Understanding breast cancer heterogeneity, point of origin

What does it mean when a woman says she has breast cancer?

There are different types of breast cancer based upon where the cancer begins. The breast is composed of lobules, the gland that produces milk in nursing women, and tiny tubes (ducts) that carry the milk to the nipple. Although the most common types of breast cancer are ductal and lobular, they are not the only types. And each type has sub-types.

Globally, more than  1,300,000 cases of breast cancer are diagnosed each  year; 450,000 patients die of the disease.

There also are intrinsic or molecular subtypes of breast cancer based on the genes that a cancer expresses.

Then there’s the stage of the cancer, from 0 to 4, as well as the grade of the cancer, from 1 to 3.

Each woman’s initial diagnosis is a complex interplay of these factors. (There will be an  article on male breast cancer later in this series.)

Types of breast cancer based on point of origin

Ductal Carcinoma in Situ and Lobular Carcinoma in Situ

In situ (in place) cancers are confined; they have not invaded other breast tissue.

Ductal carcinoma in situ (DCIS) is the most common type of non-invasive, stage 0, breast cancer.

About 83% of the 60,000 or so new in situ (in place) cases diagnosed in 2015 were DCIS. About 7,000 of those 60,000 women were diagnosed with lobular carcinoma in situ (LCIS).

DCIS is very small, it’s contained in the breast duct. It’s not a lump and is detected only when a radiologist observes micro-calcifications (clusters of white specks of calcium) on a mammogram.

There are five architectural subtypes:

  • comedo,
  • solid,
  • cribriform,
  • papillary, and
  • micropapillary.

The chance of DCIS recurring is under 30%. Treatment may help prevent a recurrence; however, it does not appear to decrease the risk of dying from breast cancer, even after 20 years of follow-up.

That said, some women diagnosed with DCIS are at a higher risk: women diagnosed at a younger age and African American women.

Even after years of research, we can’t tell which variants of DCIS will become invasive and which will not. The hypothesis is that DCIS is a precursor to invasive ductal carcinoma (IDC) but researchers have not identified which women are at risk. So all are treated.

Lobular carcinoma in situ (LCIS), on the other hand, is usually found in a biopsy after a radiologist sees something else that looks suspicious on a mammogram. It is not considered a pre-cancer like DCIS. Instead, its presence means an increased risk of developing breast cancer in either breast.

LCIS is marked by a loss of E-cadherin, which is due to gene mutation.

Researchers still don’t know what to make of LCIS.

According to Theresa Schwartz, a breast surgical oncologist at Saint Louis University School of Medicine who published a study  in the February 2015 Journal of Surgical Research, notes the challenges of screening:

We know that if you have an LCIS diagnosis, that you should have an annual mammogram and breast exam…. For women [with LCIS] who have a family history of breast cancer or other risk factors, MRI is more likely to be beneficial. But for other women [with LCIS], there is no good recommendation.

According to BreastCancer.org:

LCIS is usually diagnosed before menopause, most often between the ages of 40 and 50. Less than 10% of women diagnosed with LCIS have already gone through menopause.

How much is risk elevated? We don’t know.

One estimate is that the lifetime risk of developing an invasive breast cancer is 30-40% for women with LCIS, versus a lifetime risk of 12.5% for the average woman. Another estimate suggests that an LCIS diagnosis increases breast cancer risk to 21% over the next 15 years.

According to the Dr. Susan Love Foundation, two research studies suggest that LCIS can progress to invasive lobular carcinoma.

An invasive or infiltrating cancer has escaped the duct or lobule. Research suggests that it’s not the point of origin that differentiates these two types of breast cancer but whether or not the tumor cells express E-cadherin, a protein involved in cell-adhesion. However, both ductal and lobular cancer can “arise from LCIS.”

Invasive Ductal Carcinoma

An invasive or infiltrating ductal cancer (IDC) forms a hard, firm lump. Ductal carcinomas average two cm before they are detected.

Ductal is the most common type of invasive breast cancer, accounting for about 80% of all new cases.

