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Needle biopsy

A physician’s hands are seen performing a needle biopsy to determine nature of lump either fluid-filled cyst or solid tumor.


Definition of Breast Carcinoma

Breast cancer, also known as mastocarcinoma, is a malignant tumor of the breast (mammary gland).

The point of origin of breast cancer may either be the mammary gland ducts or the lobules. Correspondingly, the two most common breast cancer types, ductal carcinoma and lobular carcinoma, are differentiated.

Epidemiology

Diagram showing the lobes and ducts of a breast

Image: ‘Diagram showing the lobes and ducts of a breast.’ By Cancer Research UK. License: (CC BY-SA 4.0).

Breast cancer is the most common form of cancer among women, accounting for 29% of all malignant diseases among women in the United States. The yearly incidence adds up to 110 cases per 100,000 women.

More than 90% of diagnoses occur in women over 40 years of age, while the median age at the time of diagnosis of breast cancer is 61 years.

Note: One out of 8–10 women gets breast cancer during her lifetime. The chances of being affected with breast cancer increase with age, but young women also can be affected. It usually affects women between the ages of 60–80 years.

Note: In the western hemisphere, the most common cause of death among women in their 35th–55th year of life is breast cancer.

However, breast cancers also occur in men: One percent of breast cancers affect men.

Age-standardised death rates from Breast cancer by country (per 100,000 inhabitants)

Image: ‘Age-standardized death rates from breast cancer by country (per 100,000 inhabitants).’ By Lokal_Profil. License: (CC BY-SA 2.5).

Etiology of Breast Cancer

Causes of breast cancer

The exact etiology of breast cancer is unknown, but it is assumed to be a multifactorial event. The majority of breast cancers forms spontaneously (= sporadically, approximately 95%), whereas only a minor fraction is of hereditary origin, in terms of familial genetic modifications (approximately 5%).

Risk factors for breast cancer

There are multiple risk factors that may promote breast cancer.

The most important population-related risk factor is advanced age.

With advanced age, the risk of contracting breast cancer increases. The other common risk factors include hormonal influences (endogenous or exogenous), positive family history (genetic predisposition), obesity, nulligravida, early menarche, late menopause, diet, and lifestyle. The following table provides an overview:

Risk factors
Diet/lifestyle Large amounts of meat and fat, overweight/obesity (especially after menopause), high intake of alcohol, and cigarette smoking
Family history Breast cancer in first- or second-degree relatives (mother, grandmother, sister), and Ashkenazi Jewish descent
Hormonal influences Long hormone exposure: early menarche and late menopause; higher age at first delivery (> 30 years of age), nulliparity, hormone replacement therapy after menopause (> 5 years), oral contraceptives (disputable)
Others Breast cancer on the contralateral side, ionizing radiation, benign findings in a biopsy, mastopathy, and hyperprolactinemia

In the majority of hereditary breast cancers, a mutation on one of the following two tumor suppressor genes can be found: the BReast-CAncer 1 and 2’ BRCA-1 (on chromosome 17q) and BRCA-2 (on chromosome 13q).

Note: Women with BRCA-1 or BRCA-2-gene mutations have a higher risk (80–90%) of breast cancer. These women also have an increased risk of ovarian cancer.

Representation of the BRCA1 gene on chromosome 17

Image: ‘Representation of the BRCA1 gene on chromosome 17.’ By Kuebi. License: (CC BY-SA 3.0).

Classification of Breast Carcinoma

WHO classification

The World Health Organization (WHO) classifies breast cancer into ductal and lobular carcinomas histopathologically on the basis of their origin. This classification covers invasive breast cancers as well as precursor lesions, lesions of low malignant potential, and benign lesions.

