Category Archives: cancer primary

Carcinoma – Paget’s Disease of the Nipple

Author Lisa Wiechmann MD

Historical notes

The first documentation of paget’s disease was carried out by John of Ardenne in 1307 who described nipple ulceration in a male priest that evolved into breast cancer. In 1874 Sir James Paget documented the association of the ulceration of the nipple with an underlying breast cancer in 15 patients, but erroneously speculated that the skin condition was benign. Such a conclusion was then rectified in 1881 by Thin who concluded that the skin condition was a malignancy.

Pathogenesis

There are two main theories for the origin of Paget’s disease of the nipple: the epidermotropic theory ( Paget cells arise in breast ducts and migrate to the epidermis) and the intraepidermal transformation theory ( Paget cells arise from the terminal portion of the lactiferous duct). The first theory is supported by the fact that more than 97% of patients with Paget’s disease of the nipple have an underlying breast carcinoma.

Clinical presentation

Paget’s disease typically presents as erythema and scaling of the nipple skin that progresses to crusting, skin erosion and ulceration if left untreated. Symptoms may include pruritus, tingling, hypersensitivity, burning or pain. Many diseases must be included when differentiating Paget’s disease from other conditions that lead to erythema and scaling of the skin. The differential diagnosis therefore includes: eczema, contact dermatitis, postradiation dermatitis, and Paget’s disease. Bilateral changes are most consistent with eczema and contact dermatitis. Less common differential diagnoses include nipple adenoma and a variety of skin cancers ( melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma).

Diagnosis

Diagnosis is obtained in a variety of ways including scrape cytology, shave biopsy, 2mm punch biopsy, wedge incisional biopsy or nipple excision. Immunohistologic staining is useful in the differentiation of Paget’s ( + for keratins- CK-7, CAM-5.2, + for S100) from other malignancies.

The typical histologic appearance of the Paget cell is that of a large pale-staining cell with round or oval nuclei and prominent nucleoli ( as shown below). Paget cells are between the normal keratinocytes of the nipple epidermis ( single cells in superficial layers and clusters near the basement membrane.

Incidence

Paget’s disease is diagnosed pathologically more frequently than it is clinically . Its clinical incidence ranges from 0.5% to 2.8% (mean 1.3%) whereas its pathological incidence is approximately 4%.

Treatment

Treatmetn of Paget’s disease varies depending on the presence of underlying breast carcinoma or DCIS. Mammogrephic evaluation looking for evidence of breast cancer is therefore part of the routine evaluation of patients with Paget’s disease (bilateral mammograms). If available, preoperative MRI of the breast can identify occult disease. When possible breast conserving surgical intervention should be considered. THe combination of radiation to breast conserving surgery has been shown to decrease recurrence rates. For patients undergoing mastectomy or breast preservation, the decision of evaluation and treatment of axillary nodes should be reserved for invasive breast cancers.

 

Carcinoma – Medullary

Author Lisa Wiechmann MD

Overview

Breast cancer is the leading cause of death in women 40-55 years of age. It represents the second leading cause of cancer death among american women (all ages) following lung cancer. Approximately 1 in 8 (12.5%) american women will be diagnosed with breast cancer during thier lifetime, and the risk of dying from the disease is approximately 3.4%. Breast cancer accounts for approximately 30% of cancers in women. It’s incidence increases rapidly after 40 years of age and after menopause the rate of increase is slower. Furthermore incidence of breast cancer has been steadily increasing over the past 70 years as demonstrated by data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER). Part of this increase has been attributed to an increased detection rate related to the use of mammography. Survival rates have also increased steadily for women with local and regional disease and this is probably due to both earlier detection of cancer and improvement in therapies.

Medullary carcinoma of the breast represents less than 5% to 7% or ivasive breast cancers. Some studies have associated it with a more favorable prognosis, but the difficulty in reproducing its diagnosis histologically, has led to significan controversy. Overall at 10 years there appears to be no difference in recurrence rates between patients with medullary carcinomas and other subtypes of invasive breast cancer.Clinically, medullary carcinoma presents at a slightly younger age (late 50s, early 60s) as a palpable mass, usually in the upper outer quadrant. Rarely, it has been documented in men; it is associated with BRCA-1 mutations in many cases.The mammographic features of medullary carcinoma include the presence of a well defined mass and the absence of calcifications. On ultrasound, these carcinomas are usually well defined , lobulated , hypoechoic masses.

 

Risk Factors

Multiple factors appear to be involved in the pathogenesis of breast cancer: these include genetic factorsenvironmental factors and endocrine factors. Gender is the most important risk factor for the development of breast cancer, which occurs 100 times more frequently in women than in men. This is due to endocrine factors as mentioned above: factors that increase the number of menstrual cycles (exposure to estrogen) such as nulliparity, late pregnancy (after 30 years of age), early menarche and late menopause( > 30 years menstrual time), are associated with an increased risk of breast cancer. Protective factors include moderate levels of exercise, and a longer lactation period. exposure to exogenous estrogens (oral contraceptive pills and hormone replacement therapy if prolonged in their duration- > 10 years) has though data is controversial. Age is an important risk factor for the development of breast cancer ( which translates in years of exposure to estrogen) ( risk of white American woman at 30 years 1:5,900, at 80 years 1:290)

Infiltrating lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges and serosal surfaces. Clinically they may present as poorly defined areas of thickening of the breast. Radiologically microcalcifications may be present or absent.

reference www.cancervic.org.au

 

Prior history of breast cancer is a significant risk factor for the development of breast cancer[0.5-1 per year of follow-up] . proliferative breast diseases have now been found to increase the risk of breast cancer slightly 1.5-2 times the risk (papillomas, florid hyperplasia without atypia, sclerosing adenosis), moderately – 4 to 5 times the risk (Atypical ductal and lobular hyperplasia) and severely- 8 to 10 times the risk (lobular carcinoma in situ).

Environmental factors include exposure to ionizing radiation (mantle radiaton therapy for Hodgkin’s lymphoma -75-fold increase in risk, survivors of the atomic bomb) if exposure was before age 30) and potentially obesity (controversial) and alcohol ( no conclusive evidence). In mice a virus called mouse mammary tumor virus (MMTV), transmitted through the mother’s milk, causes breast cancer in suckling mice. No such virus has been identified in humans to this date.

Family history

Any family history of breast cancer increases a woman’s risk of breast cancer, especially if found in first degree relatives. Such risk is dependent on the characteristics of the cancer in relatives ( age at presentation, unilateral or bilateral, number of relatives with cancer).

Genetics

Recently attention has been focusing on genetic alterations that determine predisposition to breast cancer. Numerous autosomal dominant conditions have been found to be associated with increased risk of breast cancer: these include Li-Fraumeni Syndrome, Muir-Torre Syndrome, Cowden Disease, Peutz-Jeghers Syndrome and possibly Ataxia – telangiectasia carriers. Approximately 5-10% of breast cancer results from inheritance of germline mutations of genes (BRCA-1 and BRCA-2); such genes are inherited in autosomal dominant pattern with varying penetrance. BRCA-1 and BRCA-2 are tumor suppressor genes and loss of both alleles is required for initiation of breast cancer. They appear to be involved in DNA-repair pathways and control of the cell cycle. BRCA-1 is located on chromosome 17q and contains 22 coding exons (1863 amino acid protein). BRCA-1 mutations ( of which more than 500 are known) determine predisposition in up to 45% of hereditary breast cancers and in 80% or more of hereditary ovarian cancers. Women carrying the mutation have up to a 90% lifetime risk of breast cancer and a 40% lifetime risk of ovarian cancer. Carcinomas associated with the presence of BRCA-1 are typically invasive ductal carcinomas, are poorly differentiated and are hormone – receptor negative. They are also more frequently bilateral, have an earlier onset and are associated with the presence of other malignancies including ovarian cancer, and possibly colon cancer and prostate cancer.

The Jewish Ashkenazi population displays a 10 fold higher frequency of 2 founder mutations (185delAG and 5382insC) therefore screening of such mutations in then above population is indicated.

BRCA-2 is located on chromosome 13q and contains 26 coding exons (3418 amino acids). The biologic function of the gene transcript has yet to be delineated, but is thought to pertain to DNA repair mechanisms. More than 250 mutations of the BRCA-2 gene have been described and the lifetime risk of carriers has been estimated at 85% or more( ovarian lifetime risk 20%). Male carriers of the BRCA-2 mutations carry a 6% lifetime risk of breast cancer (100 fold increase from controls). Carcinomas associated with the presence of BRCA- 2 are usually well differentiated invasive ductal carcinomas and more frequently express hormone receptors. BRCA-2 associated breast cancers are frequently bilateral and may be associated with other malignancies including ovarian, prostate, colon, pancreas, gallbladder, bile duct, and stomach cancers as well as melanoma. A founder mutation (999del5) is observed in the Icelandic and Finnish populations.

The interaction of many different risk factors in the initiation of breast cancer has lead to the creation and use of risk-assessment models. This helps predict the risk of management and determine the best course of action. The most frequently used model was designed by Gail in 1970 and incorporates age at menarche, number of breast biopsies, age at first live birth and the number of first degree relatives with breast cancer. It is used to predict the risk of developing breast cancer per decade of life. One of the disadvantages of this model is that it doesn’t take into account age at which a family member was diagnosed and whether the disease occurred in both breasts — early onset and bilateral disease suggesting a BRCA mutation carrier

Numerous software programs incorporating the Gail model are available. One example is given below. Further links may be found at http://bcra.nci.nih.gov/brc

The Claus model, when compared with the Gail model, incorporates more information on family history. Both risk assessment models do not take into consideration risk factors such as diet, obesity, use of oral contraceptives, lactation or radiation exposure.

reference www3.utsouthwestern.edu/ cancergene/Gail1.pn

 

Identification of BRCA mutation carriers

Four steps are required for the accurate identification of BRCA carriers

  1. Comprehensive multigenerational history
  2. Assessment of appropriateness of genetic testing in patient
  3. Genetic counseling
  4. Interpretation of results

Adequate identification of risk ( BRCA mutations + other risk factors) will lead to sound medical decision making by both patient and physician. Use of hormone replacement therapy, timing of mammographic screening , chemoprevention and use of prophylactic mastectomies( which reduce the risk of breast cancer by 90%) and oophorectomies are all part of this decision making process.

