Breast cancer

Differential diagnosis


 The oldest record of breast cancer dates back to 1600 BC.  A 4,68 meters long papyrus describing 48 surgical cases included at least 8 breast diseases, and among these one was almost certainly breast tumor (45th case).  Edwin Smith discovered this papyrus (Teba 1862. Year), which is  believed to be written by Imhotep who was proclaimed as a God in an old Egypt.  This document on papyrus is the oldest known medical record.  It is supposed that the papyrus was in fact a transcript made in 1600 BC, the original papyrus was much older, from about 3000 BC.

Also described in the treatment of these tumors or ulcers of the breast was the use of cauterization, with a tool called the “fire drill".  The author concluded that there was no successful treatment for breast cancer.

A well-known patient from the end of 6th century BC, the queen of Atos, Kiros’s daughter and Darius’s wife supposedly had breast cancer.  Herodot (a Greek historian) wrote, “she had a swelling of the breast (phyma) which broke and started to enlarge”.  However, she was completely cured without mutilation of the breast by the Persian doctor Democedes from Kroton.  Hence it is now believed that the queen did not have a malignant tumor but rather mastitis.  In fact, Herodot who was usually very precise in his technical writing, in this case used the ambiguous word phyma which can either mean abscess or neoplasm (4).  Herodot described Alase’s (daughter of Cyrusa) case (535 BC).  She found a nodule in her breast, but she concealed it until it broke through the skin like an open wound.  Then her father called a doctor who successfully took out the tumor (1).

Celzo realized the value of surgery in the early stages of the breast tumor and said that only small tumors could be removed, while larger tumors were only irritated by surgical intervention.  Hippocrates (460 AD) distinguished between benign and malignant tumors.  He considered breast cancer incurable (2).  According to the doctrines of the Greek physician Galen (130-200 AD), melancholia was the chief factor in the development of breast cancer.  Special diets and exorcism (5) were the recommended treatments.

Santa Agatha is the women’s patroness for breast cancer.  According to the legend, she was an extremely beautiful girl from rich and respected family.  She lived in Catania on Sisily during the rule of the roman emperor Decia (200-251 AD).  Decia sent his regent (governor) Kvintian to Sisily to exterminate the Christian’s.  There he heard about the young and beautiful Agatha and he ordered for her to be brought to him.  Agate, who was a Christian woman, declined him due to her religion.  Therefore, Kvintian decided to throw her into prison.  Then he sent Afrodisia, who was infamous for prostituting even her own daughters.  For thirty days she unsuccessfully tried to convince Agatha to become Kvinian’s.  Exasperated, he ordered Agatha to be tortured.  Her arms and legs were stretched by ancient devices then with glowing pincers one breast was amputated (Tiepolo depicted, figure 1).  Then Agatha asked: “Aren’t you ashamed to cut off what your mother used to feed you with?”  She was also forced to walk barefoot on hot coals.  But, then a huge earthquake caused one wall to fall into the court, which resulted her death.  Agatha was sainted, the woman martyr and the patroness of breast diseases.  Her sacrifice is remembered on February the 5th (7-11).

Leonidus from Alexandria described breast cancer surgery for the first time in the first century after Christ.  The procedure included removal of the cancer and some undiseased tissue and skin.  To stop bleeding he used cauterization.  Cutting and cauterization was performed until the whole tumor and the breast was removed and the injured surface became covered with a crust.

An English physician, Thommas Willis (1621-1675), used almost the same definition of tumor with respect to neoplasia as it is used today.  According to him, tumor is the “disturbance of growing primary characterized cells with uncontrolled, non purposefully dividing cells”

During the Renascence, Andreas Vesalius (a Flemish anatomist who questioned the medical doctrines of Aristotle and Galen and whose “DeHumani croporis fabrica” formed the basis from which modern research was developed), recommended mastectomy as well as ligatures (sutures) to control the bleeding, rather than cautery.  Recognition that breast cancer could spread to the regional auxiliary nodes (lymph nodes under the underarm) was first recognized by the physician LeDran (1685-1770).  Dr. LeDran was likely the first to associate poor prognosis with the spread of breast cancer to the lymph nodes (6). 

The first epidemiological data of breast cancer came from Middlesex Hospital in London (1791-1805), where the first breast cancer cases were registered, 250 of these patients refused treatment (12). Although the study of anatomy improved in the 18th century, the outcome of breast surgery did not, due to infection, lack of good anesthesia, and the use of complete radical mastectomy.  A new era of surgery and medicine began with the discovery of NO as an anesthetic in 1846, antiseptic technique in 1867, and microscopic histological analysis.

