Atypical and In-Situ Conditions of the Breast: Section 4.b.

CONTENTS:

4.2 Carcinoma In-Situ
4.2.1 Ductal Carcinoma In-Situ (DCIS)
i. Classification of DCIS
ii. Grading of DCIS
iii. Cancer Risk for DCIS
iv. Treatment for DCIS
4.2.2 Paget’s Disease of the Breast
4.2.3 Lobular Carcinoma In-Situ (LCIS)
i. Cancer Risk for LCIS
ii Treatment of LCIS
4.2.4 Pleomorphic Lobular Carcinoma In-Situ (PLCIS)

The good news is that the cure rate for women with a diagnosis of early-stage breast cancer is excellent.

Forward to 4C on papillomas. Back to 4A on atypical hyperplasia

4.2 Carcinoma In-Situ

Carcinoma in-situ is a condition of the breast milk ducts and lobules where malignant (cancer) cells of varying differentiation (grade) are present but do not break through the wall of the duct or lobule.

The 2010 American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) gives carcinoma in-situ the designation of Tis and Stage O (TisNoMo).

Lobular carcinoma in-situ (LCIS) (or ‘lobular neoplasia’) is often grouped with ductal carcinoma in situ (DCIS) as non-invasive breast cancer.

The 2012 World Health Organization (WHO) classification of breast tumors lists both DCIS and LCIS (‘lobular neoplasia’) as precursor lesions for breast cancer, but emphasizes their different clinical behavior. DCIS and LCIS also have differences in treatment recommendations and treatment options.

It is important for the Pathologist to distinguish between ductal carcinoma in-situ (DCIS) and lobular carcinoma in-situ (LCIS) on the breast tissue biopsy or excisional biopsy specimen. It is important that the patient is aware of what the differences in terminology between a DCIS diagnosis and a LCIS diagnosis mean.

So, what is the difference between ductal and lobuluar carcinoma again?

Very briefly, if you can Doc, I’ve already got brain-ache and we’ve only just started.

Very simply then, ductal carcinoma forms in the lining of a milk duct and lobular begins in the lobules connect to the ducts and produce breast milk.

The difference between DCIS and LCIS

An abnormality detected by mammography may be assessed by core needle biopsy (CNB), incision biopsy jenny02 or local excision. Fine needle aspiration cytology cannot distinguish between in-situ or invasive carcinoma.

Sentinel lymph node (SLN) dissection is not indicated in the evaluation of the patient with confirmed DCIS undergoing breast-conserving surgery (BCS). Axillary nodes are rarely positive for metastatic disease, even with extensive multi-focal, high-grade DCIS. Your breast specialist may offer a sentinel lymph node biopsy to ascertain if cancer has spread to the lymph nodes. However, the very definition of DCIS means the cancer cells remain in the breast ducts.

Assessment of risk for hereditary breast cancer (e.g. BRCA1/BRCA2) is made following a diagnosis of invasive breast cancer and DCIS. If the patient is at high risk (greater than 10 % chance) for carrying a high-risk mutation or wishes to undergo genetic testing for personal interest, a referral for genetic counselling is appropriate, particularly for women with a family history of breast cancer.

4.2.1 Ductal Carcinoma In-Situ (DCIS)

Ductal carcinoma in-situ (DCIS) is not a life-threatening condition, but the diagnosis can be alarming.

In 2006, the European Organisation for Research and Treatment of Cancer (EORTC) Trial 10853, reported a 10-year cancer-specific survival for DCIS of more than 97% (Bijker et al., 2006).

97% that is superb. I’m not keen on statistics though, for me the only time a pie chart is appropriate is at a baker’s convention.

The risk of DCIS increases with age. It is uncommon in women younger than 30 and is as high as 88 per 100,000 in women aged 50 to 64 years. The risk of death from breast cancer in women with DCIS is low, at only around 1.9 % within ten years. Most cases of DCIS are detected only on imaging studies (most commonly by the presence of micro-calcifications on screening mammography.)

Specialists believe that DCIS inevitably progresses to invasive ductal carcinoma and so medics consider DCIS to be a true ‘pre-malignant’ condition. However, how long this progression might take in any individual woman is still unknown.