Classification

www.digitalclinic.com/tnm.htm

Anatomical Sites and Subsites (Fig. 1)

  1. Nipple (C50.0)
    2. Central portion (C50.1)
    3. Upper-inner quadrant (C50.2)
    4. Lower-inner quadrant (C50.3)
    5. Upper-outer quadrant (C50.4)
    6. Lower-outer quadrant (C50.5)
    7. Axillary tail (C50.6)

Regional Lymph Nodes

The regional lymph nodes are:

  1. Axillary (ipsilateral):interpectoral (Rotter) nodes along the axillary vein and its tributaries, which may be divided into the following levels:
  2. i) Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle
    ii) Level Ii (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter) lymph nodes
    iii) Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis minor muscle including those designated as subclavicular, infraclavicular or apical
    Note: Intrammamary lymph nodes are coded as axillary lymph nodes.
  3. Internal mammary (ipsilateral):lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia.
    Any other lymph node metastasis is coded as distant metastasis (M1), including supraclavicular, cervical, or contralateral internal mammary lymph nodes nvasive ductal carcinoma

TN Clinical Classification

T – Primary Tumor

TX Primary tumor cannot be assessed
TO No evidence of primary tumor
Tis Carcinoma in situ: intraductal carcinoma, or lobular carcinoma in situ, or Paget disease of
the nipple with no tumor

Note: Paget disease associated with a tumor is classified according to the size of the
tumor.
T1 Tumor 2 cm or less in greatest dimension

Tla 0.5 cm or less in greatest dimension
TIb More than 0.5 cm but not more than 1 cm in greatest dimension
TIc More than I 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

T4a Extension to chest wall T4b Edema (including peau d’orange), or ulceration of the skin of the breast, or satellite skin
nodules confined to the same breast

T4c Both 4a and 4b above
T4d Inflammatory carcinoma

Notes: Inflammatory carcinoma of the breast is characterized by diffuse, brawny induration of the skin with an erysipeloid edge, usually with no underlying palpable mass. If the skin biopsy is negative and there is no localized measurable primary cancer, the T category is pTX when pathologically staging a clinical inflammatory carcinoma (T4d).
Dimpling of the skin, nipple retraction or other skin changes, except those in T4b and 4d, may occur in T1, T2 or T3 without affecting the classification.

Note: Chest wall includes ribs, intercostal muscles and serratus anterior muscle but not pectoral muscle.

N – Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed (e.g. previously removed)
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral axillary node(s)

N2 Metastasis to ipsilateral axillary node(s) fixed to one another or to other structures

N3 Metastasis to ipsilateral internal mammary lymph node(s)

The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc.The tumor staging system for breast cancer published by the American Joint Committee on Cancer (AJCC) was modified extensively in 2002. When compared to the classification published in 1997, the major differences are as listed: 1) reclassification of nodal status based on number of positive lymphnodes ( axilla) , differentiation between micrometastases and macrometastases, identifiers to indicate the use of specific techniques ( immunohistochemistry,molecular biology), surgical technique ( sentinel lymphnode biopsy ), and a reclassification of metastasis to internal mammary nodes, and supraclavicular nodes (now designated N3 rather than M1 disease) .These changes have been shown to dramatically affect stage-specific survival.

pTN Pathological Classification

pT – Primary Tumor

The pathological classification requires the examination of the primary carcinoma with no gross tumor at the margins of resection. A case can be classified pT if there is only microscopic tumor in a margin. The pT categories correspond to the T categories. When classifying pT the tumor size is a measurement of the invasivecomponent. If there is a large in situ component (e.g. 4 cm) and a small invasive component (e.g. 0.5 cm), the tumor is coded pTl a.

pN – Regional Lymph Nodes

The pathological classification requires the resection and examination of at least the low axillary lymph nodes (level 1) (see above). Such a resection will ordinarily include six or more lymph nodes.

pNX Regional lymph nodes cannot be assessed (not removed for study or previously removed)
pNO No regional lymph node metastasis
pNI Metastasis to movable ipsilateral axillary node(s)

pN1 a Only micrometastasis (none larger than 0.2 cm) (Fig. 9)
pN I 1b Metastasis to lymph node(s), any larger than 0.2 cm (Fig. 10)
pN1bi Metastasis to one to three lymph nodes, any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1bii Metastasis to four or more lymph nodes,any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1biii Extension of tumor beyond the capsule of a lymph node metastasis less than 2.0 cm in greatest dimension
pN1biv Metastasis to a lymph node 2.0 cm or more in greatest dimension

pN2 Metastasis to ipsilateral axillary lymph nodes that are fixed to one another or to other structures
pN3 Metastasis to ipsilateral internal mammary lymph node(s)

Staging of breast cancer

Staging Breast Cancer
Stage Tumor Size Lymph Node Involvement Metastasis (Spread)
I
II
III
IV
Less than 2 cm
Between 2-5 cm
More than 5 cm
Not applicable
No
No or in same side of breast
Yes, on same side of breast
Not applicable
No
No
No
Yes
Stage Tumor (T) Node (N) Metastasis (M)
Stage 0 Tis N0 M0
Stage 1 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

Source: American Joint Commission on Cancer and International Union Against Cancer

http://imaginis.com/breasthealth

Breast Cancer Survival Rate by Stage

Health care professionals are able to be predict a patient’s survival rate based on the determined stage of breast cancer. The following chart is an approximate survival rate for each stage of breast cancer. Percentages will vary depending on individual medical situation.

Stage 5-year Relative
Survival Rate
0 100%
I 98%
IIA 88%
IIB 76%
IIIA 56%
IIIB 49%
IV 16%

Source: American Cancer Society

A five-year survival rate refers to the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer. After seven years, the survival rate decreases for each stage. The average Stage I breast cancer survival rate is 92%. The Stage II survival rate is 71%, Stage III survival rate is 39%, and the Stage IV survival rate is 11%.

It is important to remember that these survival rates are based on averages. Some women with advanced breast cancer live significantly longer than seven years. Researchers are constantly developing new treatment alternatives to prolong breast cancer survival.

General

Invasive lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges and serosal surfaces. Clinically they may present as poorly defined areas of thickening of the breast. Radiologically microcalcifications may be present or absent.

Statistics

Breast cancer accounts for 33% of all female breast cancers and represents the most frequent cause of death in women age 40-45 years. In the 1970s the estimated probability of developing breast cancer for a white American woman was 1:13, in the 1980s it was 1:11 and in 2002 12.5% of women develop breast carcinoma.

Geogrpahic Distribution

The incidence of breast cancer varies significantly among differennt countries, and is highest in Northern European countries and in the United States, intermediate in Southern America and Southern and Eastern Europe, and lowest in Asia (Japan, Singapore and urban China have seen a rise in rates with the advent of Western-style economy). Breast cancer incidence and mortality vary sigificatly within the United States. The incidence of breast cancer appears to be highest in white women from Hawaii (128:100,000) followed by those from San Fransisco and the Northeast.The lowes incidence is found in Utah(98:100,000)  and New Mexico

The variation of incidence for African-American woment is relatively small ( 94-106:100,000)

 

Socieconomics

Unlike most other illnesses a positive correlation has been noted between the lifetime risk of breast cancer and higher socioeconomic status.

Population and age distribution

There is significant variation among different populations in the incidence of breast cancer: as shown below, in the United States the African-American population has a slightly higher risk until the age of forty, after which there is crossover and the highest risk is in the white population.

Patients of Jewish- Ashkenzi-ancestry have a higher risk of developing breast cancer as discussed in the genetics section.

reference  http://cdmrp.army.mil/graphics/ bc_incidence.gif

www.netwellness.org

 

 

Diagnosis

Clinical presentation has changed significantly with the advent of mammography. In the past 55%-75% of breast cancers were diagnosed by self-examination, but currently mammographic screening programs have determined an increase in the identification of cancers that are non palpable and clinically occult.

Evaluation of the patient with potential breast cancer involves a multistep process that includes history, physical exam, ( routine breast self-examination remains an important diagnostic screening modality) and radiologic studies. Further investigations ( genetic analysis and biopsies) are guided by the findings within the three steps described above.

It is important the physical examination by complete: it should start with visual inspection ( peau d’orange, nipple inversion, erythema, asymmetry, masses, nipple changes), followed by examination in the sitting position including palpation of the breasts, axillary and supraclavicular lymphnode stations and the tail of the breast which is oftentimes overlooked). Palpation of the breast parenchyma is done with the patient in the supine position with the ipsilateral arm placed over the head. Additional evaluation in warranted for any palpable lesion in patients over 30 years of age seeing as physical exam cannot adequately differentiate between malignant and benign lesions( 20-40% error rate even among expert examiners)

Evaluation of a palpable lesion

Evaluation of a palpable lesion  should be undertaken based on the individual characteristics of each patient

1) Mammography is usually the first step in this evaluation and serves two purposes. This is less accurate in youn patients with dense breast tissue and rarely used in patients under the age of 30( Ultrasound is used in such patients).

  1. a) Assessment of the risk of malignancy of the mass (Calcifications, spiculation, nipple changes, axillary adenopathy)
  2. b) Bilateral screening of non-palpable lesions

2) Fine needle aspiration (FNA) or core needle biopsy is usually the next step of the evaluation. Some advocate needle aspiration prior to mammographic evaluation, but a needle-puncture hematoma may confuse radiologic evaluation, and therefore mammography should precede biopsy.FNA is done with a 22 gauge needle and allows for differentiation between cystic and solid masses and provides a specimen for cytology.Oftentimes aspiration is curative for cystic lesions. Bloody cyst aspirate may be indicative of malignancy and should therefore always be sent for cytology (1% incidence of malignancy within breast cysts). Recurrent or complex (loculated ) cysts also have a greater incidence of malignancy. FNA provides material for cytologic evaluation of solid lesions. Once aspirated , the material is immediately fixed in 95% ethanol and sent to pathology. FNA , unlike core – needle biopsy- does not allow differentiation between in situ  and invasive carcinoma.