Note: Ductal carcinomas comprise 80% of breast cancers, while lobular carcinomas account for the remaining 20%. The following is a simplified overview of the WHO classification:

Invasive breast carcinomas
  • Invasive carcinoma of no special type (NST)
  • Invasive lobular carcinoma
  • Tubular carcinoma
  • Cribriform carcinoma
  • Mucinous carcinoma
  • Carcinoma with medullary features
  • Carcinoma with signet ring differentiation
Epithelial-myoepithelial tumors
  • Pleomorphic adenoma
  • Adenomyoepithelioma
Precursor lesions
  • Ductal carcinoma in situ
  • Lobular neoplasia
    • Lobular carcinoma in situ
    • Atypical lobular hyperplasia
Papillary lesions
  • Intraductal papilloma
  • Intraductal papillary carcinoma
  • Encapsulated papillary carcinoma
  • Solid papillary carcinoma
Benign epithelial proliferations
  • Sclerosing adenosis
  • Apocrine adenosis
  • Microglandular adenosis
  • Radial scar/complex sclerosing lesion
  • Adenomas
Fibroepithelial tumors
  • Fibroadenoma
  • Phyllodes tumor
  • Hamartoma
Tumors of the nipple
  • Nipple adenoma
  • Syringomatous adenoma
  • Paget’s disease of the nipple

TNM classification of breast cancers

The Tumor, Nodes, and Metastasis (TNM) classification is an important instrument to classify malignant tumors with regard to their spreading, effect on regional lymph nodes, and the presence or absence of distant metastases. Using this classification, the prognosis and the treatment strategy is determined.

The following table depicts the TNM classification of the mastocarcinoma using the classification of the Union for International Cancer Control (UICC) (per the Diagnostic Breast Center Munich).

Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor ≤ 20 mm in the greatest dimension
T2 Tumor > 20 mm but ≤ 50 mm in the greatest dimension
T3 Tumor > 50 mm in the greatest dimension
T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed (e.g., previously removed)
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral level 1, two axillary lymph node(s)
N2 Metastases in ipsilateral level 1, two axillary lymph nodes that are clinically fixed or matted

or

In clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis

N3 Metastases in ipsilateral infraclavicular (level 3 axillary) lymph node(s), with or without level 1, two axillary node involvement

or

In clinically detected ipsilateral internal mammary lymph node(s) and in the presence of clinically evident level 1, two axillary lymph node metastasis

Distant metastasis (M)
M0 No clinical or radiographic evidence of distant metastasis
M1 Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven > 0.2 mm

Pathology and Pathophysiology of Breast Cancer

Histologic examination of breast cancer

Invasive Lobular Carcinoma of the Breast

Image: ‘Invasive lobular carcinoma of the breast.’ By Ed Uthman. License: (CC BY 2.0).

As already mentioned, breast cancer is classified in ductal or lobular and invasive or non-invasive (in situ) types. The ductal carcinoma in situ (DCIS) and the lobular carcinoma in situ (LCIS) remain locally and do not break through the basal membrane, whereas invasive carcinomas infiltrate the surrounding tissues. After a period of latency, the in situ carcinomas may develop into invasive carcinoma. The most frequent one is adenocarcinoma.

Diagram showing ductal carcinoma in situ

Bild: ‘Diagram showing ductal carcinoma in situ (DCIS).’ By Cancer Research UK. License: (CC BY-SA 4.0).

DCIS originates from the ducts of the mammary gland and may be differentiated differently: solid (most frequently), comedo-type, cribriform, or papillary. The various subtypes differ in their progression, prognosis, and therapy.

In DCIS, central necrosis may develop into calcium-precipitation (‘micro-calcification), which can be critical for diagnostics. The period of latency of invasive ductal carcinoma is approximately 10 years.

Diagram showing lobular carcinoma in situ

Image: ‘Diagram showing lobular carcinoma in situ (LCIS).’ By Cancer Research UK. License: (CC BY-SA 4.0).

LCIS originates from monomorphic cell proliferation with small tumor cells in the lobules of the mammary gland. The acini extend to a bulb-shaped form. The period of latency before transformation into an invasive lobular carcinoma is up to 25 years, which is longer than the period of latency of DCIS. This is why LCIS is also called a pre-cancer. Often, it is multicentric.

Clinical Symptoms of Breast Cancer

Localization and metastasis of breast cancer

Breast quadrant – breast cancer

Image: ‘Breast quadrant – Breast cancer.’ By Cadelli. License: Public domain.

