Educational Programs: Current
Topics in Oncology
Dr. Nuhad K Ibrahim
Session 2: Staging & Diagnosis
Date: September 8, 2009
Time: 32:12
Nuhad K Ibrahim, M.D.
Professor, Breast Medical Oncology
The University of
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Dr. Nuhad Ibrahim: Hello I am Dr. Nuhad
Ibrahim. I am a Professor of Breast Medical Oncology
at
As you know, breast cancer continues to be the most frequent cancer among females. In 2008, 26% of female cancers were breast cancer, almost equal the sum of lung and rectum and colon together. However it claims 15% of death among females with cancer. Therefore this is a very risky disease for the patient and there usually follow some risk factors for those women who develop breast cancer including age, family history, personal history, benign breast diseases, radiation exposure, obesity, alcohol, smoking, estrogen exposure and exogenous estrogen as well.
The list continues to grow and all we can do for that patient with cancer prevention is many maneuvers which can be the focus of another lecture in this series. However, we're always encouraging the patient to do breast self examination, as early in life as in her 20's, and doing breast self examination every month and also to do a clinical breast examination, i.e. by a professional, every three years in her younger age and certainly annually after the age of 40.
Mammograms become an essential part of early detection, particularly at the age of 40 and thereafter. As we always do in medical school and with every medical course, we start with anatomy and here is a slide of anatomy of breast to make one major point, which is (about) Cooper's Ligaments. Anytime a tumor involves the Cooper's Ligaments it may track on the skin or may cause retraction of the nipple, which may give an impression of a locally advanced tumor. Therefore this issue has to be very carefully assessed by the examining physician to differentiate between involvement of the skin or the nipple complex with the tumor or just involvement of the Cooper Ligament that's causing retraction of the nipple and of the skin and therefore giving a false impression of more advanced stage.
However as medical professionals, we look at the breast as composed of several quadrants, although the distinction between these quadrants, which are used to describe the location of the tumor, have little significance in terms of management, since the quadrant now is more adequately described as the area where the tumor can be removed without causing any disruption in the dissection of the tumor.
Many of our surgeons would like to describe the tumors as multifocal or multicentric. Multifocal if the tumor can be removed in one segment, while multicentric may imply more radical surgery, i.e. mastectomy. Breast cancer usually presents as a painless lump in the breast and that's why we encourage breast self examination on a routine basis. Also it may give some signs and symptoms including nipple discharge, erosion or ulceration, erythema of the skin, axillary adenopathy or enlargement of the lymph nodes in the axilla, as well as symptoms that are associated with metastases, i.e. distant metastases.
Therefore the diagnosis follows breast self examination or clinical breast examination and an essential part of it is a mammogram and essentially a biopsy. It's of note here that we need to pay special attention that if we examine a breast mass and a mammogram was negative, it should not be passed on that there is no abnormality there since some histologies in particularly invasive lobular carcinoma, may not show on a mammogram and therefore a breast mass is a breast mass and should be dealt with, even if it does not show on a mammogram. And quite often confirmation with ultrasonography is essential.
As you see here on this mammogram, it shows a very dense area which may present a breast mass and also it's not showing on this mammogram, but a mammogram may also show calcifications. The calcifications can be graded or classified in several categories including benign calcifications, intermediate calcifications, or highly suspicious for malignancy calcifications. If you and your mammographer are not sure of the etiology of these calcifications then stereotactic biopsy or needle localized biopsy is essential to rule out a malignancy and therefore this issue has to be addressed seriously.
When a mass is felt and it is seen also on a mammogram, quite often it can not be determined whether it is cystic or solid and therefore ultrasonography of the breast mass should be done. Quite often the ultrasonographer is able to tell of a benign nature of the tumor, intermediate or almost diagnostic features of a malignancy. If the ultrasonographer is not able to determine, certainly a needle biopsy aspirate or core biopsy is a very well established step of diagnosis. At this point also it is legitimate and advisable that the ultrasonographer will look at the regional lymph nodes including the axilla, infraclavicular, supraclavicular and internal mammary lymph nodes, obviously indicating early phases of staging a workup.
Therefore when we deal with a lump, the first step would be to do a mammogram, most often followed by ultrasound and depending upon the level of the suspicion, we do a needle biopsy, FNA or core biopsy and action would be taken accordingly whether the pathology is benign or malignant. However if it is only a cyst, full aspiration of the cyst is recommended. Ultrasonography is also recommended after full aspiration of the cyst to make sure that there is no composite features there and that the fluid is not hiding a small nidus of malignancy and some also would take it further and repeat the ultrasonography in about 6 months to make sure the complete resolution of the problem.