 

3) For lesions with contradictory results , open biopsy remains the definitive test.

Evaluation of Non-palpable lesions

Mammography represents the main diagnostic modality for non-palpable lesions

Mammographic signs of cancer can be divided in two main classes: density changes and microcalcifications

Treatment

Most of the recommendations for treatment of invasive breast cancer derive from the results of  controlled, randomized, prospective trials performed by the National Surgical adjuvant breast and bowel project (NSABP)

Breast cancer is diagnosed at an early stage in 75% of cases ( T1, T2, N0, N1). When this is the case, two surgical options are available:

Breast conservation ( Lumpectomy + radiation)

Mastectomy  ( with or without reconstruction)

Lymphnode status is assessed in the same session when indicated ( Sentinel lymphnode biopsy or axillary lymphnode dissection).

Breast conservation has been shown to be equal to mastectomy for patients with Stage I and II ( no difference in disease free survival- NSABP B-04), though patients must be willing to accept a 10% to 12% risk of local recurrence and conservation commits the patient to radiotherapy.When the decision is made between conservation and mastectomy, other factors need to be considered including breast size , tumor size, tumor multicentricity, patient age and tumor histology.

At this point there is no evidence that T3 lesions can be safely treated with breast conservation.

Localization. Preoperative needle localization of a breast cancer is used for non-palpable lesions. This is done by using either mammography or ultrasound to insert a fine wire that the surgeon follows to locate and remove the targeted area.

Evaluation of lymph nodes  Assesment of the lyphnode status may be done in different ways. Fine needle aspiration may be performed before surgery if lymph nodes appear abnormal by ultrasound exam. Sentinel lymphnode biopsy is based on the principle that the sentinel lymph node (SLN) is the first one to receive lymphatic drainage from a primary breast cancer and therefore the node most likely to contain metastatic disease. It can be done using radiolabled colloid, vital blue dye, or both. Intraoperatively it is identified by the use of a handheld gamma probe or by visualization of blue dye or both. Limitations to the identfication of the SLN include:  1) palpable axillary adenopathy, 2) medial hemisphere location ( wiht negative preoperative lymphoscintigraphy),3) Large primary tumors(>5 cm ) drainage to multiple nodes, 4) previous axillary surgery, 6) larger biopsy cavity – distortion of lymphatic drainage- 7) Tumors treated with neoadjuvant chemotherapy in patients with nodal disease on presentation. Accuracy rates for SLN biopsy are quoted to be 97%-100% whereas false negative rates are 0%-29% in the literature.

For patients not undergoing breast conservation, breast reconstruction should be considered part of the cancer therapy.Such reconstruction can be immediate or delayed, though immediate carries a significant psychological benefit.Breast reconstruction is feasible in most cases. Numerous techniques are described

Chemotherapy

CThe histologic status of the axilla, age of the patient, size of the primary tumor and extrogen/proesterone receptor status determine whether or not the patient will receive chemotherapy as an adjuvant or neoadjuvant therapy. Further factors that are considered include tumor pathologic characteristics ( ploidy, S-phase fraction, c-erbB-2 oncogine amplification, cathepsin D status) and the general health of the patient.

Multidrug chemotherapeutic regimens appear to significantly reduce the risk of recurrence and death in both lymphnode positive and lymphnode negative patients. The most frequently used regimen includes cyclophosphamide, methotrexate and 5-fluorouracil (4-8 weeks). The indications to the use fo tamoxifen are currently being broadened ( originally indicated for post-menopausal women with estrogen receptor-positive breast cancer) The use of tamoxifen for 5 years ( independent of age / menopausal status) is associated with a 47% reduction in the risk of breast cancer recurrence and a 26% reduction in the risk of death. Tamoxifen therapy has the added benefit of decreasing morbidity and mortality relate to cardiovascular disease, of increasing bone density and lowering cholesterol . Complications related to the use of such medication include an increase in the risk of thromboembolic disease and endometrial cancer.

Taxanes ( paclitaxel and docetaxel) represent a class of drugs that works by stabilizing the polymerization of microtubules, therefore arresting the cell cycle in the G2/M phase. They result in lack of resistance with other classes of drugs and have been used in crossover protocols for patients with anthracycline resistant tumors.

Trastuzumab (Herceptin) is a monoclonal antibody against the HER-2 / neu gene which codes for a Tyrosine Kinase that is overexpressed in 25% of breast cancers. Trials are currently looking at its efficacy in multidrug combination regimens.

Radiation Therapy

Radiation theraby can be delivered in the form of External beam radiation, Internal beam radiation, and intra-operative radiation. Radiation therapy is typically initiated 2-3 weeks after surgery or at the completion of postoperative chemotherapy. Daily outpatient radiation treatment lasts 5 o 6 weeks.

Prognosis

Numerous factors influence the prognosis of patients with breast cancer. The graphic representation below lists the factors associated with a poor prognosis

Breast Cancer Survival Rate by Stage

Patient’s survival rates are usually determined based on the stage of breast cancer.

Staging Breast Cancer
Stage Tumor Size Lymph Node Involvement Metastasis (Spread)
I
II
III
IV
Less than 2 cm
Between 2-5 cm
More than 5 cm
Not applicable
No
No or in same side of breast
Yes, on same side of breast
Not applicable
No
No
No
Stage 5-year Relative
Survival Rate
0 100%
I 98%
IIA 88%
IIB 76%
IIIA 56%
IIIB 49%
IV 16%

Source: American Cancer Society

A five-year survival rates represent the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer.These survival rates are based on averages and are subject to significant variability between individuals

Carcinoma Invasive Lobular

Author Lisa Wiechmann MD

Overview

Breast cancer is the leading cause of death in women 40-55 years of age. It represents the second leading cause of cancer death among american women (all ages) following lung cancer. Approximately 1 in 8 (12.5%) american women will be diagnosed with breast cancer during thier lifetime, and the risk of dying from the disease is approximately 3.4%. Breast cancer accounts for approximately 30% of cancers in women. It’s incidence increases rapidly after 40 years of age and after menopause the rate of increase is slower. Furthermore incidence of breast cancer has been steadily increasing over the past 70 years as demonstrated by data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER). Part of this increase has been attributed to an increased detection rate related to the use of mammography. Survival rates have also increased steadily for women with local and regional disease and this is probably due to both earlier detection of cancer and improvement in therapies..

 Infiltrating lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multifocal and multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges, serosal surfaces the GI tract and the retroperitoneum. Clinically they may present as poorly defined areas of thickening of the breast or as a palpable , firm mass, similar to the presentation of ductal carcinoma. Radiologically microcalcifications may be present or absent and a spiculated mass may be present on mammography. Lobular carcinoma in situ coexists with invasive lobular carcinoma in most cases (70%-80%).

Risk Factors

Multiple factors appear to be involved in the pathogenesis of breast cancer: these include genetic factorsenvironmental factors and endocrine factors. Gender is the most important risk factor for the development of breast cancer, which occurs 100 times more frequently in women than in men. This is due to endocrine factors as mentioned above: factors that increase the number of menstrual cycles (exposure to estrogen) such as nulliparity, late pregnancy (after 30 years of age), early menarche and late menopause( > 30 years menstrual time), are associated with an increased risk of breast cancer. Protective factors include moderate levels of exercise, and a longer lactation period. exposure to exogenous estrogens (oral contraceptive pills and hormone replacement therapy if prolonged in their duration- > 10 years) has though data is controversial. Age is an important risk factor for the development of breast cancer ( which translates in years of exposure to estrogen) ( risk of white American woman at 30 years 1:5,900, at 80 years 1:290)

Infiltrating lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges and serosal surfaces. Clinically they may present as poorly defined areas of thickening of the breast. Radiologically microcalcifications may be present or absent.

 reference www.cancervic.org.au

Prior history of breast cancer is a significant risk factor for the development of breast cancer[0.5-1 per year of follow-up] . proliferative breast diseases have now been found to increase the risk of breast cancer slightly 1.5-2 times the risk (papillomas, florid hyperplasia without atypia, sclerosing adenosis), moderately – 4 to 5 times the risk (Atypical ductal and lobular hyperplasia) and severely- 8 to 10 times the risk (lobular carcinoma in situ).

Environmental factors include exposure to ionizing radiation (mantle radiaton therapy for Hodgkin’s lymphoma -75-fold increase in risk, survivors of the atomic bomb) if exposure was before age 30) and potentially obesity (controversial) and alcohol ( no conclusive evidence). In mice a virus called mouse mammary tumor virus (MMTV), transmitted through the mother’s milk, causes breast cancer in suckling mice. No such virus has been identified in humans to this date.

Family history

Any family history of breast cancer increases a woman’s risk of breast cancer, especially if found in first degree relatives. Such risk is dependent on the characteristics of the cancer in relatives ( age at presentation, unilateral or bilateral, number of relatives with cancer).

Genetics

Recently attention has been focusing on genetic alterations that determine predisposition to breast cancer. Numerous autosomal dominant conditions have been found to be associated with increased risk of breast cancer: these include Li-Fraumeni Syndrome, Muir-Torre Syndrome, Cowden Disease, Peutz-Jeghers Syndrome and possibly Ataxia – telangiectasia carriers. Approximately 5-10% of breast cancer results from inheritance of germline mutations of genes (BRCA-1 and BRCA-2); such genes are inherited in autosomal dominant pattern with varying penetrance. BRCA-1 and BRCA-2 are tumor suppressor genes and loss of both alleles is required for initiation of breast cancer. They appear to be involved in DNA-repair pathways and control of the cell cycle. BRCA-1 is located on chromosome 17q and contains 22 coding exons (1863 amino acid protein). BRCA-1 mutations ( of which more than 500 are known) determine predisposition in up to 45% of hereditary breast cancers and in 80% or more of hereditary ovarian cancers. Women carrying the mutation have up to a 90% lifetime risk of breast cancer and a 40% lifetime risk of ovarian cancer. Carcinomas associated with the presence of BRCA-1 are typically invasive ductal carcinomas, are poorly differentiated and are hormone – receptor negative. They are also more frequently bilateral, have an earlier onset and are associated with the presence of other malignancies including ovarian cancer, and possibly colon cancer and prostate cancer.

