62. Breast carcinoma. Pathogenesis, types, prognosis

Page created on May 3, 2019. Last updated on December 18, 2024 at 16:57

Definition and epidemiology

Breast cancer is the most common malignancy in women and it’s the second most common cause of cancer mortality. The condition is related to increased oestrogen. When we talk about breast cancer we can mean either non-invasive or invasive carcinoma. These tumors develop from different parts of the terminal duct lobular unit (TDLU). They most frequently affect the upper outer quadrant of the breast.

Breast cancer is most common in older, post-menopausal women. Cancers in younger women are commonly hereditary rather than sporadic. 90% of cases are sporadic and 10% are familial. Breast cancer in men is very rare but it does occur.

The lifetime risk of developing breast cancer in an American woman is 1 in 8 (12.5%), which is really high.

Etiology

• Female gender
• Risk increases continuously after age 30
• Living in western countries
• Positive family history
• Increased oestrogen exposure
  • Nulliparity
  • Early menarche
  • Oestrogen-containing contraceptives
• Obesity
• Germ-line mutations in BRCA1 or BRCA2
• Atypical hyperplasia in benign breast disease

Pathology

Overexpression of HER2/NEU proto oncogene is present in 30% of invasive breast cancer. Many breast cancers express oestrogen receptors (ER) and/or progesterone receptors (PR) as well. Breast cancers should be examined immunopathologically for which of these three proteins they express, as specific treatments exist for each of them, thereby improving the prognosis. Cancers which express none of the three HER2/NEU, oestrogen receptor or progesterone receptor are known as triple negative cancers, and they have a poor prognosis.

Of the familial cases, mutations in BRCA1 and BRCA2 are most common. Germ-line mutations in BRCA1 or BRCA2 is found in one third of cases with hereditary breast cancer. They’re rarely mutated in sporadic cases of cancer. These proteins are tumor suppressors involved in DNA repair.

Increased oestrogen exposure is highly associated with breast cancer. Many of the risk factors like obesity, early menarche and nulliparity cause increased oestrogen/progesterone ratio. Oestrogens stimulate the production of growth factors which may promote tumor development. Factors which reduce unopposed oestrogen exposure, like late menarche and breast feeding are protective.

Types

• Non-invasive carcinoma
  • Ductal carcinoma in situ (DCIS)
  • Lobular carcinoma in situ (LCIS)
• Invasive carcinoma
  • Invasive ductal carcinoma
  • Invasive lobular carcinoma
  • Tubular carcinoma
  • Mucinous carcinoma
  • Medullary carcinoma
  • Inflammatory breast carcinoma (mastitis carcinomatosa)
  • Other types

Ductal carcinoma in situ (DCIS) is the most common non-invasive carcinoma. The tumor cells originate from the cells of the terminal duct lobular unit and fill ducts of the breast. The name is a bit misleading as it doesn’t always develop from the ducts.

At this stage the tumor cells do not invade past the basement membrane of the ducts. If the tumor cells start to invade past the basement membrane the tumor becomes an invasive carcinoma.

Cells in the centre of the ducts die by necrosis as they don’t receive enough nutrients and oxygen. This forms calcifications that are visible on mammography. High grade DCIS is called the comedo type is characterised by severe atypia and extensive central necrosis and calcification.

DCIS rarely causes a palpable mass and is often discovered during routine mammography. Treatment by surgery and irradiation is curative in almost 100% of cases.

DCIS can also be present simultaneously as an invasive carcinoma, as seen in the invasive ductal carcinoma slide.

Lobular carcinoma in situ (LCIS) also originates from the the cells of the terminal duct lobular unit. This name is also a bit misleading, suggesting that it only develops in the lobule, but this is false. However, they are more frequently present in the lobules.

Like for DCIS the tumor cells don’t invade past the basement membrane of the lobules; when they do the condition is called invasive lobular carcinoma. The most important difference between LCIS and DCIS is that LCIS very rarely produces calcifications or masses, so they’re often discovered incidentally.

Unlike DCIS, LCIS is often multifocal and occurs in both breasts simultaneously. They’re not removed surgically but rather treated with chemotherapy and regular follow-up.

The tumor cells in LCIS have lost an intercellular adhesion molecule called E-cadherin, which causes them to be disconnected from each other.

Invasive carcinoma: Many subtypes of invasive carcinoma exist. All of them can cause clinical findings like:

• Firm, palpable mass
• Skin retraction
• Nipple retraction
• Orange peel-like skin
• Nipple discharge

Invasive ductal carcinoma accounts for 80% of invasive carcinomas. It occurs when DCIS invades past the basement membrane of the ducts. Histologically the tumor consists of duct-like structures embedded in a desmoplastic (fibrous) stroma. It is this desmoplastic stroma that causes the tumor to be hard and firm and visible on mammography. 2/3 express estrogen or progesterone receptors, while 1/3 express HER2/NEU.