Up to 90% of cases of DCIS have micro-calcifications on mammography. The pattern of micro-calcification can be characteristic; Low-grade DCIS on mammography shows as fine granular calcifications. Whereas high-grade DCIS tends to show as linear branching or segmental types of pleomorphic micro-calcifications.

This is why, ladies, it is so important to attend regular screening tests for breast cancer.

Yes, catching these changes early makes a huge difference to a positive outcome.

Figure 4.3. Micro-calcifications and DCIS.

Mammographic X-ray finding of micro-calcifications.
B. Photomicrograph of the histology of the abnormal breast tissue.
Medium-grade DCIS with micro-calcifications (*). (H&E x 60)

Fig-4-3 Moderate Grade DCIS
Mammography will underestimate the extent of DCIS. All patients with suspected DCIS should have a diagnostic bilateral mammogram with magnification views to assess the morphology and extent of any micro-calcifications.

Magnetic resonance imaging (MRI) is no better than mammography for distinguishing between DCIS and benign, atypical proliferative breast lesions or micro-invasion. At present, MRI is not the imaging procedure of choice to evaluate a new case of DCIS.

However, what is important in new cases of DCIS is the grade, or degree of differentiation, of the cells. The classification of DCIS or the different descriptive types of DCIS may just be a reflection of the grade of the component epithelial cells and how rapidly they divide.

T.M.I.! Too much information, I’m getting tired already.

Have a nice cup of coffee, that will perk you up.

It’s true, caffeine is proof that god loves us and wants us to pay attention.

i. Classification of DCIS

The classification of Ductal carcinoma in-situ (DCIS) lesions is dependent upon the growth pattern and cytological appearances of the atypical cells within the ducts. Breast cancer specialists recognise five main types of DCIS:-

The cribriform type of DCIS: has back-to-back glands without intervening breast stroma. The epithelial cells in this subtype are typically small- to medium-sized, with uniform, dark cell nuclei. There are few mitoses and necrosis is only present in single cells or small cell clusters.
The micro-papillary type of DCIS: small tufts of cells, oriented perpendicular to the basement membrane and projecting into the duct lumena. The apex of these projections can be broader than the base, giving a ‘club-shaped’ appearance. These intraluminal ‘micro-papillae’ do not have fibrovascular cores. The cells are usually small to medium in size, with dark cell nuclei and few mitoses.

There are a lot of different types of breast cancer dcis, aren’t there?

You don’t have to get too bogged down with it. They’re just classifications based on the type, structure and growth patterns of the abnormal cells in the breast ducts.

More Classifications of DCIS

The papillary type of DCIS: intraluminal projections of tumor cells that do have fibrovascular cores. A variant of papillary DCIS is ‘intracystic papillary carcinoma’ which has tumor cells present in a single dilated space.
The solid type of DCIS: tumor cells completely fill and distend the involved duct spaces, without necrosis, fenestrations or papillary projections. The tumor cells may be large, medium, or small.
The ‘comedo’ type of DCIS: has necrosis in the center of the involved duct spaces. This material is often calcified. These micro-calcifications may show up mammographically as linear or branching calcifications. Tumor cells are large with nuclear pleomorphism and mitotic activity. The degree of ‘comedo necrosis’ in DCIS is a strong predictor for the risk of recurrence after treatment (Fisher et al., 1999).

What is the difference between Atypical Ductal Hyperplasia (ADH) and DCIS?

Both conditions are very closely related. In ADH there is an increase in cell growth and abnormality whereas in DCIS there are malignant cells present but these are enclosed within the breast duct.

ii. Grading of DCIS

The grading of DCIS is based upon the nuclear features of the cells. These features include the size or extent of the DCIS, cell polarization, the presence and location of micro-calcifications (with DCIS with normal tissues) and the presence and type of necrosis.

College of American Pathologists (CAP) Guidelines for grading DCIS:

Grade 1: Monotonous cell nuclei, 1.5 to 2.0 red blood cells in diameter; finely dispersed chromatin & only occasional nucleoli.
Grade 2: Neither nuclear grade 1 nor nuclear grade 3.
Grade 3: Markedly pleomorphic nuclei, usually greater than 2.5 red blood cells in diameter; coarse chromatin & prominent or multiple nucleoli.

Figure 4.4. Grades of DCIS.

