Pleomorphic Breast Cancer

A breast cancer tumor in which greater than 50% of the cell population is characterized by pleomorphic shapes, is often termed ‘pleomorphic breast carcinoma’. Tumor cell pleomorphism usually implies six or more variations in bizarre-looking malignant cells, and is one of a number of different histological aspects a pathologist will consider when considering the malignant or benign nature of a breast tumor.

 
 

Pleomorphic breast cancer is not well recognized within the morphological spectrum of breast carcinoma, but more and more is tending to be considered a distinct breast cancer phenotype.

Pleomorphic breast carcinoma is considered a rare high-grade variant of invasive ductal carcinoma (not otherwise specified, NOS), with a somewhat less favorable diagnosis than other common breast cancers.

Pleomorphic breast cancer may also develop in lobules

There is also kind of pleomorphic breast carcinoma which develops in the breast lobules rather than the ducts, termed invasive pleomorphic lobular carcinoma (IPLC), which may also now be considered a unique sub-type of breast cancer.

Pleomorphic tumor cells can also occur in other kinds of breast cancer, such as carcinoma with osteoclastic giant cells, mammary sarcoma, and in metastatic tumors, so there is a danger for an initial misdiagnosis. (The rate of initial misclassification is actually very high, over 50% in some studies.)

 
 

The average age in which women tend to develop pleomorphic breast cancer is around 51-55 years of age, though it has known to develop in women as young as the mid 20s, and as late as the 80s to 90s. In most cases, pleomorphic breast carcinoma is discovered clinically as a palpable mass, with a minority found via screening mammography.

In many instances pleomorphic breast cancer is initially diagnosed as sarcoma (cancer of muscle tissue), and later determined to be pleomorphic breast carcinoma. A ‘spindle-cell’ component (spindle cells are often associated with smooth muscle and connective tissue) is found in up to 40% of pleomorphic breast carcinoma tumors, sometimes accounting for more than 25% of the total tumor mass.

Mammographic features common to pleomorphic breast cancer

Pleomorphic breast cancer tumors will often fail to show the ‘classic’ features of breast carcinoma on mammography, and ultrasound is not necessarily any clearer. Mammograms of pleomorphic breast cancer tumors will tend to show well-circumscribed lesions without evidence of calcification.

Sometimes X-ray images of pleomorphic breast carcinoma tumors can given the impressions of benign breast tumors such as fibroadenoma, of inflammatory breast conditions, or possibly a malignant phyllodes tumor.

Ultrasound images often show intracystic elements

Sonograms of pleomorphic breast carcinoma tend to present as either low echo tumors with distinct circumscription or tumors well-distributed internal echoes. Ultrasound often reveals intracystic features within the tumor as well.

Magnetic resonance imaging (MRI) is sometimes used in the diagnosis of pleomorphic breast carcinoma, and will tend to show showed a homogeneous hyperintense cystic mass on T2-weighted images, and contrast-enhanced MRI might show contrast enhancement in irregular portions of the tumor walls.

Histological aspects of pleomorphic carcinomas of the breast

In order to be classified as pleomorphic breast carcinoma, the tumor should be comprised of a pleomorphic cell population of 50-100%, though up to 1/3 of tumors also show a prominent spindle-cell morphology.

 
 

Most pleomorphic breast tumors will present with a histological grade III. Some pleomorphic breast carcinomas will feature ‘giant’ cells with multiple nuclei (Giant cells can be 10 times larger than typical mono-nuclear cells). Pleomorphic breast carcinomas tend to be hyper-chromatic, with coarsely clumped chromatin, and multiple prominent nucleoli. The rate of cell mitosis tends to be very high (often greater than 20 mitotic figures per 10 HPFs ( ‘high power field’ microscopic views). Abnormal mitosis is also frequent.

Immunoreactive features typical of pleomorphic breast carcinoma

Almost all pleomorphic breast cancer tumors will stain negative for estrogen receptors, and most are also negative for progesterone receptors. They are also generally negative for Bcl-2. However, pleomorphic breast carcinoma tends to be positive for PCNA and AE1/AE3. p53 tends to be expressed in about two thirds of pleomorphic breast cancer tumors, and S-100 in perhaps 40% of tumors. Expressions of C-erbB-2, PCNA, S-100, EMA, and p53 are frequently associated with promotion of tumor cell growth and metastasis through different modes of actions, are often suggestive of a poorer breast cancer prognosis.

Furthermore, the lack of expression of ER, PR, and Bcl-2 tends to occur in tumors with high histological grade, all contributing to the poorer outlook generally associated with pleomorphic breast carcinoma. The image below shows positive PCNA and p53 staining on the cell nuclei of a pleomorphic breast carcinoma tumor.