Two physicians, Halstead and Meyer, brought light to the ill-fortuned women diagnosed with the breast cancer.  In 1894 each independently announced their surgical procedures and results for treatment of breast cancer.  They described, for that period of time, superior local control of disease by en bloc radical mastectomy which included total removal of affected breast, total ipsilateral axillary lymph node dissection in levels I-III, resection of pectoral major and minor muscles, and routine resection of thoracodorsal neurovascular network including the long thoractic nerve.  Halsted’s opinion was based on the study of well known German cellular pathologist Rudolf Virchow, who considers cancer local disease and the lymph nodes were the natural barrier to the dissemination of cancer cells.  Based on this hypothesis, complete cure can only be achieved by the local removal of tumor along with adjacent healthy tissue.  Halsted focused on treating the patients with high stage of the disease, but he noticed the breast cancer in earlier stages as well.  He reported the removal of an ‘early’ breast tumor 8 x 7 cm in size.  A ten years survival rate of 34% was realized, which at that time was clearly superior to other efforts.  Radical mastectomy according to Halsted brought a new era and approach to breast cancer treatment (5,12-15).

Wilhelm Conrad Rontgen (1845. – 1923.) discovered X-rays in 1895 and one year after Henry Becquerel uranium radioactivity.  Pierre and Marie Curie isolated radium from uranium.  Several attempts and failures occurred until 1912 when W. Sampson Handley said: “The principle of using X-ray for treatment of breast cancer is prophylactic against postoperative relapse.  Even in late stages of breast cancer X-rays are an effective way of palliating the pain.“  During the mid 1900’s, x-ray diagnosis of breast improved so dramatically that detection of non palpable tumor in the breast was enabled.  This allowed new surgical operations such as lumpectomy, quadrantectomy and segmentectomy to be used. 

From 1896, when Beatson published that the surgical castration (bilateral oopherectomy) of two patients resulted in tumor regression, hormonal therapy of breast cancer has progressed through several stages, but correlation between hormones and tumor growth was not proven until hormonal receptors were discovered on breast cancer cells (1,3).  In 1955 Engell published proof of hematogenous dissemination of malignant cells.  This research pushed efforts for systemic chemotherapeutic agents and immunotherapeutic agents for the treatment of metastatic breast cancer.

“Sisters of Mercy Hospital” in Zagreb, established in 1845 by the bishop Haulik in the monastery of St. Vinko, had 12 beds only for women and some of them were treated for breast cancer.  The first hospital surgeon was Dr. Theodor Wicherhauser for whom Cackovic wrote, “he does not perform large operations even in cases of obvious carcinoma, he rather removes the breast containing cancer along with the axillary lymph nodes“



Breast cancer is the most common malignant tumor among women.  In many countries it is the leading cause of death from the malignant diseases among women.

According to the data of most countries of the world, except Asia, the incidence and mortality increases with age.  The highest rate being among women over 85 where the incidence is over 350/100.000 (20).

The risk of breast cancer development in women is one out of eight, which means that every eighth woman in the life period will have breast cancer.  Breast cancer occurs 100 times more often in women than in men (4,21).

According to the State cancer registry, Croatian department for public health, incidence and mortality rate of breast cancer in Croatia has been rising steadily over the last two decades and increases with the age of the patient.  In Croatia, breast cancer is the leading cause of mortality among all cancer in general.  The major cause of death in women between forty and fifty years old is breast cancer. More women die from breast cancer than from all other disease put together.  In Croatia, 1400 new cases of breast cancer are discovered each year with tendency to constant growth as it is the case in the rest of the world.  In our country each year approximately 31,5/100.000 women are diagnosed.  In older women the incidence is higher per annum, 128/100.000 between ages 65-69 and 191/100.000 over the age of 85.  Herewith, Croatia belongs to the counties with the high rate of risk of breast cancer morbidity and mortality (4,20,22).

There are great geographical differences in the number of newly discovered cases, and there is even distribution counties of high risk (North America and North Europe), middle risk (South America and South Europe) and low risk countries (Asia and Africa) (figure 15) (4,23).

According to the data from 1990 in the USA every 15th minute 4.28 new cases of breast cancer are registered and within the same period of time one woman dies from breast cancer (4).

Black women have significantly lower incidence of breast cancer (maybe because of earlier and numerous deliveries), but higher mortality (probable due to the later detection, rarely positive hormonal receptors and worse socio-economical status, although molecular factors are not significantly different), as it is shown on the figure 16 (24-66).