1. DCIS Grade Low power photomicrograph.
2. Grade 2 DCIS. Low power photomicrograph.
3. Grade 3 DCIS. Low power photomicrograph.

Fig-4-4 Grades of DCIS

Some specific diagnostic features of the different grades of DCIS:

Comedo-type necrosis is present with high-grade (poorly differentiated) DCIS.
Low-grade DCIS is typically diploid, estrogen and progesterone receptor-positive, with a low cell proliferative rate, and rarely shows abnormalities of the HER2/neu or p53 oncogenes.
High-grade DCIS lacks estrogen recept and progesterone receptors, has a high proliferative rate, over-expresses the HER2 oncogene, has mutations of the p53 oncogene and is associated with angiogenesis in the surrounding breast stroma.

Figure 4.5. High Grade ‘Comedo’ DCIS

Photomicrograph of the breast duct filled with atypical,
crowded cells with a high mitotic rate and areas of
cell death (apoptosis). The lumen of the duct is full of
dead cells, inflammatory cells and fine calcium granules.
There is no invasion of cells beyond the duct. (H&E x 40)

Fig 4-5 High Grade DCIS

iii. Cancer Risk for DCIS

Women with DCIS have a good clinical prognosis. With a diagnosis of DCIS, your breast cancer doctor will advise you to maintain a screening schedule to monitor for any local recurrence in the original breast and also to monitor the healthy breast.

When a diagnosis of ductal carcinoma in-situ (DCIS) has been made, without invasion, there is no risk of metastatic spread to other sites in the body (infiltrating ductal carcinoma). For women having local excision of the DCIS lesion with radiation therapy, the risk of local recurrence ranges from 5% to 15%.

For women having mastectomy as a treatment option, the risk of local recurrence of DCIS is less than 2 %.

Women who are treated with hormonal therapy, such as tamoxifen, after surgery, have a further reduction in risk of recurrence by 50%.

However, breast cancer specialists know that a history of DCIS in one breast slightly increases the risk for breast cancer in the other breast (as a new primary cancer). So, your consultant may advise careful follow-up monitoring of both breasts.

In 2011, clinical trials from the Surveillance, Epidemiology, and End Results (SEER) study of 8,466 cases of DCIS reported an equivalent long-term survival regardless of local treatment (Schonberg et al. 2011). Thus, a summary of the study results are:-

These are only general statistics and each case is individual and each year brings new potential.

Remember, You are the most important person in your recovery.

Survival and Mortality risk of DCIS

Overall survival for women aged 67 years or older was similar to women not diagnosed with breast cancer.
The SEER data estimate the mortality risk from DCIS at around 1.9 % within ten years. (Schonberg et al. 2011).
Women aged 67 years or older were more likely to die of unrelated causes, such as cardiovascular disease.

For a full updated discussion on DCIS risk, survival and mortality rates please click here for our brand new post.

Here’s something inspirational, if your future depends on your dreams….. go to sleep!

iv.Treatment for DCIS

DCIS treatment is done to prevent invasive cancer (see Section 8). Treatment may involve excision alone or excision with radiotherapy. Your multidisciplinary care team will guide and advise you on the decision-making process for treatment options.

‘Extensive DCIS’ occupies several ducts and quadrants of the breast. Multi-centric DCIS is when the abnormal cells occupy when found at several areas throughout the breast.

For women with multi-centric DCIS, their physician may recommend a mastectomy.

The Van Nuys Prognostic Index (VNPI) is a scoring system used to predict the likelihood of local recurrence following wide excision alone in patients with DCIS. The scoring system (out of 12) analyzes four prognostic factors: patient age, lesion size, excision margin and histologic classification/grade of DCIS.

The 2010 American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control (UICC) gives carcinoma in-situ the designation of Tis and Stage O (TisNoMo). For ductal carcinoma of the breast, the AJCC staging classification is Tis (DCIS) (see Section 7).

4.2.2 Paget’s Disease of the Breast

Although ductal carcinoma cells may not have become invasive, they do migrate along ducts and lobules. So, ‘cancerization’ is the term for this migration of the cancer cells.

Neoplastic ductal epithelial cells involving breast lobules is termed ‘cancerization of lobules.’

These malignant, but non-invasive ductal cells may travel along the lactiferous ducts to involve the nipple and the skin of the nipple. This is Paget’s disease of the breast.