The Jewish Ashkenazi population displays a 10 fold higher frequency of 2 founder mutations (185delAG and 5382insC) therefore screening of such mutations in then above population is indicated.

BRCA-2 is located on chromosome 13q and contains 26 coding exons (3418 amino acids). The biologic function of the gene transcript has yet to be delineated, but is thought to pertain to DNA repair mechanisms. More than 250 mutations of the BRCA-2 gene have been described and the lifetime risk of carriers has been estimated at 85% or more( ovarian lifetime risk 20%). Male carriers of the BRCA-2 mutations carry a 6% lifetime risk of breast cancer (100 fold increase from controls). Carcinomas associated with the presence of BRCA- 2 are usually well differentiated invasive ductal carcinomas and more frequently express hormone receptors. BRCA-2 associated breast cancers are frequently bilateral and may be associated with other malignancies including ovarian, prostate, colon, pancreas, gallbladder, bile duct, and stomach cancers as well as melanoma. A founder mutation (999del5) is observed in the Icelandic and Finnish populations.

The interaction of many different risk factors in the initiation of breast cancer has lead to the creation and use of risk-assessment models. This helps predict the risk of management and determine the best course of action. The most frequently used model was designed by Gail in 1970 and incorporates age at menarche, number of breast biopsies, age at first live birth and the number of first degree relatives with breast cancer. It is used to predict the risk of developing breast cancer per decade of life. One of the disadvantages of this model is that it doesn’t take into account age at which a family member was diagnosed and whether the disease occurred in both breasts — early onset and bilateral disease suggesting a BRCA mutation carrier

Numerous software programs incorporating the Gail model are available. One example is given below. Further links may be found at http://bcra.nci.nih.gov/brc

 The Claus model, when compared with the Gail model, incorporates more information on family history. Both risk assessment models do not take into consideration risk factors such as diet, obesity, use of oral contraceptives, lactation or radiation exposure.

reference www3.utsouthwestern.edu/ cancergene/Gail1.pn

 

Identification of BRCA mutation carriers

Four steps are required for the accurate identification of BRCA carriers

  • Comprehensive multigenerational history
  • Assessment of appropriateness of genetic testing in patient
  • Genetic counseling
  • Interpretation of results

Adequate identification of risk ( BRCA mutations + other risk factors) will lead to sound medical decision making by both patient and physician. Use of hormone replacement therapy, timing of mammographic screening , chemoprevention and use of prophylactic mastectomies( which reduce the risk of breast cancer by 90%) and oophorectomies are all part of this decision making process.

Classification

www.digitalclinic.com/tnm.htm

Anatomical Sites and Subsites (Fig. 1)

  1. Nipple (C50.0)
    2. Central portion (C50.1)
    3. Upper-inner quadrant (C50.2)
    4. Lower-inner quadrant (C50.3)
    5. Upper-outer quadrant (C50.4)
    6. Lower-outer quadrant (C50.5)
    7. Axillary tail (C50.6)

Regional Lymph Nodes

The regional lymph nodes are:

  1. Axillary (ipsilateral):interpectoral (Rotter) nodes along the axillary vein and its tributaries, which may be divided into the following levels:
  2. i) Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle
    ii) Level Ii (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter) lymph nodes
    iii) Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis minor muscle including those designated as subclavicular, infraclavicular or apical
    Note: Intrammamary lymph nodes are coded as axillary lymph nodes.
  3. Internal mammary (ipsilateral):lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia.
    Any other lymph node metastasis is coded as distant metastasis (M1), including supraclavicular, cervical, or contralateral internal mammary lymph nodes nvasive ductal carcinoma

TN Clinical Classification

T – Primary Tumor

TX Primary tumor cannot be assessed
TO No evidence of primary tumor
Tis Carcinoma in situ: intraductal carcinoma, or lobular carcinoma in situ, or Paget disease of
the nipple with no tumor

Note: Paget disease associated with a tumor is classified according to the size of the
tumor.
T1 Tumor 2 cm or less in greatest dimension

Tla 0.5 cm or less in greatest dimension
TIb More than 0.5 cm but not more than 1 cm in greatest dimension
TIc More than I 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

T4a Extension to chest wall T4b Edema (including peau d’orange), or ulceration of the skin of the breast, or satellite skin
nodules confined to the same breast

T4c Both 4a and 4b above
T4d Inflammatory carcinoma

Notes: Inflammatory carcinoma of the breast is characterized by diffuse, brawny induration of the skin with an erysipeloid edge, usually with no underlying palpable mass. If the skin biopsy is negative and there is no localized measurable primary cancer, the T category is pTX when pathologically staging a clinical inflammatory carcinoma (T4d).
Dimpling of the skin, nipple retraction or other skin changes, except those in T4b and 4d, may occur in T1, T2 or T3 without affecting the classification.

Note: Chest wall includes ribs, intercostal muscles and serratus anterior muscle but not pectoral muscle.

N – Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed (e.g. previously removed)
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral axillary node(s)

N2 Metastasis to ipsilateral axillary node(s) fixed to one another or to other structures

N3 Metastasis to ipsilateral internal mammary lymph node(s)

The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc.The tumor staging system for breast cancer published by the American Joint Committee on Cancer (AJCC) was modified extensively in 2002. When compared to the classification published in 1997, the major differences are as listed: 1) reclassification of nodal status based on number of positive lymphnodes ( axilla) , differentiation between micrometastases and macrometastases, identifiers to indicate the use of specific techniques ( immunohistochemistry,molecular biology), surgical technique ( sentinel lymphnode biopsy ), and a reclassification of metastasis to internal mammary nodes, and supraclavicular nodes (now designated N3 rather than M1 disease) .These changes have been shown to dramatically affect stage-specific survival.

pTN Pathological Classification

pT – Primary Tumor

The pathological classification requires the examination of the primary carcinoma with no gross tumor at the margins of resection. A case can be classified pT if there is only microscopic tumor in a margin. The pT categories correspond to the T categories. When classifying pT the tumor size is a measurement of the invasive component. If there is a large in situ component (e.g. 4 cm) and a small invasive component (e.g. 0.5 cm), the tumor is coded pTl a.

pN – Regional Lymph Nodes

The pathological classification requires the resection and examination of at least the low axillary lymph nodes (level 1) (see above). Such a resection will ordinarily include six or more lymph nodes.

pNX Regional lymph nodes cannot be assessed (not removed for study or previously removed)
pNO No regional lymph node metastasis
pNI Metastasis to movable ipsilateral axillary node(s)

pN1 a Only micrometastasis (none larger than 0.2 cm) (Fig. 9)
pN I 1b Metastasis to lymph node(s), any larger than 0.2 cm (Fig. 10)
pN1bi Metastasis to one to three lymph nodes, any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1bii Metastasis to four or more lymph nodes,any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1biii Extension of tumor beyond the capsule of a lymph node metastasis less than 2.0 cm in greatest dimension
pN1biv Metastasis to a lymph node 2.0 cm or more in greatest dimension

pN2 Metastasis to ipsilateral axillary lymph nodes that are fixed to one another or to other structures
pN3 Metastasis to ipsilateral internal mammary lymph node(s)

Staging of breast cancer

Staging Breast Cancer
Stage Tumor Size Lymph Node Involvement Metastasis (Spread)
I
II
III
IV
Less than 2 cm
Between 2-5 cm
More than 5 cm
Not applicable
No
No or in same side of breast
Yes, on same side of breast
Not applicable
No
No
No
Yes
Stage Tumor (T) Node (N) Metastasis (M)
Stage 0 Tis N0 M0
Stage 1 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

Source: American Joint Commission on Cancer and International Union Against Cancer

http://imaginis.com/breasthealth

Breast Cancer Survival Rate by Stage

Health care professionals are able to be predict a patient’s survival rate based on the determined stage of breast cancer. The following chart is an approximate survival rate for each stage of breast cancer. Percentages will vary depending on individual medical situation.

Stage 5-year Relative
Survival Rate
0 100%
I 98%
IIA 88%
IIB 76%
IIIA 56%
IIIB 49%
IV 16%

Source: American Cancer Society

A five-year survival rate refers to the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer. After seven years, the survival rate decreases for each stage. The average Stage I breast cancer survival rate is 92%. The Stage II survival rate is 71%, Stage III survival rate is 39%, and the Stage IV survival rate is 11%.

It is important to remember that these survival rates are based on averages. Some women with advanced breast cancer live significantly longer than seven years. Researchers are constantly developing new treatment alternatives to prolong breast cancer survival.

General

Invasive lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges and serosal surfaces. Clinically they may present as poorly defined areas of thickening of the breast. Radiologically microcalcifications may be present or absent.

Statistics

Breast cancer accounts for 33% of all female breast cancers and represents the most frequent cause of death in women age 40-45 years. In the 1970s the estimated probability of developing breast cancer for a white American woman was 1:13, in the 1980s it was 1:11 and in 2002 12.5% of women develop breast carcinoma.

Geogrpahic Distribution

The incidence of breast cancer varies significantly among differennt countries, and is highest in Northern European countries and in the United States, intermediate in Southern America and Southern and Eastern Europe, and lowest in Asia (Japan, Singapore and urban China have seen a rise in rates with the advent of Western-style economy). Breast cancer incidence and mortality vary sigificatly within the United States. The incidence of breast cancer appears to be highest in white women from Hawaii (128:100,000) followed by those from San Fransisco and the Northeast.The lowes incidence is found in Utah(98:100,000)  and New Mexico

The variation of incidence for African-American woment is relatively small ( 94-106:100,000)

Socieconomics

Unlike most other illnesses a positive correlation has been noted between the lifetime risk of breast cancer and higher socioeconomic status

.

Population and age distribution

There is significant variation among different populations in the incidence of breast cancer: as shown below, in the United States the African-American population has a slightly higher risk until the age of forty, after which there is crossover and the highest risk is in the white population.

Patients of Jewish- Ashkenzi-ancestry have a higher risk of developing breast cancer as discussed in the genetics section.

reference  http://cdmrp.army.mil/graphics/ bc_incidence.gif

www.netwellness.org

Diagnosis

Clinical presentation has changed significantly with the advent of mammography. In the past 55%-75% of breast cancers were diagnosed by self-examination, but currently mammographic screening programs have determined an increase in the identification of cancers that are non palpable and clinically occult.

