Breast cancer

 
 
History
Epidemiologija
Etiology
Pathology
Diagnosis
Classification
Differential diagnosis
Treatment
Prognosis
Screening
 

DIAGNOSIS 

Main diagnostic methods for detection of breast cancer are anamnesis, physical examination and mammography. However, a biopsy for pathological evaluation should be performed for exact diagnosis. Different techniques are used to obtain pathological material, but two of them are mostly used: 1. cytological evaluation of the breast discharge i.e. of the aspirated material from the breast; 2. intraoperative biopsy with histologic evaluation of the frozen section.The first method is suitable for diagnosis.The second method is extremely valuable for the selection of the treatment for breast cancer depending on histological verification of the relation of malignant cells towards basal membrane, in other words, whether the cancer is invasive or non-invasive.

Indirect diagnostic methods are: self-examination (harmless, easy to learn, free of charge), anamnesis, physical examination, native mammography, ultrasound, and new diagnostic techniques such as MRI (Magnetic Resonance Imaging), digital mammography, CAD (computer-aided diagnosis), PET (positron emission tomography), SPECT (single photon emission imaging and computed tomography) termography, diaphanoscopy, markers (14,79).

Anamnesis is consisted of two parts: 

Physical breast examination should be done with the patient in both the sitting and supine positions, and care should be taken at all times to be gentle.  A thorough physical breast examination should be done to locate any lump or suspicious area. The skin of the breast and the nipples should also be carefully inspected. It is important to notice any discharge from the nipple.  The lymph node under the armpit should be palpated.

Porrath’s form of physical examination of breast is shown in figure 27 (79).  Although, by this exam is possible to discover only lumps which are greater than 1 cm, its importance is very emphasized, especially when combined with mammography due to its importance as a complementary examination method (4).  But, sometimes ultrasound can give dubious results although mammography result is negative (80).  Sensitivity of mammography, ultrasound and palpation is shown in figure 26(81).

 

Mammography and ultrasound of breast

Ultrasound (after physical examination) is important diagnostic technique in the population of younger women (figure 30), due to its sensitivity and specificity that is higher in that period compared to mammography (figure 28 and 29).  The reason for that is the fact that the largest volume of the breast in the generative age is made of hyperechogenic gland tissue, while in the menopause gland tissue is replaced with hypoechogenic fat tissue.  In elder population, methods are complementary, but since mammography is easier to perform and adequately sensitive, it is the preferred method.  It is important to know that these methods give us opportunity to find out whether the change exists or not.  In order to decrease the number of unnecessary biopsies, each suspicious change should be verified by citopunction.  Moreover, certain number of breast cancers can not be discovered by mammography, 10-25% palpable breast cancers are not visible by mammography, and the patients discover additional 20-25% in the period between mammographic and clinical controls (105).  The sensitivity of those techniques is showed in figures 29 and 34 (5,12,20,82,83).


Markers of the breast cancer are the substances that exist in the body of the patient in higher concentration than in healthy organism. 
The level of the carcinoembryonic antigen (CEA) is increased for a few percentages in I and II stage of breast cancer.Although, other markers, CA 15-3 and CA 549, are higher in 20% to 50% of patients with primary breast cancer, are also higher in 20% of patients with benign breast tumors and with gastrointestinal diseases.Katepsin D could be more important diagnostic test due to its specificity in breast cancer.But, generally speaking, we can not say that any of the markers separately are specific only for breast cancer, nor any of them, even in combination could imply to early stage of the breast cancer.In order to propose diagnosis of breast cancer and to observe treatment success, elementary laboratory techniques such as sedimentation, total blood exam, biochemical examination (SGOT, SGPT, gamma GT, alcaline phosphatase with isoenzymes, LD, LDH) are needed.X-ray of lung is compulsory before any therapeutic treatment.

CLASSIFICATION 

TNM CLASSIFICATION
Besides histopathological features, clinical stage of tumor is considered as an important factor in order to get valid prognosis and proper treatment.Frenchman, Pierre Denoix, in the period from 1943 to 1953 gave the basic classification of the malign tumors according to their dissemination. He classified tumor (T) according to tumor dissemination to regional lymph nodes (N), or if it has already given metastasis (M). For this reason he named this classification the TNM system. Today, staging of cancer is determined by UICC (International Union against Cancer).The UICC classification is based on the TNM system and it was changed in 1987 in order to bring closer UICC’s and AJC’s (American Joing Commission on Cancer Staging and End Results Reporting) classifications. It is the result of clinical, radiological and laboratory exams (table 5.) (4,65).

Table 4. TNM breast cancer classification (65)
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
TisCarcinoma in situ: intraductal carcinoma, lobular carcinoma in situ or Paget  disease of the nipple with no tumor
T1 Tumor 2 cm or less in greatest dimension

T1a Tumor 0.5 cm or smaller

T1b More than 0.5 cm but not more than 1 cm in greatest dimension

T1c More than 1 cm but not more than 2 cm in greatest dimension

T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3 Tumor more than 5 cm in greatest dimension
T4 Tumor of any size with direct extension to chest wall or skin (Chest wall includes ribs, intercostal muscles and serratus anterior muscle, but not the pectoral muscles)

T4a Extension to chest wall

T4b Edema, ulceration of the skin of the breast (including peau d’orange) or satellite skin nodules confined to the same breast

T4c Both (T4a and T4b)

T4dInflammatory carcinoma

PNx Regional lymph node metastasis cannot be assessed
pN0 No regional lymph node metastasis
pN1 Metastasis to one or more movable ipsilateral axillary node
pN2 Metastasis to ipsilateral axillary lymph nodes that are fixed to one another or to other structures
pN3 Metastasis to one or more ipsilateral internal mammary lymph node
Mx Presence of distant metastases cannot be assessed
M0 No distant metastasis
M1 Distant metastasis (including metastases to one or more ipsilateral supraclavicular lymph node)
pN1a Micrometastasis, none larger than 0.2 cm
pN1b Metastasis to one or more lymph node, any of which is larger than 0.2 cm

pN1bI Metastases in one to three lymph nodes, any of which is larger than 0.2 cm and all of which are less than 2 cm in greatest dimension

pN1bIV Metastasis to a lymph node 2 cm or more in greatest dimension

 

STAGING
Staging refers to the grouping of patients according to the extent of their disease.It is important in determining the choice of treatment for individual patients, estimating their prognosis, and comparing the results of different treatment programs. (table 5 and figure 33) (20, 86,87).