Paget’s disease of the breast can be associated with ulceration and thickening of the nipple. When there is a diagnosis of Paget’s disease, there is usually an underlying ductal catrcinoma in-situ (DCIS). An invasive underlying breast cancer should be excluded.

Figure 4.6 Paget’s Disease of the Nipple

Photomicrograph of the nipple biopsy. The histology show skin with surface
strands of keratin. Within the epidermis of the skin there are atypical ductal
epithelial cells, similar in appearance to the cells seen in Figure 4.5.
(H&E x 40)

Fig 4-6 Pagets disease of the breast

4.2.3 Lobular Carcinoma In-Situ (LCIS)

‘Lobular neoplasia’ refers to a spectrum of proliferative changes within the breast lobule that includes atypical lobular hyperplasia (ALH) and lobular carcinoma in-situ (LCIS). Although both are associated with an increased risk of invasive breast cancer, the magnitude of risk with LCIS is much greater than with ALH. Because of this difference and the because of the implications for patient treatment, most experts continue to separate the two entities rather than using the all-encompassing term ‘lobular neoplasia.’

Lobular carcinoma in-situ (LCIS) is associated with a 7- to 11-fold increased risk of subsequent development of breast cancer in either breast.

All this information must be so hard to digest if you’ve just found out you have breast cancer.

It’s pretty hard to digest if you haven’t, but pancakes and waffles now, they’re easier to digest.

LCIS has a higher risk of subsequent invasive breast cancer than ALH.

Lobular carcinoma in-situ (LCIS) is distinguished from atypical lobular hyperplasia (ALH) histologically. The distension of more than half of the acini of the lobular unit by uniform, but non-cohesive, small, atypical epithelial cells is diagnostic for LCIS.

There is little evidence that high-grade features of LCIS (cellular pleomorphism, necrosis and solid involvement of ducts) is predictive of a higher subsequent risk of invasive breast cancer.

There are no clinical recommendations for the complete excision of either ALH or LCIS or the pleomorphic variant of LCIS (PLCIS). Treatment of lobular carcinoma in-situ (LCIS) should be based upon the individual patient and their clinical situation.

Figure 4.7 Lobular Carcinoma In-Situ (LCIS)

Photomicrograph of the breast lobule, filled with bland,
‘pink’ cells. There is an intact basement membrane around
the lobular acini. (H&E x10)

Fig 4-7 LCIS

i. Cancer Risk for LCIS

LCIS is an indolent lesion with very low malignant potential, but it does convey a risk for ipsilateral as well as contralateral invasive breast cancer (lobular carcinoma).

I love that word ‘ipsilateral’ it means…. oh well, still a great sounding word.

It means on the same side of the body as the original tumour.

I knew that, I knew that. Bring on the test!

The relative risk of developing invasive cancer in women with LCIS is approximately twice that of women without LCIS. The absolute risk is approximately 1 % per year and appears to be life-long.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of 180 women with LCIS, 5 % of women studied developed an invasive lobular carcinoma (ILC) in the same breast after 12 years of follow-up; a similar fraction (5.6 %) developed a contralateral invasive lobular carcinoma (Fisher et al., 2004).

In a series of 4,853 cases of lobular neoplasia reported to the NCI SEER (Surveillance, Epidemiology and End Results) registry between 1973 and 1998, 7.1 % of women developed invasive carcinoma by 10 years (Chuba et al., 2005).

LCIS is often present in association with invasive carcinoma in approximately 5 % of breast cancer specimens. Women with invasive cancer and LCIS in the specimen may be at greater risk of disease recurrence than those without LCIS.

The presence of LCIS in association with an invasive cancer is not a contraindication to breast-conserving therapy. The only exception is with a diagnosis of pleomorphic LCIS (PLCIS).

The percentages of recurrence rates are actually quite low.

Yes and breast conserving surgery is still an option in most cases.

So it’s not all bad news.

ii. Treatment of LCIS

When lobular carcinoma in-situ (LCIS) is identified in the histology from a core needle biopsy (CNB), an excision biopsy will then be performed to exclude an associated invasive malignancy (see Section 8) and possibly a lymph node biopsy.

Studies have identified either DCIS or invasive cancer in between 15 % to 38 % of patients with LCIS.

