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science (1987);235:17782.
- Nicholson RI,. McClelland RA,. Gee JM,. et al . Epidermal growth factor receptor expression in breast cancer: association with response to endocrine therapy. Breast Cancer Res Trea t(1994);29:11725.
- Veronese SM, Maisano C, Scibilia JComparative prognostic value of Ki-67
and MIB1 proliferation indices in breast cancer. Anticancer Res (1995);15:271722
Copyright Steven B. Halls, MD Last edited 14-December-2010