Table 5. Breast Cancer Stage grouping (86,87).
  T(Tumor) N(Nodes) M(Metastasis)
Stage 0 Tis N0 M0
Stage I T1 N0 M0
Stage IIA T0 N1 M0
T1 N1 M0
T2 N0 M0
Stage IIB T2 N1 M0
T3 N0 M0
Stage IIIA T0 N2 M0
T1 N2 M0
T2 N2 M0
T3 N1,N2 M0
Stage IIIB T4 Any N M0
Any T N3 M0
Stage IV Any T Any N M1


DIFFERENTIAL DIAGNOSIS

There is an important principle that each suspicious change in the breast must be considered as a malign tumor, until proved differently.  That principle imposes biopsy of all those lesions.

It is prudent to pay attention to some of the lesions that appear more often in certain women age.Cystic hyperplasia, fibroadenoma and mastitis occur more often before the age of 35.Between the ages of 40 and 60, breast tumors are the most numerous.  Incidence rate of breast cancer is growing with the age.


TREATMENT

Breast cancer treatment is conducted according to the protocol, depending on histological type of tumor, stage of malign process and total physical condition.Different combinations are used: surgical treatment, radiotherapy, chemotherapy, hormonal therapy and immunotherapy.In most cases treatment begins with surgery.Today, radical mastectomies, according to Halsted and super radical interventions with toracotomia are mostly replaced with breast-conserving surgery like quadrantectomia.At patients with histological signs of invasive breast cancer, more often, besides surgery and radiation, systematic therapy is used in order to prevent relapses.

Figure 34. shows decrease of mortality rate from breast cancer in England and Wells and that can be explained by earlier diagnosis and better treatment.


PROGNOSIS


Prognostic factors of breast cancer are summarized in table 6.Some of them are reliably approved, like tumor size, histological differentiation and PHD, while reliability of other prognostic factors still needs to be approved.

The most malign development according to histological classification has ductal invasive carcinoma, followed by invasive lobular carcinoma. Medullary and mucinous carcinoma have better prognosis.

It is known that tumor development as well as prognosis depend on histological differentiation.  Well-differentiated tumors have slower development and metastasize later.  Poorly differentiated tumors are more malign; the most malign tumors are anaplastic tumors.

Good prognostic factor is inflammatory cell reaction composed of lymphocytes and/or plasma cells in tumor stroma, and around metastases.  Medullary carcinoma in whose stroma is extensive inflammatory reaction is taken as a model.

BCDDP (Breast Cancer Detection Demonstration Project) study showed that the survival rate depends not only on clinical stage of disease but also on patient’s age (figure 35,36 and 37) (92,93).


The 5-year survival rate for patients with localized breast cancer, properly cured, is 98%, i.e. 95% after 10 years, whereas patients with metastasis have 30%, i.e. 50% after 10 years (83).

Today, breast cancer research is mainly related to molecular biology.  There are many new insights; some of them are shown in table 6.

Table 6.Prognostic factors of breast cancer
Patient age (35,92,94)
Obesity (43,44,95,96)
Correlation against tumor and basal membrane (97)
Size of the primary tumor (98-100)
Histological type of tumor (10,35,94,99)
Histological differentiation of tumor (35,99)
Proliferate ability of tumor cells (mitotic index, index of signed cells with 3H timidine-LI) (35,97)
Characteristics of the inflammatory reactions in the tumor (97, 101)
Presence of blood vessels invasion (35, 97, 101)
Status of lymph nodes (number, localization and size of positive lymph nodes) (97, 100)
Metastases and their locations (102)
Expression of the estrogen and progesterone receptors (103, 104)
Ploidy (DNA index)
Proliferating cell nuclear antigen(PCNA) (97)
Proliferation marker MB-1 (97)
Expression of HER-2/neu oncogene (36,97)
Expression of tumor suppressor gene p53 (31,33,35)
Expression of tumor suppressor gene MMP-2 (97)
Expression of tumor suppressor gene nm23 (35)
Expression of receptors for epidermal growth factor (EGFR) (97)
Expression of laminin receptors (LR) (106)
Srp-27 protein expression (106)
Katepsin D expression (35,97)
Level of the 5-hidroksimetil-2’-deoksiuridin UDNA (107)



SCREENING

Because of the connection between early detection and improved outcome, proper screening method is the main aim. Many studies have proved that screening of breast cancer is evidently useful for women aged 50 to 74, but it is under debate for women aged 49 and younger (5,108,109).

Methods of early detection are self-examination, physical examination, ultrasound and mammography (19).

The best guidelines for early detection of breast cancer are shown in figure 38.Women aged 20 or older should perform breast self-examination every month. Over age 35, women should have a breast exam by health professional every year.Base line mammography, women should have at age 40 or earlier if they are in a high-risk category (after age 35).Mammography should be repeated every two years, i.e. every year for women aged 50 (88, 110).

Regular mammograms (figure 38) can decrease breast cancer mortality rates for women aged 50 to 69 years by 30% (111).