Guidelines from the National Comprehensive Cancer Network (NCCN) suggest re-excision for all cases of LCIS diagnosed by core needle biopsy, under the following circumstances:-

If the histology tests diagnose LCIS an excision breast biopsy may be necessary, however, no further surgery is necessary. Wide surgical excision is not required.
If an invasive carcinoma is detected on histology, appropriate management should be initiated. But there are no randomized trials addressing the comparative efficacy of surveillance versus prophylactic mastectomy in a population of high-risk women.

In 1990, Bradley and colleagues published a meta-analysis of published data, including 389 women diagnosed with LCIS, followed for a mean of 10.9 years. In this analysis, breast cancer-specific mortality was 2.8 % among women who had initial excision followed by surveillance and mastectomy for recurrence. The results were not significantly different from the 0.9 % disease-specific mortality rate in women whose first line of treatment was a mastectomy.

Many women decide to have a preventative mastectomy – it’s a very difficult and serious choice.

Cancer is serious, so you have to be seriously determined to get well!

Too right, so much depends on attitude.

Mastectomy and Lobular Carcinoma In-Situ

Most clinical experts consider prophylactic bilateral mastectomy to be a very drastic approach for the moderate level of risk associated with LCIS in the absence of other contributory risk factors.

While women with LCIS have a significantly higher risk of developing invasive breast cancer compared with the general population, most will not develop invasive cancer.

The presence of LCIS in association with an invasive cancer is not a contraindication to breast-conserving therapy (BCT). The only exception to this is pleomorphic LCIS (PLCIS).

Did you hear that? Most women with Lobular Carcinoma In-Situ will NOT develop invasive cancer. Always hold on to the good bits.

4.2.4 Pleomorphic Lobular Carcinoma In Situ (PLCIS)

Variants of classic LCIS exist and include forms with marked distension and comedo-type necrosis, as well as pleomorphic and apocrine pleomorphic LCIS. The clinical significance of these variants and the appropriate management is uncertain at the present time.

Your breast consultant will manage classic LCIS as a marker of an increase in the risk for breast cancer, rather than as a precursor lesion for invasive cancer. But the exception is pleomorphic LCIS (PLCIS).

PLCIS consists of larger cells that demonstrate marked nuclear pleomorphism, cytologic dyscohesion and intracytoplasmic inclusions. PLCIS demonstrates central necrosis and micro-calcifications.

Recognition of the pleomorphic subtype is important because the nuclear features, necrosis, and calcifications can make the differentiation from DCIS challenging. PLCIS can be associated with an infiltrating pleomorphic lobular carcinoma.

Surgeons usually advise patients, who have a core biopsy for a diagnosis of PLCIS, to undergo a surgical excision of the lesion.

Remember, laughter is the best medicine, but if you’re laughing without any reason you need medicine!

Figure 4.8 Pleomorphic Lobular
Carcinoma In-Situ (PLCIS)

Photomicrograph of the histology from a core needle biopsy (CNB) shows
a focus of PLCIS. There is no evidence of invasion below the basement membrane (*) but very abnormal cells are present with different sizes and shapes, cell mitoses and cell necrosis. There are necrotic tumor
cells within the lumen. (H&E x 60)

Fig 4-8 PLCIS

References

Bijker, N., Meijnen, P., Peterse, J.L., et al. (2006). Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: Ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III Trial 10853—A study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 24:3381-3387. (Retrieved November 6^th 2014): https://www.ncbi.nlm.nih.gov/pubmed/16801628

Fisher, E.R., Land, S.R., Fisher, B., Mamounas, E., Gilarski, L., Wolmark, N. (2004). Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer. 2004;100(2):238. (Retrieved November 6^th 2014): https://www.ncbi.nlm.nih.gov/pubmed/14716756

More references for this section are on this page

Patient Information:

Breast Cancer Org.. Diagnosis of DCIS. (Retrieved January 13^th2015):
http://www.breastcancer.org/symptoms/types/dcis/diagnosis

WebMD Breast Cancer Health Care: Lobular Carcinoma (Invasive and In Situ). (Retrieved February 26^th 2015): https://www.webmd.com/breast-cancer/lobular-carcinoma-invasive-and-in-situ#1

More patient information for this section is on this page

Forward to 4C on papillomas Back to 4A on atypical hyperplasia