Evaluation of the patient with potential breast cancer involves a multistep process that includes history, physical exam, ( routine breast self-examination remains an important diagnostic screening modality) and radiologic studies. Further investigations ( genetic analysis and biopsies) are guided by the findings within the three steps described above.

It is important the physical examination by complete: it should start with visual inspection ( peau d’orange, nipple inversion, erythema, asymmetry, masses, nipple changes), followed by examination in the sitting position including palpation of the breasts, axillary and supraclavicular lymphnode stations and the tail of the breast which is oftentimes overlooked). Palpation of the breast parenchyma is done with the patient in the supine position with the ipsilateral arm placed over the head. Additional evaluation in warranted for any palpable lesion in patients over 30 years of age seeing as physical exam cannot adequately differentiate between malignant and benign lesions( 20-40% error rate even among expert examiners)

Evaluation of a palpable lesion

Evaluation of a palpable lesion  should be undertaken based on the individual characteristics of each patient

1) Mammography is usually the first step in this evaluation and serves two purposes. This is less accurate in youn patients with dense breast tissue and rarely used in patients under the age of 30( Ultrasound is used in such patients).

  1. a) Assessment of the risk of malignancy of the mass (Calcifications, spiculation, nipple changes, axillary adenopathy)
  2. b) Bilateral screening of non-palpable lesions

2) Fine needle aspiration (FNA) or core needle biopsy is usually the next step of the evaluation. Some advocate needle aspiration prior to mammographic evaluation, but a needle-puncture hematoma may confuse radiologic evaluation, and therefore mammography should precede biopsy.FNA is done with a 22 gauge needle and allows for differentiation between cystic and solid masses and provides a specimen for cytology.Oftentimes aspiration is curative for cystic lesions. Bloody cyst aspirate may be indicative of malignancy and should therefore always be sent for cytology (1% incidence of malignancy within breast cysts). Recurrent or complex (loculated ) cysts also have a greater incidence of malignancy. FNA provides material for cytologic evaluation of solid lesions. Once aspirated , the material is immediately fixed in 95% ethanol and sent to pathology. FNA , unlike core – needle biopsy- does not allow differentiation between in situ  and invasive carcinoma.

3) For lesions with contradictory results , open biopsy remains the definitive test.

Evaluation of Non-palpable lesions

Mammography represents the main diagnostic modality for non-palpable lesions

Mammographic signs of cancer can be divided in two main classes: density changes and microcalcifications

Treatment

Most of the recommendations for treatment of invasive breast cancer derive from the results of  controlled, randomized, prospective trials performed by the National Surgical adjuvant breast and bowel project (NSABP)

Breast cancer is diagnosed at an early stage in 75% of cases ( T1, T2, N0, N1). When this is the case, two surgical options are available:

Breast conservation ( Lumpectomy + radiation)

Mastectomy  ( with or without reconstruction)

Lymphnode status is assessed in the same session when indicated ( Sentinel lymphnode biopsy or axillary lymphnode dissection).

Breast conservation has been shown to be equal to mastectomy for patients with Stage I and II ( no difference in disease free survival- NSABP B-04), though patients must be willing to accept a 10% to 12% risk of local recurrence and conservation commits the patient to radiotherapy.When the decision is made between conservation and mastectomy, other factors need to be considered including breast size , tumor size, tumor multicentricity, patient age and tumor histology.

At this point there is no evidence that T3 lesions can be safely treated with breast conservation.

Localization. Preoperative needle localization of a breast cancer is used for non-palpable lesions. This is done by using either mammography or ultrasound to insert a fine wire that the surgeon follows to locate and remove the targeted area.

Evaluation of lymph nodes  Assesment of the lyphnode status may be done in different ways. Fine needle aspiration may be performed before surgery if lymph nodes appear abnormal by ultrasound exam. Sentinel lymphnode biopsy is based on the principle that the sentinel lymph node (SLN) is the first one to receive lymphatic drainage from a primary breast cancer and therefore the node most likely to contain metastatic disease. It can be done using radiolabled colloid, vital blue dye, or both. Intraoperatively it is identified by the use of a handheld gamma probe or by visualization of blue dye or both. Limitations to the identfication of the SLN include:  1) palpable axillary adenopathy, 2) medial hemisphere location ( wiht negative preoperative lymphoscintigraphy),3) Large primary tumors(>5 cm ) drainage to multiple nodes, 4) previous axillary surgery, 6) larger biopsy cavity – distortion of lymphatic drainage- 7) Tumors treated with neoadjuvant chemotherapy in patients with nodal disease on presentation. Accuracy rates for SLN biopsy are quoted to be 97%-100% whereas false negative rates are 0%-29% in the literature.

For patients not undergoing breast conservation, breast reconstruction should be considered part of the cancer therapy.Such reconstruction can be immediate or delayed, though immediate carries a significant psychological benefit.Breast reconstruction is feasible in most cases. Numerous techniques are described

Chemotherapy

CThe histologic status of the axilla, age of the patient, size of the primary tumor and extrogen/proesterone receptor status determine whether or not the patient will receive chemotherapy as an adjuvant or neoadjuvant therapy. Further factors that are considered include tumor pathologic characteristics ( ploidy, S-phase fraction, c-erbB-2 oncogine amplification, cathepsin D status) and the general health of the patient.

Multidrug chemotherapeutic regimens appear to significantly reduce the risk of recurrence and death in both lymphnode positive and lymphnode negative patients. The most frequently used regimen includes cyclophosphamide, methotrexate and 5-fluorouracil (4-8 weeks). The indications to the use fo tamoxifen are currently being broadened ( originally indicated for post-menopausal women with estrogen receptor-positive breast cancer) The use of tamoxifen for 5 years ( independent of age / menopausal status) is associated with a 47% reduction in the risk of breast cancer recurrence and a 26% reduction in the risk of death. Tamoxifen therapy has the added benefit of decreasing morbidity and mortality relate to cardiovascular disease, of increasing bone density and lowering cholesterol . Complications related to the use of such medication include an increase in the risk of thromboembolic disease and endometrial cancer.

Taxanes ( paclitaxel and docetaxel) represent a class of drugs that works by stabilizing the polymerization of microtubules, therefore arresting the cell cycle in the G2/M phase. They result in lack of resistance with other classes of drugs and have been used in crossover protocols for patients with anthracycline resistant tumors.

Trastuzumab (Herceptin) is a monoclonal antibody against the HER-2 / neu gene which codes for a Tyrosine Kinase that is overexpressed in 25% of breast cancers. Trials are currently looking at its efficacy in multidrug combination regimens.

Radiation Therapy

Radiation theraby can be delivered in the form of External beam radiation, Internal beam radiation, and intra-operative radiation. Radiation therapy is typically initiated 2-3 weeks after surgery or at the completion of postoperative chemotherapy. Daily outpatient radiation treatment lasts 5 o 6 weeks.

Prognosis

Numerous factors influence the prognosis of patients with breast cancer. The graphic representation below lists the factors associated with a poor prognosis

Breast Cancer Survival Rate by Stage

Patient’s survival rates are usually determined based on the stage of breast cancer.

Staging Breast Cancer
Stage Tumor Size Lymph Node Involvement Metastasis (Spread)
I
II
III
IV
Less than 2 cm
Between 2-5 cm
More than 5 cm
Not applicable
No
No or in same side of breast
Yes, on same side of breast
Not applicable
No
No
No
Stage 5-year Relative
Survival Rate
0 100%
I 98%
IIA 88%
IIB 76%
IIIA 56%
IIIB 49%
IV 16%

Source: American Cancer Society

A five-year survival rates represent the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer.These survival rates are based on averages and are subject to significant variability between individuals

Carcinoma – Invasive Ductal

 

Author Lisa Wiechmann MD

 

History

The Smith Surgical Papyrus from was the first document to ever describe breast cancer.In 1862 Sir Edwin Smith discovered a 4.68 meter long papyrus from 1600 B.C (thought to be a transcript from an older document- 3000 B.C.)  and this represents the oldest record on breast cancer. The description included common clinical findings encountered on routine examination in patients with breast cancer  and referred to a carcinoma found in a man (case # 45 of 48). The Papyrus proceeds to describing 8 cases of tumors or ulcers of the breast that were treated with a tool called ” the fire drill” similar to the cautery.  The conclusion of the text states “there is no treatment” for breast cancer. The document was thought to be written by Imhothep who was later proclaimed God.

Hippocrates ( 460-370 BC) described lesions that affected the breast (distinguished benign and malignant disease), the skin, the stomach, the rectum and the cervix, and classified them. Aulus Cornelius Celsus (25 BC-50AC) described the different stages of evolution of the disease:  Cacoethes (early stage) was followed by a carcinoma without ulcer and then by an exophytic lesion. He realized the value of surgery in the early stages of cancer and that only small tumors could be removed whereas  “the rest are irritated by every method of cure. The more violent the operations are, the more angry they grow”. ( De Medicina)

Leonidus of Alexandria (180 AC) described breast cancer surgery  for the first century after Christ. The procedure included removal of the cancer and of some skin (and healthy tissue). Galen (130-201 AC) believed melancholia and evil humors ( black bile) were the chief factor in the pathogenesis of breast cancer and his treatment consisted of purges, special diets and exorcism. In the second century, Galen inscribed his clinical observation: ” We have often seen in the breast a tumor exactly resembling the animal the crab. Just as the crab has legs on both sides of the body, so in this disease the veins extending out from the unnatural growth take the shape of the crab’s legs. We have often cured this disease in its early stages, but after it has reached a large size, noone has cured it.  In all operations we attempt to excise the tumor in a circle where it borders on healthy tissue”. Theories consistent with galenic practice predominated until the Renaissance. In the late 1600s Thomas Willis described a tumor as a “disturbance of growth primarily characterized by cells with uncontrolled, non purposeful division. Fabricius Hildanus (1560-1634) from Germany performed axillary dissections in patients with breast cancer and Marco Aurelio Severini (1580-1656) not only described the different benign and malignant tumors, but also in his description of fibro-adenoma, advised its removal because of its potential to degenerate. Johann Schultes (1595-1645) drew the different stages of a mastectomy  in his work “Armamentarii Chirurgici”. Thomas Willis (1621-1675) described tumors as “a disturbance of growing primary cells that are substituted by uncontrolled , non purposefully dividing cells.”