Invasive pleomorphic lobular breast carcinoma (IPLC)

Invasive lobular breast carcinoma represents somewhere between 5 and 10% of all breast cancer tumors, and lobular carcinomas generally have a much better prognosis than ductal carcinomas. Invasive pleomorphic lobular breast carcinoma (IPLC) is considered a distinctive subtype of invasive lobular carcinomas, accounting for under 0.7% of all breast cancers, and less than 5% of lobular breast carcinomas. Pleomorphic lobular breast carcinoma,however, is highly aggressive, and usually presents as a grade II to III tumor. Pleomorphic lobular carcinoma of the breast seems to develop most often in postmenopausal women, with an average age of about 59.

As compared to lobular invasive carcinoma of a general type, invasive pleomorphic lobular breast carcinoma tends to present with a higher histological grade, a greater degree or vascular invasion, and more multifocality. The rate of metastasis is moderate at about 12%, and the mortality rate due to invasive pleomorphic lobular carcinoma of the breast might be estimated at around 6%. That is significantly higher than for invasive lobular breast carcinoma, which is considered a fairly mild form of breast cancer.

Histological characteristics of invasive pleomorphic lobular breast carcinoma

Similar to pleomorphic carcinoma, invasive pleomorphic lobular carcinoma of the breast will typically present with enlarged nuclei with hyperchromasia, irregularities, and marked plemorphism.

However, the growth pattern for invasive pleomorphic lobular breast carcinoma is different than for pleomorphic (ductal) breast carcinoma, as tumor cells tend to either disperse through fibrous connective tissues or arrange themselves in a ‘single-file’ line, which would be typical for invasive lobular breast carcinoma of a general type.

Cells also may develop into ‘targetoid’ distributions around benign ducts, also typical of invasive lobular breast carcinoma, but the cell pleomorphism is much more marked than with invasive lobular breast carcinoma, which tends to have a relatively uniform tumor cell population.

In terms of immunoreactivity, pleomorphic lobular breast carcinomas tend to be ER positive, and consistently positive for gross cystic disease fluid protein­15 (GCDFP-15), (which is considered a marker of apocrine differentiation.

The term -“Pleomorphic lobular apocrine carcinoma”, is sometimes also used). Significantly, invasive pleomorphic lobular breast carcinomas are usually negative for the E-cadherin protein.

 
 

Lack of E-cadherin protein and loss of heterozygosity also characteristic for invasive pleomorphic lobular breast carcinoma

Analysis of tumor samples for the E-cadherin glycoprotein expression has proven to be a very useful tool for distinguishing lobular from ductal carcinomas. A complete loss of E-cadherin expression occurs in most infiltrating lobular tumors and lobular carcinomas in situ, but is almost never the case with ductal breast carcinomas. (reduced levels of membrane-bround E-cadherin are reported in about 50% of ductal breast cancers, but there is never a complete loss of E-cadherin.) E-cadherin is a ‘transmembrane glycoprotein’ which functions to mediate cell-to-cell- adhesion in epithelial tissue, and dysfunction of the E-cadherin/catenin adhesion complex is a very common development in many cancers, not just breast cancer.

Loss of heterozygosity is common in invasive pleomorphic breast carcinomas

It is generally believed that there is a strong association between loss of E-cadherin expression and subsequent loss of genetic heterozygosity. Heterozygosity essentially refers to gene diversity, and ‘high heterozygosity’ implies lots of genetic variability, while ‘low heterozygosity’ suggests little genetic variability. Heterozygosity is often measured according to an ‘observed level’ versus an ‘expected level’ (the Hardy-Weinberg equilibrium) The loss of heterozygosity in a cell represents the loss of normal function of one allele of a gene in which the other allele was already inactivated. This often indicates the absence of a functional tumor suppressor gene in a tumor, and is a common occurrence in cancer. (Alleles are different versions of the same gene that are expressed as different phenotypes, and new alleles appear in a population by the random and natural process of mutation. If new alleles do not appear, this is evidence of abnormal genetic activity, most likely due to cancer) Almost all invasive pleomorphic lobular breast cancers demonstrate this loss of heterozygosity.

Treatment and Prognosis for Pleomorphic carcinomas of the breast

Pleomorphic breast cancer tends to be treated aggressively, and in a manner consistent with conventional invasive ductal breast carcinomas. Most women are treated with radical or modified radical mastecomy, and a minority with breast conserving surgery. Axillary dissection is generally undertaken. The rate of positive lymph node metastasis will of course vary in individual cases, but it on the high side, and might be estimated at around 50% of cases. Metastasis to other body sites occurs most commonly to the liver, followed by the lung, pleura, and bone.