Considering the location in the breast, cancer occurs more often in the outer upper quadrant (38,5%) (figure 17) (4).


Etiological factors responsible for breast cancer development is still not known completely, but epidemiological evidence significantly suggests on three possible group of genetic, endocrine and exogenous factors (28).

Genetic mutations responsible for genesis of breast cancer are:

1.      activation of protoonkogen (HER-2/neu (17q)),

2.      inactivation (loss or mutation) of tumor suppressor gene: 1p, 1q, 3p, 5p, 6q, 7q, 8p, 9q, 13q, 15q, 16q, 17p (p53), 17q (BRCA1 i NF1) and 18q

3.      inactivation of genes responsible for the repairing of damaged DNA (29-40).

Breast cancer family history is important for the first generation of female family members i.e. mother, daughter and sister.  Women whose mothers had bilateral breast cancer before menopause carry the highest risk.  They have even nine times higher risk than others, i.e. 50% of them can get ill (28).

Endocrine factors are connected to the endogenous hyperestrogenism, and exogenous intake is connected to the intake of oral contraception (OC) and with hormone replacement therapy (HRT).  The most mentioned risk factors are: long period of generative time (earlier menstruation and later menopause), infertility, late age at first full-term pregnancy and obesity (41-44).

Influence of physical exercise to the age of the first menstruation is very significant, due to that the girls who exercise regularly whether they practice ballet, swim or run, get menstruation later than others.  In one study girls who played ballet got menstruation at 15,4 in comparison to the control group who got menstruation at 12,5 years (45).

  There are evidences that hyperestrogenism is connected to the fibrocystic epithelial hyperplasia. Moderately increased (although disputed) risk is determinated by exogenous estrogen (long usage of oral contraception or HRT in menopause) and rare breast cancer in castrated girls before puberty.  Many studies have been published about the influence of OC and HRT on breast cancer, which results are controversial, but the only clear conclusion is that they do not protect from the breast cancer (46-56).  Normal epithelium of the breast has estrogen and progesterone receptors.  They are proved only with some, but not with all breast cancers. Breast cancer cells in women produce different growth factors (TGF-alfa, PDGF).  Estrogens stimulate the production of these growth factors and it is possible that cross interaction of circulated hormones, hormonal receptors of cancer cells and autocrine growth factors have role in progression of breast cancer.

In order to predict response of breast cancer cells on the hormonal therapy, measurement of quantity of hormonal receptors in breast tissue is used (2). In postmenopausal period larger source of estrogen is fat tissue, where conversion of adrenal androstenedione into estrogen occurs (57).  Women aged under 50 have little or not at all increased risk connected to the body mass (TM), while women over 60 with 10 kilos increased body mass have about 80% increased risk of breast cancer development (58).  Visceral obesity, which can be evaluated by CT, significantly occurs with obesity patients with breast cancer (16,43,59-61).

Exogenous factors are connected to the viral infections, higher consumption of alcohol, exposure to ionized radiation (natural and artificial), smoking, long term hair dyeing and stress (4,28,62-64).

Virus, as an etiological factor of breast cancer, incriminated in 1936 year by Bittner’s discovery that a filterable agent transmitted through the mother’s milk, causes breast cancer in suckling mice.  The virus, called mouse mammary tumor virus (MMTV) was later recognized as a retrovirus.

There are some indications of the existence of the similar virus in the breast cancer in the humans, but research results are not convincible.

According to the numerous prospective studies alcohol consuming increases the risk of the breast cancer development, meanwhile the moderate consumption of alcohol acts as a protective factor on the cardiovascular system. 

The level of selenium in the serum of the patients with breast cancer is significantly lower then in healthy population.  Vitamin A and increased consuming of vegetables and fruits decreases the risk.  In the Mediterranean countries, in women who consume olive oil, the incidence is lower.

Radiation exposure increases the risk of breast cancer development.  For example, A - bomb thrown on Hiroshima and Nagasaki significantly increased incidence of the breast cancer in that region after latent period of 20 years.  In other words, the highest incidence was noticed in women who were 10 to 14 years old in the moment of explosion and the cancer was diagnosed most often when they were between 30 and 49 years old. 

Certain number of patients connects trauma to the disease.  But, trauma could not be connected as a possible risk of breast cancer development.  It is quite possible that trauma just warns on already existing tumor (70).