Breast cancer is most frequently located (55%) in the upper outer quadrant of the breast due to increased breast density, whereas it is located in the retro-areolar quadrant in 15%, in the upper inner quadrant in 15%, and in the lower outer quadrant in 10% of the cases. The lower inner quadrant is affected very rarely, accounting for only 5%.  

A carcinoma is said to be multifocal if multiple foci in the same quadrant are present. If it is multicentric, different quadrants of the breasts are affected. Furthermore, in 5–10% of cases, the contralateral breast is also affected by the tumor.

Breast cancers can metastasize at an early stage through lymphogenous and/or hematogenous routes:

Lymphogenous metastasis is into the regional lymph nodes of the axilla, while the hematogenous spread is into the skeleton (most common), lung, liver, or brain. Also, metastasis into the ovaries is possible.

Affected axillary lymph nodes are used as an indicator of hematogenous metastasis. During further procedures, examinations that verify metastases in organs should follow. For this, a chest X-ray, ultrasonic examination of the liver, and bone scintigraphy is used.

Diagram showing most common sites breast cancer spreads to

Image: ‘Diagram showing most common sites breast cancer spreads to.’ By Cancer Research UK. License: (CC BY-SA 4.0).

Symptoms of breast cancer

Breast cancer is often asymptomatic in the early stages. A dense palpable lump in the breast, which is detected by the patient herself in the majority of cases, is the leading symptom of breast cancer. Further symptoms are the following:

  • Changes in size, shape, and symmetry of the breast
  • Eczema of the nipple (always needs clarification!)
  • Skin changes in color or texture
  • Dimpled skin (plateau phenomenon)
  • Orange-peel skin (peau d’orange)
  • Retraction of the nipple
  • Bloody nipple secretion
  • Swollen axillary lymph nodes
  • Localized chest pain (rarely)

Note: A palpable node always needs to be tested.

Early signs of breast cancer

Image: ‘Early signs of breast cancer.’ By Morning2k. License: Public domain.

Special Types of Breast Cancer

The special types of breast cancer, inflammatory breast cancer and Paget’s disease of the nipple, are outlined briefly in the following section.

Inflammatory breast cancer (IBC)

IBC is a rare and aggressive type of breast cancer that is characterized by erythema and pitting of the skin, orange-peel skin, and breast swelling.   

Inflammatory Breast Cancer

Image: ‘(a) IBC case. (b) IBC: erythema, edema, and peau d’orange of the right breast, no tumor mass, with duration of signs at 1 month. (c) IBC: erythema, edema, and peau d’orange of the left breast, with duration of signs at 12 months. (d) IBC: erythema, edema, and peau d’orange of the right breast, with duration of signs at 72 months.’ By Openi. License: (CC BY 2.5).

IBC accounts for 1–4% of all breast cancers. It is often hard to diagnose due to the lack of a defined palpable tumor. Mammography and sonography often do not deliver distinct results.

Therapy includes neoadjuvant chemotherapy or radiation to be followed by surgery (modified radical mastectomy). Having a 5-year survival rate of only 5%, the prognosis of IBC is poor.

Paget’s disease of the nipple

Paget’s carcinoma grows intraepidermal ductal and appears in a nipple and/or areola changed due to eczema. It may be accompanied by DCIS or invasive ductal carcinoma.

Paget Disease of the Nipple

Image: ‘Scaly, erythematous, crusty, and thickened plaque on the nipple of Paget’s disease of the breast.’ By Lily Chu. License: Public domain.

Because mammography is usually without pathologic findings, exfoliative cytology is a proper way to detect the typical Paget’s cells (large cells, bright cytoplasm, and large round/oval nucleus). Magnetic resonance imaging (MRI) scans can be equally helpful.

For therapy, the modified radical mastectomy and, in individual cases, a breast-preserving therapy (BPT) comes into consideration. In these cases, the therapy plan depends on the type of carcinoma.

High magnification micrograph of extramammary Paget's disease

Image: ‘High magnification micrograph of extramammary Paget’s disease (EMPD).’ By Nephron. License: (CC BY-SA 3.0).

Note: With an eczematous nipple, Paget’s disease should always be ruled out! Further diagnostic and therapeutic steps can be found in the next article: The mastocarcinoma II – diagnosis, therapy, and prognosis.

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