Survival rates are higher without metaplastic spindle-cell features

Overall statistics tend to show a five year disease free survival rate of about 40%, although about 40% of women with pleomorphic breast cancer may succumb to the disease in 2-3 years. However, the absence of a significant spindle-cell component has been demontrated to have a positive effect on survival, as well as a tumor size of less than 5cm at the time of diagnosis. It may be estimated that patients with pleomorphic carcinoma of the breast but without a significant metaplastic spindle-cell component will survive the disease about 90% of the time.
 

Please note, this page is actually quite old, written many years ago. Since then, treatment results of breast cancer have improved a lot. You must disregard the survival numbers you read here, and know they are better. To find out how much better, see our full NEW index of Articles on Survival.

 

References

1. Silver SA, Tavassoli FA. Pleomorphic carcinoma of the breast: clinicopathological analysis of 26 cases of an unusual high-grade phenotype of ductal carcinoma. Histopathology. 2000 Jun;36(6):505-14.
2. Gil Deza, E., Japaze, H., Garcia Gerardi, C., Diaz, C., Gercovich, N., Morgenfeld, E., Rivarola, E., Russo, M., Frahm, I., Gercovich, FG.,Lobular invasive pleomorphic breast cancer (BC) should be isolated from the classic type. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 17024
3. Palacios, J., Sarrio, D., Garcia-Macias, MC., Bryant, B., Sobel, M, Merino, MJ., Frequent E-cadherin Gene Inactivation by Loss of Heterozygosity in Pleomorphic Lobular Carcinoma of the Breast. Mod Pathol 2003;16(7):674–678
4. Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 1991; 251: 1451–1455.
5. Cleton-Jansen AM, Callen DF, Seshadri R, Goldup S, Mccallum B, Crawford J, et al. Loss of heterozygosity mapping at chromosome arm 16q in 712 breast tumors reveals factors that influence delineation of candidate regions. Cancer Res 2001; 61: 1171–1177.
6. Page DL, Anderson TJ, Rogers LW. Diagnostic histopathology of the breast. 2nd ed. Edinburgh, Scotland: Churchill Livingstone; 1988.
7. Gamallo C, Palacios J, Suarez A, Pizarro A, Navarro P, Quintanilla M, et al. Correlation of E-cadherin expression with differentiation grade and histological type in breast carcinoma. Am J Pathol 1993; 142: 983–987.
8. Nguyen, CV., Falcón-Escobedo, R.,Hunt, K K., Nayeemuddin, KM., Lester, TR., Harrell, RK., Bassett, R L,. Gilcrease, MZ Pleomorphic Ductal Carcinoma of the Breast: Predictors of Decreased Overall Survival.American Journal of Surgical Pathology: April 2010 – Volume 34 – Issue 4 – pp 486-493
9. Kini, H., Pai, R., Rau, AR., Lobo, FD., Augustine, AJ., Ramsesh, BS., Pleomorphic lobular carcinoma of the breast – a diagnostic dilemma. J Cytol 2007;24:193-5
10. Weidner N, Semple JP. Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol 1992; 23:1167-71.
11. Auger M, Huttner I. Fine needle aspiration cytology of pleomorphic lobular carcinoma of the breast. Cancer (Cancer Cytopathol) 1997; 81: 29-32
12. Dabbs DJ, Grenko RT, Silverman JF. Fine needle aspiration cytology of pleomorphic lobular carcinoma of the breast. Acta Cytol 1994; 38: 923-6.
13. Yamaguchi, R., Tanaka, M., Yamaguchi, M., Fukushima, T., Kaneko, Y., Otsuka, H., Isobe, S., Terasaki, H., Nakashima, O., Kage, M., Yano, H., Pleomorphic carcinoma of the breast in a 17-year-old woman. The Japanese Society for Clinical Moldecular Morphology,(2010) 43:43–47.
14. Zhao, J., Lang, R., Guo, X., Chen, L., Gu, F., Fu, X., Fu, L. Clinicopathologic characteristics of pleomorphic carcinoma of the breast.Virchows Arch (2010) 456:31–37
15. Kymionis GD, Dimitrakakis CE, Konstadoulakis MM et al (2001) Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients? J Surg Res 99:161–168
16. Wahed A, Connelly J, Reese T (2002) E-cadherin expression in pleomorphic lobular carcinoma: an aid to differentiation from ductal carcinoma. Ann Diagn Cytopathol 6:349–51
17. Tavassoli FA, Eusebi V (2009) Tumors of the breast. American Registry of Pathology/AFIP, Washington
18. Hardy, Gh Mendelian Proportions in a mixed population.". Science (Jul 1908). 28 (706): 49–50.
19. Weinberg, W. "Über den Nachweis der Vererbung beim Menschen". Jahreshefte des Vereins für vaterländische Naturkunde in Württemberg (1908). 64: 368–382.

 

Back to Types of Lesions list.