Well-known fact is that the incidence of breast cancer in Japan or in China is 4 to 7 times lower than in the USA, but after few generations cancer incidence in Japanese, Chinese immigrants in the USA has become as equal as in domicile population. Thus, international mortality (1/100000) varies (in the period from 1983. – 1987.) from less than 6 in Japan, till almost 30 in England and Wales (7).

Psychiatric patients have 3,5 times higher incidence of breast cancer in comparison to other patients, i.e. 9,5 times higher in comparison to all women population.  It is still not known whether the stress caused by disease or medication therapy or something else (72).

One of exogenous predisposed factors in disease development is stress, however, as we find stress hard subject to any kind of measurement in the literature there are little information about it. 

On the other hand, there are few cases of breast cancer where it was not possible to prove the influence of any aforementioned factor.



The breast is composed of epithelium, connective and fatty tissue, so the tumors that can be developed in the breast are the tumors of those tissues, and can be benign or malign.  Malign breast tumors are more often epithelium origin (cancers) (4).

There are so many classifications of malign breast tumors but two are most used: classification according to the World Health Organization (WHO) (table 1) and classification according to the Armed Forces Institute of Pathology (AFIP) (table 2.) (28, 73, 74).

In regard of the relation between malign cells to basement membrane, cancers can be noninvasive (cells do not invade through the basement membrane) or invasive (cell invade through the basement membrane). The most common pathohistological type of breast cancer is the invasive ductal carcinoma (makes over 80% of all breast cancers) then follows, according to the frequency invasive lobular (10%), than medullary carcinoma (5%).  Medullary carcinoma is less common in older age than younger age.  Mucinous and papillary carcinoma are more common among older women, but make less than 10% of all breast cancers (20).

Table 1. WHO classification of breast cancer (28).
A. Noninvasive 
1. Intraductal carcinoma
2. Intraductal papillary carcinoma
3.  Lobular cancer in situ
B. Invasive (infiltrating)
1.  Invasive ductal carcinoma - not otherwise specified (NOS)
2. Invasive lobular carcinoma
3. Medullary carcinoma
4. Colloid carcinoma (mucinous carcinoma)
5.  Paget’s disease
6. Tubular carcinoma
7.Adenoid cystic carcinoma
8. Invasive comedo carcinoma
9. Apocrine carcinoma
10.  Invasive papillary carcinoma


Table 2. AFIP (Armed Forces Institute of Patology) classification of malign breast tumors modified according to Rosen (73,74).

Intraductal carcinoma
Intraductal carcinoma with Paget’s disease
Lobular carcinoma in situ


Invasive ductal carcinoma
Invasive ductal carcinoma with Paget’s disease
Invasive ductal carcinoma with predominant intraductal component
Invasive lobular carcinoma
Medullary carcinoma
Mucinous carcinoma
Invasive papillary carcinoma
Tubular carcinoma
Adenoid cystic carcinoma
Secretory (juvenile) carcinoma
Apocrine carcinoma
Carcinoma with metaplasia
Carcinoma with giant cells that are like osteoclasts
Cystic hypersecretory carcinoma with invasion
Carcinoma with endocrine differentiation
Carcinoma rich with glycogen
Carcinoma rich with lipids
Invasive cribriform carcinoma

Inflammatory breast carcinoma
Carcinoma during the pregnancy and lactation
Occult carcinoma with metastases in the axillary lymphatic nodules
Carcinoma of the ectopic breast
Carcinoma in men
Carcinoma in children
Malign cystosarcoma phyllodes
mesenchymal CANCER
Dermatofibrosarcoma protuberans
Melanoma of the nipple
Carcinoma of the
squamous cells of the nipple
Carcinoma of the basal cells of the nipple
Carcinoma of the skin
Non-Hodgkin lymphoma
Leucemical infiltration
Hodgkin disease

Histopathological gradation of breast cancer according to Blom-Richardson is also important to mention.  That gradation shows the way of growth of ductal invasive cancer and cytological characteristic of differentiation (table 4) (75,76).

