Breast cancer: Pathology review

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Case Study0:00–0:56

64-year-old Cassie comes to the office because of a new breast mass that she found on her monthly self-examination. A mammogram shows microcalcification clusters so an excisional biopsy is performed.
Pathology shows high-grade cells with central necrosis in the lumen and dystrophic calcification in the center of the ducts without invasion of the basement membrane.
Later that day, a 58-year-old named Linda comes to the physician's office with eczematous dermatitis of the left nipple and areolar area for the past 24 months.
Her history reveals that the lesion has been treated unsuccessfully with topical steroids and has progressively distorted the nipple, resulting in nipple inversion.
Physical examination reveals scaly, crusted, and deformed left nipple with multiple plaques overlying the surrounding areola.
At first glance, you’d think Cassie and Linda have nothing in common, but the fact is, they have different forms of breast cancer!

Pathology0:56–3:07

Breast cancer is the most common malignancy in women and it’s typically seen in postmenopausal women, over 50 years of age.
Most breast cancers are adenocarcinomas and they typically arise from the terminal duct lobular units. Breast cancer can present as a palpable hard mass, most commonly located in the upper outer quadrant of the breast.
Now, some breast cancers can be associated with amplification and overexpression of genes for estrogen receptors, progesterone receptors, and HER2/neu receptors.
For your exam, you have to remember that these receptors are important therapeutic and prognostic factors of breast cancer.
In other words, breast cancers that are associated with overexpression of estrogen and progesterone receptors are more susceptible to anti-estrogen medications, such as tamoxifen.
On the other hand, HER2/neu receptors, also known as erbB2 receptors, are coded by the ERB-B2 gene. These receptors are transmembrane glycoproteins with tyrosine kinase activity that plays an important role in epithelial growth and differentiation.
HER2/neu receptors are present in small amounts in normal breast and ovarian cells; while they are overexpressed in 25-30% of breast cancers as well as in adenocarcinomas of the ovary, lung, stomach, and salivary glands.Moreover, breast cancers that are associated with HER2/neu positivity are linked to more aggressive tumors; however, they are more likely to respond to anti-HER-2 monoclonal antibodies, like trastuzumab.
Another high-yield fact is that breast cancers that are estrogen negative, progesterone negative, and HER2/neu negative, or in other words, triple-negative, are linked to a more aggressive form of breast cancer.
Finally, breast cancer tends to metastasize first to the axillary lymph nodes, while in the later stages, the most common sites of metastases include lungs, liver, and bones.
Now, switching gears and moving on to risk factors! The most common risk factors in females include advanced age and family history of breast cancer, which is considered the strongest risk factor.

Risk Factors3:07–4:54

The risk of hereditary breast cancer is increased even more in young women who have had more than one close relative with premenopausal breast cancer.
Also, a family history of ovarian cancer is linked to an increased risk for ovarian and breast cancer, because both of these cancers are associated with autosomal dominant mutations of BRCA1 and BRCA2 genes.
BRCA genes codes for BRCA proteins that acts as a tumor suppressor that controls the cell cycle, helps repair DNA, and regulates transcription of DNA.
Moreover, women with the BRCA1 mutation have a 70-80% higher risk for developing breast cancer; and a 40% increased risk for developing ovarian cancer compared to women without the BRCA1 mutation.
Another commonly high yield factor on your exam is increased estrogen exposure like nulliparity, late first pregnancy, early menarche, and late menopause.
Other risk factors include alcohol consumption, absence of breastfeeding, and obesity in postmenopausal women. Remember that after menopause, estrogen levels typically drop, but adipose tissue converts androstenedione to estrone, which is a weak estrogen.
Finally, you shouldn’t forget the influence of race in breast cancer: Caucasians are at the highest risk while people of African descent are at increased risk for the development of triple-negative breast cancer.
Alternatively, risk factors for breast cancer in men include BRCA2 mutation and Klinefelter syndrome. In terms of screening and diagnosis, according to the American Cancer Society guidelines, women aged 45-54 years should also undergo screening mammography every year.

Diagnosis4:54–5:24

If a breast mass is palpated during physical exam, a woman should undergo mammography which is the initial imaging technique used for palpable breast lesions in women older than 35 years.
Clinicians can also use needle biopsy to evaluate suspicious breast lesion since this is the most specific diagnostic tool.As far as the treatment goes, breast cancer is treated with surgery, radiation therapy, and systemic therapy.
Surgical management of breast cancer can be performed as a radical mastectomy, which stands for removal of one or both breasts; or breast-conserving, which stands for removal of cancerous tissue while avoiding mastectomy.

Treatment5:24–6:04

Chemotherapy agents include trastuzumab, a monoclonal antibody against HER-2/neu receptors and tamoxifen, which is a selective estrogen receptor modulator.
Finally, aromatase inhibitors like anastrozole can also be used to treat estrogen receptor positive breast cancers in postmenopausal individuals.
Now breast cancer can be subdivided into non-invasive and invasive breast cancers. First, let’s start with non-invasive breast cancers.