Invasive lobular carcinoma accounts for 5 – 10% of invasive carcinoma. It occurs when LCIS invades past the basement membrane of the lobules. As these cells lack E-cadherin the tumor cells don’t form structures. The tumor cells often forms single rows with each other. Signet ring cells may be present. Almost all express hormone receptors, very few express HER2/NEU.

Tubular carcinoma is characterised by the presence of well-formed tubular or glandular structures infiltrating the stroma. This type has a favourable prognosis.

Mucinous carcinoma accounts for 1 – 2% of invasive carcinoma. It is characterised by tumor cells that have lost their orientation. Instead of secreting mucus into a lumen they secrete mucus outward. This causes the tumor cells to be surrounded by “pools of mucus”, as can be seen in the histo slide. This type has a favourable prognosis.

Medullary carcinoma is characterised by high grade tumor cells with inflammatory infiltrate. It’s more frequent in women with BRCA1 mutations. These cancers consist of sheets of large anaplastic cells with well circumscribed pushing borders. Clinically they can be mistaken for fibroadenomas. They lack hormone receptors and do not overexpress HER2/NEU –> Triple- negative.

Inflammatory breast carcinoma (mastitis carcinomatosa) is a rare and aggressive form of breast cancer. It is characterised by an inflamed breast, with erythema and oedema. This inflammation is sterile and occurs because tumors cells have filled the lymphatic vessels of the breast, similar to lymphangitis carcinomatosa. What’s important for this subtype is that mastectomy is not performed; chemotherapy and irradiation are performed instead. This condition should be considered in women with mastitis that doesn’t resolve with antibiotics.

Diagnosis

Breast cancers are usually detected during routine mammography screening of postmenopausal women, or in women with self-palpated breast lump. The breasts are usually asymmetric as the breast with the tumor changes size or shape. Thanks to mammography screening, presentation by a palpable mass is becoming more and more rare.

Mammography can detect calcifications, which occurs in most breast cancers. Calcifications can also be present in benign conditions like fat necrosis and sclerosing adenosis.

Histologically cancers can be distinguished from benign conditions based on the absence of myoepithelial cells, which are absent in cancers.

Prognosis

The prognosis of breast cancer depends on its TNM stage. Distant metastasis (M1) equals a very poor prognosis but is uncommon. Many cases present with spread to the axillary lymph nodes however, so biopsy of this lymph node is very important in determining stage and prognosis.

The procedure where axillary lymph nodes are biopsied is called sentinel lymph node biopsy. During this procedure the breast is injected with radioactive material. This material will then drain to the sentinel (first-in-line) lymph node, which is then removed and examined. If not for this method, we would have to remove all axillary lymph nodes and examine them all. This causes lymphoedema of the arm of the patient, which should be avoided.

The subtypes of breast cancer arranged from worst prognosis to best prognosis are: Inflammatory carcinoma > invasive ductal carcinoma > the rest.

The degree of which the tumor expresses three different proteins determine how easy it can be treated with drugs. The more of these three proteins a tumor expresses, the possibilities for drug treatments exist. These proteins are:

• Oestrogen receptor (ER)
• Progesterone receptor (PR)
• Her2/neu, also called ERBB2

Tumors that express none of these three are called triple-negative and carry a poor prognosis as they can’t be treated with drugs. Medullary carcinoma is always triple negative.

Complications

Paget disease of the breast is the condition where tumor cells originating from DCIS or invasive carcinoma extend into and replace the epithelial cells of the epidermis of the nipple. This causes the nipple to become firm, ulcerated, hyperkeratotic and inflamed.

Breast cancer can metastasize anywhere, but most commonly they metastasize to the lungs, skeleton and liver.

Treatment

Most cases are treated with surgical removal of the breast (mastectomy) and/or chemotherapy. Women with high risk for developing breast cancer (like positive BRCA mutation) may be offered prophylactic double mastectomy.

Patients with tumors that express both oestrogen receptor and progesterone receptor can often be treated with anti-oestrogenic drugs like tamoxifen. The treatment is less likely to succeed if only one of the receptors are expressed.

Her2/neu is a gene that codes for a protein of the same name. The protein is membrane-bound and related to the epidermal growth factor receptor (EGFR). Tumors that express this protein can be treated with Herceptin (trastuzumab), a monoclonal antibody that binds to and inhibits its function.