Table 3. Histopathological gradation of invasive ductal cancer according to Blom-Richardson – Elston’s modification (75,76).
Grading parameters
a) Formation of the gland tubules and acini
1 point; characteristic formation of tubules (>75%)
2 points; moderate formation of tubules (10-75%)
3 points, little or without tubules at all (<10%)
b) Pleomorphism of cancer cells nucleus
(abnormality in size, shape and structure)
1 point; isomorphism of nuclei
2 points; moderate variability in size, shape and in structure of nucleus
3 points; characteristic polymorphism
c) Mitoze / 10 hpf
1 point; < 9 mitosis
2 points; 10-19 mitosis
3 points; > 20 mitosis
After summing the points of all parameters the level of differentiation can be determined according to the following scheme:
G1; well differentiated (3-5 points)
G2; moderate differentiated (6-7 points)
G3; poorly differentiated (8-9 points)

Ductal carcinoma are the most common forms of breast cancers.  According to the certain authors they make 90% of all mammographically found beforehand undiscovered cases.  That is the most aggressive type of breast cancer.  Very often it becomes invasive type, in twice as shorter period of time than lobular, so it takes 20 years for intralobular form to become invasive, and ductal takes only 10 years.  All ductal cancers are not equally aggressive.  These tumors are divided in subtypes: comedocarcinoma, cribriform, apocrine, papillary, micropapillary and solid type.  Comedo and cribriform are the most aggressive ones (2).

Lobular carcinoma represents 11% of all breast cancers.  Its characteristic is manifestation in both breasts, whether at the same time or in one breast after another.

Invasive ductal carcinoma (NOS) is the most common type of breast cancer, and makes 75% of all breast carcinomas.  Macroscopically, the cancer is obviously invasive and invades connective tissue stroma. It has very hard consistency that crunches when scraping with knife.  Small foci of calcifications are often evident on the cut surface.  It could cause retraction of skin or/and retraction of nipple, and fixation to the underlying chest wall.  Histologically, hard connective stroma can be seen, in which focuses or the rays of tumor cells are scattered about.  On the edges of tumor, tumor cells are infiltrated into surrounding tissue, very often invading perivascular and perineural spaces as well as lymphatic and blood vessels (figure 18) (2,9).

Tubular carcinoma or well-differentiated adenocarcinoma is diagnosed in 10 to 20% of cases and it can be relatively easily discovered by mammography. Macroscopically, tubular cancer is usually a small lesion, often smaller than 1 cm.  It has hard structure. Histologically, areas of sclerosis or deposits of elastin can be seen. Tubular cancer is often combined with intraductal cancer (in 65% cases).  Tumor cells are often atypical and show numerous mitosis.  About 10% of tubular cancers give metastasis. (figure 19) (2, 20).

 Lobular carcinoma is developed from one or more terminal ducts and/or from ductules (acini).  Often appears mutually (20%).  Two types are described: lobular cancer in situ and invasive lobular cancer.   In the first type cells are bigger than normal, with oval or round nuclei and small nucleoli.  Generally there are no mitosis and neither polymorphism.  Dilatation of acinus is characteristic indication.  Around 30% of patients develop cancer in the same or in other breast, but the infiltrating carcinomas that developed are either lobular or ductal.  Invasive lobular cancer makes 5 to 10% of breast carcinoma.  Macroscopically, lobular carcinoma is poorly edged and usually of rubber consistency, sometimes hard and scirrhous.  Histologically, cancer cells are mostly small and uniformed with small rate of polymorphism (figure 20) (2, 77)

Medullary carcinoma (carcinoma medullare) represents about 1% of breast carcinoma.  It is rather soft and fleshy than hard on external palpation.  On section usually stands out.  Histologically, the carcinoma is characterized by solid, syncytium-like sheet of large cells that are mainly undifferentiated, although sometimes are well differentiated.  Lymphatic infiltration is common finding. (figure 21) (2).

Colloid or mucinous carcinoma (carcinoma colloids seu mucinosum) is characterized by intracellular and extracellular mucinous formation.  Macroscopically, colloid carcinoma is consisted of tender and extensive gray-blue nodules, gelatinous consistency.  Histologically, there are two forms of tumor.  In the first form, cancer cells are visible as small islands or even as isolated cells that float in great lakes of mucin, which leaks into surrounding tissue space.  In the second form, the cells grow into well-presented gland formations.  In both forms, tumor cells can be vacuolated by the mucin content (figure 22) (2).

Paget’s disease (morbus Paget) is the special type of ductal carcinoma, which afflicts women in older age.  It begins as the typical intraductal cancer that arises from main excretory ducts of the breast and extends intraepithelially to involve the skin of the nipple and areola.  Afflicted skin is frequently fissured, ulcerated and oozing.  There is surrounding inflammatory hyperemia and edema and often also bacterial infections follow.  The histologic hallmark of this tumor is invasion of the epidermis with characteristic tumor cells called Paget’s cells.  These cells are large and hyperchromatic, surrounded with a lightly stained ring that represents intracellular deposit of mucopolysaccharides.  Morphologic picture is similar to the intraductal carcinoma, but this type of cancer has better prognosis (figure 23) (2,9).