Non-Invasive Cancer6:04–9:33

Now, remember that at the time when they are found, they have not crossed the basement membrane and invaded other tissue.
These include ductal carcinoma in situ, Paget disease of the breast, and lobular carcinoma in situ. Ductal carcinoma in situ, or DCIS, is a precancerous lesion characterized by a mass of neoplastic cells that arise from epithelial cells in the terminal duct lobular unit.
As they proliferate, neoplastic cells fill the lumen of the duct, but at the same time, they do not invade into the basement membrane, which is why they are “in situ”.
In most cases, DCIS affects only one ductal system; but in some individuals, it can present as a more extensive lesion that spread to surrounding breast tissue.
In addition, DCIS accounts for 15-30% of all carcinomas found on screening mammograms; and 50% of all carcinomas identified on diagnostic mammograms.
Now there are two subtypes of ductal carcinoma in situ: comedo DCIS and non-comedo DCIS. Comedo DCIS, also referred to as comedocarcinoma, is associated with solid sheets of pleomorphic, high-grade malignant cells, which indicate that this cancer is growing rapidly.
Moreover, central malignant cells can die and result in central necrosis, which can eventually calcify and form dystrophic calcifications.
Additional findings can include chronic inflammation and periductal concentric fibrosis. Finally, if left untreated, malignant cells can eventually penetrate the basement membrane and invade the surrounding breast tissue, forming a poorly defined palpable breast nodule.
So for your exam, you have to remember that comedocarcinoma typically does not produce a mass lesion unless it has invaded the surrounding breast tissue; instead, it’s most commonly identified as microcalcification clusters on mammography.
In contrast to comedo DCIS, non-comedo DCIS is not associated with central necrosis and it’s subdivided into three types: papillary and micropapillary DCIS, which are characterized by malignant cells that are arranged in a finger-like pattern within the duct; cribriform DCIS, which is characterized by gaps between malignant cells; and solid DCIS, where cancer cells completely fill the duct.
The next non-invasive breast malignant condition is Paget disease of the breast! Paget disease occurs when ductal carcinoma, either in situ or invasive, extends up to the lactiferous ducts and into the nipple and areola.
So, you have to know that women with this condition typically present with an eczematous skin lesion or persistent dermatitis in the nipple and adjacent areas.
The diagnosis of Paget disease of the breast is established by obtaining a biopsy, but women with Paget disease must undergo mammography to detect the presence of underlying breast cancer.
Histologically, Paget disease of the breast demonstrates Paget cells, which are intraepithelial adenocarcinoma cells. As far as the treatment goes, the initial management of Paget disease of the breast is a mastectomy.
In addition, Paget disease of the breast that is positive to estrogen receptors can be treated using an estrogen receptor antagonist like tamoxifen.
Finally, there’s lobular carcinoma in situ, or LCIS, which arises in lobules and acini of the terminal duct lobular unit.
LCIS is not associated with the classic presentation of breast cancers, such as a palpable breast lesion, radiological features, or microcalcifications; instead, it’s most commonly diagnosed as an incidental finding on biopsy for some other mass lesion, such as fibroadenoma.

Lobular Carcinoma In Sit9:33–10:13

Finally, for your exam, you have to remember that LCIS is associated with an increased risk of breast cancer developing in both breasts, in contrast to DCIS, where the risk is increased in the affected breast.
Now, switching gears and moving on to invasive breast cancers, which typically present as a poorly-defined, firm, palpable breast mass or a mammographic finding.
As cancer invades surrounding breast tissue, it can infiltrate pectoral muscles and deep fascia, thereby form immobile masses.