During the 17th century cancer was felt to be contagious and therfore patients with cancer were not allowed in hospitals for fear of an epidemic. This led to the birth of dedicated cancer hospitals , the first of which was founded in Reims in 1740( Hopital St-Louis)

Henri Le Dran (1685-1770) first recognized the spread of cancer to regional axillary nodes and recommended that both the tumor and the axillary lymphnodes be excised. He also recognised that lymph nodes with cancer were indicative of a more advanced stage of the disease.

Gian Battista Morgagni(1682-1771) carried out 700 autopsies on patients with breast, stomach, pancreas and rectal cancer and described his findings in his work ” De Sedibus et Causis Morborum”. John Hunter (1728-1793) was the first physician to observe a predisposition to cancer based on genetics, age, and environmental factors. He estimated that  the average age at which people developed cancer was 40-60 years and that if a woman was found to have cancer before the age of 40, the cancer was soon lethal. Astly Cooper (1768-1841) was Hunter’s student and described the fibrocystic mastopathy of the breast and Sir James Paget (1841-1899) desbribes the homonymus disease of the breast.

In the 19th century Moore, of the Middlesex Hospital of London, emphasized the importance of removal of axillary lymph nodes ( palpable and non-palpable) together with the complete resection of the breast. In 1894 Halstead and Meyer each independently brought to the attention of the public , the results of their treatment of breast cancer and described the advantages offered by a radical mastectomy ( Ipsilateral breast, Axillary nodes levels I-III, resection of pectoralis major and minor muscles, resection of thoracodorsal and long thoracic nerves. Halstead reported ” early” breast tumors to measure approximately 8x 7 cm in size. Ten year survival approached 34% .

After Wilhelm Roentgen (1845-1923) discovered X-rays in 1895, Sampson Handley stated that ” the principle of using x-rays for treatment of breast cancer is prophylactic against postoperative relapse.” Ther role of x-ray in evaluating and treating breast cancer continued to grow and allowed detection of non-palpable tumors, therefore leading to new surgical therapies (lumpectomies, quadrantectomies).

In 1948 Patey and Dyson of the Middlesex Hospital in london, advocated a modified radical mastectomy for the management of advanced, operable cancer (with removal of pectoralis minor muscle).

It was Madden who described the Modified Radical Mastectomy as we now know it, with preservation of both pectoralis major and minor and lymphadenectomy of levels I-II ( but not III).

Overview

Breast cancer is the leading cause of death in women 40-55 years of age. It represents the second leading cause of cancer death among american women (all ages) following lung cancer. Approximately 1 in 8 (12.5%) american women will be diagnosed with breast cancer during thier lifetime, and the risk of dying from the disease is approximately 3.4%. Breast cancer accounts for approximately 30% of cancers in women. It’s incidence increases rapidly after 40 years of age and after menopause the rate of increase is slower. Furthermore incidence of breast cancer has been steadily increasing over the past 70 years as demonstrated by data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER). Part of this increase has been attributed to an increased detection rate related to the use of mammography. Survival rates have also increased steadily for women with local and regional disease and this is probably due to both earlier detection of cancer and improvement in therapies.Risk Factors

Multiple factors appear to be involved in the pathogenesis of breast cancer: these include genetic factors, environmental factors and endocrine factors. Gender is the most important risk factor for the development of breast cancer, which occurs 100 times more frequently in women than in men. This is due to endocrine factors as mentioned above: factors that increase the number of menstrual cycles (exposure to estrogen) such as nulliparity, late pregnancy (after 30 years of age), early menarche and late menopause( > 30 years menstrual time), are associated with an increased risk of breast cancer. Protective factors include moderate levels of exercise, and a longer lactation period. exposure to exogenous estrogens (oral contraceptive pills and hormone replacement therapy if prolonged in their duration- > 10 years) has though data is controversial. Age is an important risk factor for the development of breast cancer ( which translates in years of exposure to estrogen) ( risk of white American woman at 30 years 1:5,900, at 80 years 1:290)

www.cancervic.org.au

Prior history of breast cancer is a significant risk factor for the development of breast cancer and proliferative breast diseases have now been found to increase the risk of breast cancer slightly 1.5-2 times the risk (papillomas, florid hyperplasia without atypia, sclerosing adenosis), moderately – 4 to 5 times the risk (Atypical ductal and lobular hyperplasia) and severely- 8 to 10 times the risk (lobular carcinoma in situ).

Environmental factors include exposure to ionizing radiation (mantle radiaton therapy for Hodgkin’s lymphoma -75-fold increase in risk, survivors of the atomic bomb) if exposure was before age 30) and potentially obesity (controversial) and alcohol ( no conclusive evidence). In mice a virus called mouse mammary tumor virus (MMTV), transmitted through the mother’s milk, causes breast cancer in suckling mice. No such virus has been identified in humans to this date.

Any family history of breast cancer increases a woman’s risk of breast cancer, especially if found in first degree relatives. Such risk is dependent on the characteristics of the cancer in relatives ( age at presentation, unilateral or bilateral, number of relatives with cancer).

The Jewish Ashkenazi population displays a 10 fold higher frequency of 2 founder mutations (185delAG and 5382insC) therefore screening of such mutations in then above population is indicated.

The interaction of many different risk factors in the initiation of breast cancer has lead to the creation and use of risk-assessment models. This helps predict the risk of management and determine the best course of action. The most frequently used model was designed by Gail in 1970 and incorporates age at menarche, number of breast biopsies, age at first live birth and the number of first degree relatives with breast cancer. It is used to predict the risk of developing breast cancer per decade of life. One of the disadvantages of this model is that it doesn’t take into account age at which a family member was diagnosed and whether the disease occurred in both breasts — early onset and bilateral disease suggesting a BRCA mutation carrier

Classification

Anatomical Sites and Subsites

1. Nipple

2. Central portion

3. Upper-inner quadrant

4. Lower-inner quadrant

5. Upper-outer quadrant

6. Lower-outer quadrant

7. Axillary tail

 

78378pb06l05 breast mammary gland lymphatic drainage lymph nodes axillary lymph nodes infraclavicular lymph nodes supralavicular lymph nodes internal mammary lymph nodes parasternal lymph nodes anatomy normal Courtesy Ashley Davidoff MD

Classification

The regional lymph nodes:

1. Axillary (ipsilateral): interpectoral (Rotter) nodes along the axillary vein and its tributaries, which may be divided into the following levels:

i) Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle
ii) Level Ii (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter) lymph nodes
iii) Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis minor muscle including those designated as subclavicular, infraclavicular or apical
Note: Intrammamary lymph nodes are coded as axillary lymph nodes.

2. Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia.
Any other lymph node metastasis is coded as distant metastasis (M1), including supraclavicular, cervical, or contralateral internal mammary lymph nodes

Classification – TN Clinical Classification

T – Primary Tumor

TX Primary tumor cannot be assessed
TO No evidence of primary tumor
Tis Carcinoma in situ: intraductal carcinoma, or lobular carcinoma in situ, or Paget disease of
the nipple with no tumor (Fig.3)
Note: Paget disease associated with a tumor is classified according to the size of the
tumor.
T1 Tumor 2 cm or less in greatest dimension (Fig. 4)
Tla 0.5 cm or less in greatest dimension
TIb More than 0.5 cm but not more than 1 cm in greatest dimension
TIc More than I 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 (Fig. 4)
T3 Tumor more than 5 cm in greatest dimension (Fig. 4)
T4 Tumor of any size with direct extension to chest wall or skin

T4a Extension to chest wall (Fig. 5)
T4b Edema (including peau d’orange), or ulceration of the skin of the breast, or satellite skin
nodules confined to the same breast (Figs. 5, 6)
T4c Both 4a and 4b above (Fig. 6)
T4d Inflammatory carcinoma (Fig. 6)Notes: Inflammatory carcinoma of the breast is characterized by diffuse, brawny induration of the skin with an erysipeloid edge, usually with no underlying palpable mass. If the skin biopsy is negative and there is no localized measurable primary cancer, the T category is pTX when pathologically staging a clinical inflammatory carcinoma (T4d).
Dimpling of the skin, nipple retraction or other skin changes, except those in T4b and 4d, may occur in T1, T2 or T3 without affecting the classification. Note: Chest wall includes ribs, intercostal muscles and serratus anterior muscle but not pectoral muscle.

Classification – N – Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed (e.g. previously removed)
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral axillary node(s) (Fig.7)
N2 Metastasis to ipsilateral axillary node(s) fixed to one another or to other structures (Fig.7)
N3 Metastasis to ipsilateral internal mammary lymph node(s) (Fig.8)

The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc.The tumor staging system for breast cancer published by the American Joint Committee on Cancer (AJCC) was modified extensively in 2002. When compared to the classification published in 1997, the major differences are as listed: 1) reclassification of nodal status based on number of positive lymphnodes ( axilla) , differentiation between micrometastases and macrometastases, identifiers to indicate the use of specific techniques ( immunohistochemistry,molecular biology), surgical technique ( sentinel lymphnode biopsy ), and a reclassification of metastasis to internal mammary nodes, and supraclavicular nodes (now designated N3 rather than M1 disease) .These changes have been shown to dramatically affect stage-specific survival.