About two-thirds of women who are diagnosed with IDC are 55 or older. Invasive ductal carcinoma also affects men.

There are several variants of ductal breast cancer, but most IDC (75%) is designated as “not otherwise specified” (NOS) or “no special type” (NST).

  • Up to 7% of IDC in published reports is medullary carcinoma which presents a well-defined tumor mass; it has a favorable prognosis and better outcome than the common IDC. Medullary carcinoma affects women about 50 years of age and is common in carriers of BRCA1 mutations.
  • About 2% is tubular carcinoma.  This well-differentiated carcinoma has an excellent prognosis. It is more common in elderly women and is less likely to have spread to lymph nodes.
  • About 2% is mucinous carcinoma,  which is associated with good prognosis. It usually occurs in post-menopausal women over 60 years of age.
  • About 2% is neuroendocrine carcinoma is more common in post-menopausal women.
  • From 1%–4% is apocrine carcinoma is a rare variant of breast carcinoma. Apocrine carcinomas are often of high grade with bad prognosis.
  • Less than 1-3.5% of IDC in published reports is invasive cribriform carcinoma; it has a favorable prognosis and is more likely to occur in patients aged 53–58 years.
  • Less than 1-2% of published reports of IDC is invasive papillar carcinoma, which has a better prognosis than classic IDC. It is most common in white, post-menopausal women.
  • Less than 1% is metaplastic carcinoma, an aggressive invasive beast carcinoma. It affects post-menopausal women with an average age of 55 years.

Other rare types include lipid-rich carcinoma, secretory carcinoma, oncocytic carcinoma, adenoid cystic carcinoma, and acinic cell carcinoma.


Invasive Lobular Carcinoma

Invasive or infiltrating lobular cancer (ILC) is a “clinically and molecularly distinct disease” from IDC. Lobular is the second most common type of invasive breast cancer, accounting for about 10% of all new cases (range 5-15% is typical presentation).

In the context of “breast cancer,” lobular variants are a small percentage. But in the context of all cancers, lobular breast cancer ranks 6th in the U.S.

Like LCIS, ILC is usually detected because a radiologist sees something else that looks suspicious. Not surprisingly, lobular cancer tends to be larger larger than ductal when detected (average five cm). From Breast Cancer Research:

Compared with patients with IDC, ILCs are generally diagnosed at a more advanced stage, with larger tumor sizes and more frequent lymph node invasion…

Women diagnosed with ILC tend to be slightly older than women diagnosed with IDC,  early 60s as opposed to the mid-to-late 50s.

Usually ILC  is estrogen receptor and progesterone receptor positive and is rarely HER2 positive. Thus for most ILC, endocrine therapy is key to treatment with aromatase inhibitors rather than with tamoxifen.

As with ductal breast cancer, there are several sub-types of ILC: conventional or classic ILC, alveolar lobular carcinoma, histiocytoid lobular carcinoma, pleomorphic lobular carcinoma, signet ring ILC, solid, and tubulolobular carcinoma.

In 2015, researchers identified three genomic features of ILC: reactive-like, immune-related and proliferative.

Inflammatory breast cancer

Inflammatory breast cancer is a rare and aggressive cancer that blocks lymph vessels in the skin of the breast. It is called “inflammatory” because the breast often looks swollen and inflamed (red). It progresses rapidly and  is either usually stage III or IV at diagnosis.

It affects younger women as well as African American women more often than white women. It also affects obese women more often than women of normal weight. It is often hormone receptor negative.


The American Cancer Society and Cancer.net forecasts these statistics for 2017:

  • About 252,710 new cases of invasive breast cancer
    • 212,068 cases of IDC (80%)
    • 25,271 cases of ILC (10%)
  • About 63,410 new cases of carcinoma in situ (CIS)
    • 52,630 cases of DCIS (83%)
    • 7,609 cases of LCIS (12%)
  • About 41,070 people (40,610 women and 460 men) will die from breast cancer

Next: Types of breast cancer based on genetic expression


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