Invasive Cancer10:13–13:00

Moreover, infiltration of the central region of the breast can lead to nipple retraction, while the invasion of the suspensory Cooper ligaments leads to retraction of the overlying skin.
Finally, if the cancer cells obstruct the dermal lymphatics, they can cause lymphedema and thickened skin around exaggerated hair follicles, eventually giving the skin the appearance of an orange peel, also referred to as peau d'orange finding.
Invasive breast cancers include invasive ductal breast carcinoma, invasive lobular breast carcinoma, medullary breast carcinoma, and inflammatory breast carcinoma.
First, let’s focus on invasive ductal carcinoma, which is the most commonly diagnosed type of invasive breast cancer. Typically, it arises from the terminal duct lobular unit and presents as a unilateral firm, fibrous, rock-hard palpable breast mass with sharp margins.
In advanced stages, invasive ductal carcinoma can cause skin dimpling or nipple retraction. Histologically, it’s characterized by small glandular cells in the stroma, and it can be tubular or mucinous.
Tubular carcinoma is characterized by well-differentiated tubular structures that lack myoepithelium; while mucinous carcinoma is associated with malignant cells that are scattered throughout abundant extracellular mucin.
For your exam, you should remember that the mucinous subtype is most commonly seen in older women after they’ve gone through menopause.
Finally, invasive ductal carcinoma has a tendency to metastasize via the lymphatic vessels and it’s also the most common type of breast cancer in males.
Moving on to invasive lobular breast carcinoma! This is the second most common type of invasive breast cancer.
It’s often associated with lobular carcinoma in situ. In contrast to invasive ductal carcinoma, invasive lobular carcinoma is often bilateral with multiple lesions in the same location that are not palpable on breast examination.
A high yield fact is that this tumor is associated with low E-cadherin expression, which is a gene that codes adhesion proteins that prevent cancer cells from spreading into the surrounding breast tissue.
Histologically, invasive lobular carcinoma is characterized by cancer cells that are clustered into strands or chains that invade into the adjacent stroma.
Remember: Lines of cells are associated with invasive Lobular carcinoma. Also, there’s no duct formation.
The next one is medullary carcinoma, which is a type of breast cancer that most commonly presents as a well-circumscribed palpable mass that can mimic benign lesions, such as fibroadenoma.
Medullary carcinoma is more common in younger women and it’s associated with BRCA1 mutation and triple-negative phenotype.
Histologically, it’s characterized by large anaplastic cells that grow in sheets and infiltrate of lymphocytes and plasma cells.
Finally, there’s inflammatory breast carcinoma, which often affect women younger than 40. Women with inflammatory breast carcinoma commonly present with peau d'orange finding, breast tenderness, pruritus, warm erythematous skin or skin discoloration, which can range from pale pink to deep red and purple.

Medullary Carcinoma13:00–13:29

On physical exam, they can lack a palpable mass, therefore the condition can be mistaken for mastitis or Paget disease of the breast.
Inflammatory breast carcinoma is very aggressive and always locally invasive at the time of diagnosis which gives it a higher stage and a poor prognosis.Unlike the name would suggest, symptoms are caused by the blockage of dermal lymphatics and not inflammation.

Inflammatory Breast Carc13:29–14:17

On histology, there are tumor cells that invade into the dermal lymphatics in the affected areas. All right, as a quick recap.
Breast cancer is the most common malignancy in women and it’s typically seen in postmenopausal women, over 50 years of age.
Most breast cancers are adenocarcinomas that typically arise from the terminal duct lobular unit and they can present as an incidental finding on a screening mammogram or as a palpable breast mass.
In most cases, they are located in the upper outer quadrant of the breast and they are evaluated by triple assessment method: clinical examination, imagining methods, such as ultrasound or mammography, and needle biopsy.

Review14:17–15:59

Next, breast cancers are subdivided into non-invasive breast cancers and invasive breast cancers. Non-invasive breast cancers include DCIS, which is further subdivided into comedo and non-comedo DCIS; Paget disease of the breast; and LCIS.
On the other hand, invasive breast cancers include invasive ductal carcinoma, invasive lobular carcinoma, medullary breast carcinoma, and inflammatory breast carcinoma.
Finally, the treatment of breast cancer includes surgical management, such as radical mastectomy or breast-conserving surgery; radiation therapy; and chemotherapy.
If the breast cancer is estrogen receptor positive, they will respond to treatment with anti-estrogen medications like tamoxifen, which is a selective estrogen receptor modulator, or aromatase inhibitors like anastrozole.
If it’s HER-2/neu receptor positive, it will respond to trastuzumab, a monoclonal antibody against HER-2/neu receptors. And that’s not all!
Here’s an overview of the most common benign and malignant breast conditions and parts of the breast that they affect! Feel free to pause the video.Now, let’s go back to our case!
First, there was Cassie who noticed a new breast mass on her monthly self-examination. A mammogram showed microcalcifications clusters so excisional biopsy was performed which showed high-grade cells with central necrosis and dystrophic calcifications.
Since there was no invasion of the basement membrane, we can say that this is a classic presentation of ductal carcinoma in situ, more specifically comedocarcinoma!
On the other hand, Linda complained about chronic eczematous dermatitis of the left nipple and areolar area for the past 24 months.

Summary15:59–16:54

Her history revealed that the lesion was treated unsuccessfully with topical steroids and physical examination showed scaly, crusted, and deformed left nipple with multiple plaques overlying the surrounding areola.
Linda must undergo mammography and detect the possible presence of underlying breast cancer. She most likely has Paget disease of the breast.
A biopsy is needed to confirm the presence of Paget cells and to rule out inflammatory breast carcinoma. chronic eczematous dermatitis of the left nipple and areolar area for the past 24 months Her history revealed that the lesion was treated unsuccessfully with topical steroids and physical examination showed scaly crusty and deformed left nipple with multiple plaques overlying the surrounding Areola Linda must undergo mammography and detect the possible presence of underlying breast cancer She most likely has Paget disease of the breast A biopsy is needed to confirm the presence of Paget cells and to rule