Classification – pTN Pathological Classification

pT – Primary Tumor

The pathological classification requires the examination of the primary carcinoma with no gross tumor at the margins of resection. A case can be classified pT if there is only microscopic tumor in a margin. The pT categories correspond to the T categories. When classifying pT the tumor size is a measurement of the invasive component. If there is a large in situ component (e.g. 4 cm) and a small invasive component (e.g. 0.5 cm), the tumor is coded pTl a.pN – Regional Lymph Nodes

The pathological classification requires the resection and examination of at least the low axillary lymph nodes (level 1) (see above). Such a resection will ordinarily include six or more lymph nodes.

pNX Regional lymph nodes cannot be assessed (not removed for study or previously removed)
pNO No regional lymph node metastasis
pNI Metastasis to movable ipsilateral axillary node(s)

pN1 a Only micrometastasis (none larger than 0.2 cm) (Fig. 9)
pN I 1b Metastasis to lymph node(s), any larger than 0.2 cm (Fig. 10)
pN1bi Metastasis to one to three lymph nodes, any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1bii Metastasis to four or more lymph nodes,any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1biii Extension of tumor beyond the capsule of a lymph node metastasis less than 2.0 cm in greatest dimension
pN1biv Metastasis to a lymph node 2.0 cm or more in greatest dimension

pN2 Metastasis to ipsilateral axillary lymph nodes that are fixed to one another or to other structures (Fig. 8, see above)
pN3 Metastasis to ipsilateral internal mammary lymph node(s)

Statistics

Breast cancer accounts for 33% of all female breast cancers and represents the most frequent cause of death in women age 40-45 years. In the 1970s the estimated probability of developing breast cancer for a white American woman was 1:13, in the 1980s it was 1:11 and in 2002 12.5% of women develop breast carcinoma.

Geographic Distribution

The incidence of breast cancer varies significantly among differennt countries, and is highest in Northern European countries and in the United States, intermediate in Southern America and Southern and Eastern Europe, and lowest in Asia (Japan, Singapore and urban China have seen a rise in rates with the advent of Western-style economy). Breast cancer incidence and mortality vary sigificatly within the United States. The incidence of breast cancer appears to be highest in white women from Hawaii (128:100,000) followed by those from San Fransisco and the Northeast.The lowes incidence is found in Utah(98:100,000)  and New Mexico

The variation of incidence for African-American woment is relatively small ( 94-106:100,000).

Socieconomics

Unlike most other illnesses a positive correlation has been noted between the lifetime risk of breast cancer and higher socioeconomic status.

Population and age distribution

There is significant variation among different populations in the incidence of breast cancer: as shown below, in the United States the African-American population has a slightly higher risk until the age of forty, after which there is crossover and the highest risk is in the white population.

Patients of Jewish- Ashkenzi-ancestry have a higher risk of developing breast cancer as discussed in the genetics section.

Sex Distribution

M:F < =1:100

Staging of breast cancer

Stage Tumor Size Lymph Node Involvement Metastasis (Spread)
I
II
III
IV
Less than 2 cm
Between 2-5 cm
More than 5 cm
Not applicable
No
No or in same side of breast
Yes, on same side of breast
Not applicable
No
No
No
Yes

 

Stage Tumor (T) Node (N) Metastasis (M)
Stage 0 Tis N0 M0
Stage 1 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

Source: American Joint Commission on Cancer and International Union Against Cancer

Pathology

13553 breast + dx infiltrating ductal carcinoma + grosspathology Courtesy Frank Reale MD

13552 breast + dx infiltrating ductal carcinoma + cytopathology histopathology Courtesy Frank Reale MD DB

Invasive carcinomas of the breast are characterized by histologic heterogeneity. The majority are adenocarcinomas of which 5 variants have been identified:

  1. Infiltrating Ductal carcinoma: represents approximately 75-85% of all breast cancers and is characterized by the absence of specific features (NST-no special type). Upon palpation it is firm and is gritty like “when cutting an unripe pear” when transected. The specimen oftentimes contains DCIS . Infiltrating ductal carcinoma metastasizes to regional lymphnodes in the axilla and then to bones, lungs , liver and brain.
  2. Infiltrating lobular carcinoma is seen in 5-10% of cases. Multicentricity and bilaterality are common. Microscopically it is famous for its cells arranged in Indian files. It metastasizes to axillary lymphnodes, and to unusual sites such as the meninges, and other serosal surfaces.
  3. Tubular Carcinoma: (2% of cancers) . The diagnosis can only bemade when more than 75% of the tumor demonstrates tubular , well-formed glands. Axillary node metastases are unusual and this tumor has the best prognosis for any breast carcinoma with very low mortality.
  4. Medullary Carcinoma: (5-7% of cancers). Microscpically it’s characterized by intense infiltration of lymphocytes and plasma cells and by the presence of a syncytial growth pattern, with little or no DCIS. This type of cancer is overrepresented in women with mutated BRCA-1 syndrome.
  5. Mucinous or Colloid Carcinoma: (3%). Grossly, the tumor is a gelatinous mass. Microscopically lakes of mucin surround clumps of cells. It’s a slow growing tumor and prognosis tends to be favorable

Other types of breast malignancy include papillary, apoocrine, spindle cell carcinomas, and squamous cell carcinomas.

Diagnosis

Clinical presentation has changed significantly with the advent of mammography. In the past 55%-75% of breast cancers were diagnosed by self-examination, but currently mammographic screening programs have determined an increase in the identification of cancers that are non palpable and clinically occult.

Evaluation of the patient with potential breast cancer involves a multistep process that includes history, physical exam, ( routine breast self-examination remains an important diagnostic screening modality) and radiologic studies. Further investigations ( genetic analysis and biopsies) are guided by the findings within the three steps described above.

It is important the physical examination by complete: it should start with visual inspection ( peau d’orange, nipple inversion, erythema, asymmetry, masses, nipple changes), followed by examination in the sitting position including palpation of the breasts, axillary and supraclavicular lymphnode stations and the tail of the breast which is oftentimes overlooked). Palpation of the breast parenchyma is done with the patient in the supine position with the ipsilateral arm placed over the head. Additional evaluation in warranted for any palpable lesion in patients over 30 years of age seeing as physical exam cannot adequately differentiate between malignant and benign lesions( 20-40% error rate even among expert examiners)

Evaluation of a palpable lesion

Such evaluation should be undertaken based on the individual characteristics of each patient

1) Mammography is usually the first step in this evaluation and serves two purposes. This is less accurate in youn patients with dense breast tissue and rarely used in patients under the age of 30( Ultrasound is used in such patients).

a) Assessment of the risk of malignancy of the mass (Calcifications, spiculation, nipple changes, axillary adenopathy)

b) Bilateral screening of non-palpable lesions

2) Fine needle aspiration (FNA) or core needle biopsy is usually the next step of the evaluation. Some advocate needle aspiration prior to mammographic evaluation, but a needle-puncture hematoma may confuse radiologic evaluation, and therefore mammography should precede biopsy.FNA is done with a 22 gauge needle and allows for differentiation between cystic and solid masses and provides a specimen for cytology.Oftentimes aspiration is curative for cystic lesions. Bloody cyst aspirate may be indicative of malignancy and should therefore always be sent for cytology (1% incidence of malignancy within breast cysts). Recurrent or complex (loculated ) cysts also have a greater incidence of malignancy. FNA provides material for cytologic evaluation of solid lesions. Once aspirated , the material is immediately fixed in 95% ethanol and sent to pathology. FNA , unlike core – needle biopsy- does not allow differentiation between in situ  and invasive carcinoma.

Mammography represents the main diagnostic modality for non-palpable lesions

Mammographic signs of cancer can be divided in two main classes: density changes and microcalcifications

The American College of Radiology (ACR) is the copyright owner of a work entitled Breast Imaging Reporting and Data System (BI-RADS), which contains a guide to standardized mammographic reporting, including a breast-imaging lexicon of terminology, a report organization and assessment structure and coding system

Category 0: Need Additional Imaging Evaluation
Category 1: Negative
Category 2: Benign Finding
Category 3: Probably Benign Finding ? Short Interval Follow-Up Suggested
Category 4: Suspicious Abnormality ? Biopsy Should Be Considered
Category 5: Highly Suggestive of Malignancy ? Appropriate Action Should Be Taken

Suspicious lesions mandate further evaluation. US – guided biopsy is not useful in the evaluation of microcalcifications seeing as these are not visible sonographically. Stereotactic needle biopsy is useful in the evaluation of non-palpable lesions with microcalcifications

Imaging

27975 breast hx 27F left breast lump fx pleomorphic calcification Rx lumpectomy dx intraductal carcinoma with high grade DCIS lymph node positive mammogram mammography Courtesy Priscilla Slanetz MD

Breast Cancer Survival Rate by Stage

Health care professionals are able to be predict a patient’s survival rate based on the determined stage of breast cancer. The following chart is an approximate survival rate for each stage of breast cancer. Percentages will vary depending on individual medical situations, etc.

Stage 5-year Relative
Survival Rate
0 100%
I 98%
IIA 88%
IIB 76%
IIIA 56%
IIIB 49%
IV 16%

Source: American Cancer Society

A five-year survival rate refers to the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer. After seven years, the survival rate decreases for each stage. The average Stage I breast cancer survival rate is 92%. The Stage II survival rate is 71%, Stage III survival rate is 39%, and the Stage IV survival rate is 11%.

It is important to remember that these survival rates are based on averages. Some women with advanced breast cancer live significantly longer than seven years. Researchers are constantly developing new treatment alternatives to prolong breast cancer survival.

Chemotherapy

CThe histologic status of the axilla, age of the patient, size of the primary tumor and extrogen/proesterone receptor status determine whether or not the patient will receive chemotherapy as an adjuvant or neoadjuvant therapy. Further factors that are considered include tumor pathologic characteristics ( ploidy, S-phase fraction, c-erbB-2 oncogine amplification, cathepsin D status) and the general health of the patient.

Multidrug chemotherapeutic regimens appear to significantly reduce the risk of recurrence and death in both lymphnode positive and lymphnode negative patients. The most frequently used regimen includes cyclophosphamide, methotrexate and 5-fluorouracil (4-8 weeks). The indications to the use fo tamoxifen are currently being broadened ( originally indicated for post-menopausal women with estrogen receptor-positive breast cancer) The use of tamoxifen for 5 years ( independent of age / menopausal status) is associated with a 47% reduction in the risk of breast cancer recurrence and a 26% reduction in the risk of death. Tamoxifen therapy has the added benefit of decreasing morbidity and mortality relate to cardiovascular disease, of increasing bone density and lowering cholesterol . Complications related to the use of such medication include an increase in the risk of thromboembolic disease and endometrial cancer.

Taxanes ( paclitaxel and docetaxel) represent a class of drugs that works by stabilizing the polymerization of microtubules, therefore arresting the cell cycle in the G2/M phase. They result in lack of resistance with other classes of drugs and have been used in crossover protocols for patients with anthracycline resistant tumors.

Trastuzumab (Herceptin) is a monoclonal antibody against the HER-2 / neu gene which codes for a Tyrosine Kinase that is overexpressed in 25% of breast cancers. Trials are currently looking at its efficacy in multidrug combination regimens.

Radiation Therapy

Radiation theraby can be delivered in the form of External beam radiation, Internal beam radiation, and intra-operative radiation. Radiation therapy is typically initiated 2-3 weeks after surgery or at the completion of postoperative chemotherapy. Daily outpatient radiation treatment lasts 5 o 6 weeks.

Prognosis

Numerous factors influence the prognosis of patients with breast cancer. The graphic representation below lists the factors associated with a poor prognosis

 

Breast Cancer Survival Rate by Stage

Patient’s survival rates are usually determined based on the stage of breast cancer.

Staging Breast Cancer
Stage Tumor Size Lymph Node Involvement Metastasis (Spread)
I
II
III
IV
Less than 2 cm
Between 2-5 cm
More than 5 cm
Not applicable
No
No or in same side of breast
Yes, on same side of breast
Not applicable
No
No
No
Stage 5-year Relative
Survival Rate
0 100%
I 98%
IIA 88%
IIB 76%
IIIA 56%
IIIB 49%
IV 16%

Source: American Cancer Society

A five-year survival rates represent the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer.These survival rates are based on averages and are subject to significant variability between individuals.

Interesting Facts

Saint 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 ( Italy) during the rule of the roman emperor Decia (200-251 AD) .  Decia sent his regent (governor) to exterminate the Christian’s but he decided to spare Agatha after hearing of her beauty. Agatha refused to go to with Quirin , the governor because she was Christian and was thrown into prison.  For thirty days he unsuccessfully tried to convince Agatha to become Quirin’s.  Exasperated, he ordered Agatha to be tortured and had her breasts torn off. Back in her cell she was visited by an angel who cleansed her wounds and in the morning, Saint Agatha’s breasts had grown back.

She was tortured further on hot coals until she passed away. At that moment a large earthquake shook Catania and Quirin was thrown in the river and died. Agatha was sainted, the woman martyr and patroness of breast disease. Her sacrifice is remembered on February 5th.

 

 

Tiepolo, Giambattista  The Martyrdom of Saint Agatha c. 1755   Gemaeldegalerie, Staatliche Museen Preussischer Kulturbesitz, Berlin

Michelangelo’s “Night.” On a trip to Florence two years ago, James Stark, oncologist and associate professor of medicine at Eastern Virginia Medical school, and Jonathan Nelson, art historian, noticed specific lumps and depressions on the left breast of Night that seemed to correlate with an advanced stage of breast cancer. Stark noted , “There’s a bulge on the op of the breast, a swelling in the nipple and a puckering to the side of the nipple. I’ve been doing this my whole life and just stood there and said, ‘That’s breast cancer.’

Photograph courtesy of the Kunsthistorisches Institut Florenz, Florence, Italy

Disease

Cancer

Common Breast Diseases

Malignant breast disease

Most diseases both benign and malignant arise from this highly active terminal ductal lobular unit (TDLU) in which there is constant change of structure.   (Stirling)

The carcinomas are the most significant lesions of the breast.  There are two major types of breast carcinoma that arise from the lobule namely ductal carcinoma and lobular carcinoma.  They both arise from the TDLU.

Carcinoma of the breast at this level is divided into the non invasive or “in situ” carcinomas on the one hand and the invasive carcinomas on the other.  The “in situ” carcinomas are restricted to the lobule and do not show invasion of the basement membrane while in the invasive group, there is obvious transgression of the basement membrane.

The “in situ” group has variable behavioral patterns and outcomes.  These lesions may remain dormant for a lifetime, or may even involute.  They do however place the woman at increased risk of developing cancer and should therefore be treated with heightened awareness.

The two types of “in situ” carcinomas are called ductal carcinoma in situ (DCIS), and lobular carcinoma in situ. (LCIS) and they are very different.  DCIS is common and occurs in 70-95% of women at autopsy and is commonly associated with microcalcifications on mammography.  It arises from ductal epithelium.   LCIS is less common, clinically and radiologically more elusive, occurs in 1-5% of biopsies, and is rarely associated with microcalcifications on mammography.  Wellings  Once LCIS is identified the risk of developing cancer if untreated is about 30% within 20 years of diagnosis. It is not considered a precancerous disease, but a marker of increased risk.

The invasive carcinomas of the breast are correspondingly called invasive ductal carcinoma and invasive lobular carcinoma and are defined by the transgression of the basement membrane by malignant cells.

The most common site of involvement is the upper outer quadrant since as we have learned it is the location of “extra” tissue called the axillary tail of Spence.  The presence of a larger amount of glandular tissue raises the relative incidence of disease in this quadrant. About 45% of carcinomas arise from this upper outer quadrant.

Invasive ductal carcinoma is the most common type of carcinoma and it has a tendency to incite a fibrous response which has structural consequences.  Firstly fibrous tissue is very dense so that this type of tumor has a relatively dense appearance on mammography.  The scirrhous and desmoplastic nature of fibrosis also causes a tugging effect on other structures such as the Cooper’s ligament, the skin or the nipple so that retraction of these structures can occur.  Peau d’orange is the dimpling of the skin in carcinoma that is reminiscent of the dimpling seen in the skin of an orange, and it is caused by the effect of the carcinoma on the ligaments of Cooper. New onset of nipple retraction is also an important warning sign of cancer.

 

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Invasive ductal carcinoma

This mammogram shows a spiculated mass in the center of the image just rightward of the marker, and was shown to be an invasive ductal carcinoma.  Courtesy Priscilla Slanetz MD MPH 42932

Fibrocystic disease

Fibrocystic changes in the breast are the most common entity of the breast and accounts for the common lumpy bumpy feel of normal breast tissue.  It is a benign entity that arises from the TDLU.  The pathology is caused by proliferation of the connective tissue and or epithelial tissue, resulting in cystic change and or fibrous changes.   It has a variety of clinical, imaging and pathological variations including a single dominant cyst, diffuse irregularity caused by fibrocystic change and diffuse irregularity with a dominant lesion (U Virginia) The entity is subject to morphologic changes with hormonal changes of the menstrual cycle, and it may be associated with pain.  The lesion is most common in the upper outer quadrant where the lobules are more voluminous in the tail of Spence.

 

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Cyst

A cyst is noted on this ultrasound in the breast of a young woman with a palpable mass.  This entity is part of the fibrocystic entity discussed above and most commonly presents as a disturbing mass.  Ultrasound is the study of choice when this condition is clinically suspected.  Note that the cyst has no internal echoes, the wall has no evidence of neither focal nor diffuse thickening and there is superb through transmission of sound.  Courtesy Priscilla Slanetz MD MPH 28241

Fibroadenoma

Fibroadenoma is a common benign disorder of younger adult women that arises from the intralobar connective tissue elements and from epithelial elements.  Unlike the cyst above the fibroadenoma presents on ultrasound as a well circumscribed solid lesion.

 

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Fibroadenoma

This ultrasound of the left breast of a young adult female reveals a well circumscribed mass that proved to be a fibroadenoma. Courtesy Priscilla Slanetz MD MPH 42714

 

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Fibroadenoma

This mammogram of the left breast of a young adult female reveals a well circumscribed mass that proved to be a fibroadenoma. Courtesy Priscilla Slanetz MD MPH 42913


Diseases of the ducts
Disease of the larger ducts is relatively uncommon. Duct ectasia is a dilatation of the major ducts just behind the nipple that occurs in women nearing menopause and is really a normal finding.  Accumulation of secretions may cause blockage of the duct which can then become symptomatic.

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Duct ectasia

This 46year old female demonstrates prominent tubular structures near the nipple of the left breast. This image was previously used to demonstrate the ducts.  A diagnosis of duct ectasia is most likely.  Courtesy Ashley Davidoff MD 43646

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Duct ectasia

This mammogram of the right breast shows a dilated duct coursing toward the nipple.  This is the mammographic finding of duct ectasia. Courtesy Priscilla Slanetz MD MPH 13563

 

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Benign tubular ductal calcifications

The mammogram of the right breast shows benign tubular calcifications all oriented in the same way toward the nipple.  The calcifications are characteristic of benign secretory calcifications within the ducts.  Courtesy Priscilla Slanetz MD MPH 42885

Nipple discharge

Nipple discharge is the third most common breast symptom after mass, and pain of the breast.  Discharge is a normal event in women who are in the reproductive age.  50-60% of women can express some secretion on self examination.   It is uncommon that a discharge is associated with breast cancer.  Causes of nipple discharge include persistent secretion after pregnancy, benign hormonal affects, and mammary duct ectasia.  Phenothiazines may also cause a nipple discharge.  Benign features include bilaterality, and the involvement of multiple orifices. Bloody discharge that is spontaneous, from a single duct should raise concern for malignancy, but even so, only 10% of these patients have an underlying malignancy.  Intraductal papilloma is the most common cause.

 

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Intraductal papilloma

This is a case of a 48 year old female with bloody nipple discharge.  Ductogram reveals a segmental lactiferous duct with filling defect consistent with a diagnosis of intraductal papilloma.  Courtesy Priscilla Slanetz MD. MPH 43030

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Intraductal papilloma

This is the correlative ultrasound of the above case. Note the dilated duct within which resides the echogenic nodule. Courtesy Priscilla Slanetz MD. MPH 43031

Pagets’s Disease of the Nipple
Paget’s disease of the nipple is a rare disease of the nipple characterized by eczematous change of the nipple and almost always associated with an underlying breast carcinoma, specifically with high grade DCIS.  The areola may also show eczematous change.  It occurs in about 12% of patients with breast carcinoma.  The findings in the nipple may be the only indication of disease, and so a new scaliness of the nipple warrants serious attention of clinician, mammography technologist, and radiologist.  Only about 50% of patients with Paget’s have a radiographic abnormality on mammography.

Infection

Breast Prosthesis Abscess

22983 breast skin prosthesis fx air dx abscess CTscan C-