At every time we look at an abnormality in the breast that isn't malignant the patient should be assured of that, that there is a lot of benign diseases in the breast that may not require any further action and therefore that patient should be reassured of that, however only after the physician is very certain of that benign nature of the tumor.
In addition there are two entities that need to be addressed as well, ductal carcinoma in situ and lobular carcinoma in situ. Ductal carcinoma in situ is usually considered as a pre-cancerous lesion in the breast and if left unattended it may evolve into invasive carcinoma. However, lobular carcinoma in situ is only considered as a marker of carcinoma and not a cancer by itself, and therefore its treatment may be either observation or for some patients it may be more convenient for them to resect it surgically or to treat it prophylactically with Tamoxifen, as indicated by the prevention trials.
Indeed LCIS or lobular carcinoma in situ may be seen to increase the risk of invasive carcinoma as is shown in the separate studies that are listed on this slide and the relative risk may range anywhere between 6 to 12 or 13%. Histologies of invasive carcinoma are wide, the most common of which is invasive ductal carcinoma that accounts for about 85%, about 10% also would be lobular carcinoma and the rest is a variety of histologies including mucinous carcinoma, medullary carcinoma, papillary carcinoma, tubular carcinoma, adenoid cystic carcinoma, secretory carcinoma, apocrine carcinoma, and carcinomas with metaplasia.
These different invasive carcinomas may behave differently, the most malignant of which will be ductal and lobular types, as indicated here by the 5, 10, and 15 year survival. The other carcinomas are considered what we call favorable histologies because they run a much (more) indolent natural history along the years, up to 15 years.
A special entity of breast cancer, along these lines, would be inflammatory breast cancer. Inflammatory breast cancer remains a clinical diagnosis. Usually the triad of symptoms are erythema, with or without ridging, peau d'orange skin edema, and rapid onset, usually within days to weeks. Tentatively we talk about 10 to 12 weeks as the range or the limit for this rapid onset.
A classical history: the patient tells you I woke up in the morning or suddenly I found out that my breast was swollen and red, sometimes painful or heavy and they usually ascribe it either to an infection or to an insect bite for instance. It's appropriate however, when a patient presents so acutely with a mastitis-like picture, to give her a trial of antibiotics. However, if the patient does not respond within a few days, things might be taken more seriously, and a workup to rule out breast cancer is very appropriate.
There are several features of breast cancer that help us give a prognosis for the patient: time tested features including tumor size as well as lymph node involvement (and this follow any number of lymph nodes as well), estrogen-progesterone receptors, histologic differentiation (and as you all know that grading is becoming very important in our assessment of the prognosis of the patient), lymphatic and blood vessel invasion, as well as specific factors-most prominent is HER2 gene over-expression or amplification.
Along these lines therefore, what we need to pay attention to is early start of the spread of the tumor and of course the main, early start of the spread of the tumor is in the lymph nodes. This diagram will show the various regional lymph nodes from which the tumor may drain and may present as metastatic lymph nodes, including the axillary, supraclavicular and mediastinal adenopathies as the mainstays, and that's why the routine use of ultrasonography to evaluate these regional lymph nodes early in the course of the disease is very important.
Also the tumor may present or may eventually spread to various organs of the body. Virtually any organ of the body or any location of the body can be involved with breast cancer. However the most frequent would be bone followed by lung and the pleura, then liver, adrenals, brain, and the skin in that order. Note that the patient may have visceral disease without having a lymph node involvement but this, however is a very rare occurrence.
This all is extremely important because the treatment of breast cancer will follow the extent of the disease and this is what we call staging. And as you will observe from the following three or four slides, that different treatment management may follow the stage of the disease. If it is a stage one or if it is a stage two then we may have a different approach. Including neoadjuvant chemotherapy might play an important role in that respect. With stage three, certainly preoperative chemotherapy is very important as well.
I know that one of the lecture series that you're going to see will deal with greater detail with management of the early breast cancer with chemotherapy, surgery, and radiation therapy as well as with metastatic breast cancer and therefore I will not elaborate further on this and I will limit my discussion to the staging process.
Certainly staging will help to assess location and the extent of the malignant disease and we need to know that to help give the patient a prognosis about the recurrence risk and mortality risk and this quite often may play a pivotal role when discussing with the patient the treatment options. Also treatment planning becomes very dependent on these staging procedures in terms of local therapy and systemic therapy, be it preoperative, postoperative and the role and need of radiation therapy.
Therefore staging will help correlate anatomy and pathology with outcomes of the disease and the treatment, and as well it will help us establish uniformity of clinical trial and reporting so that we will be able to compare studies that address patients of a certain category and not compare very early disease, for example, to very advanced disease and so forth, and this therefore would increase our knowledge of cancer biology.
The staging has historically followed the TNM staging and this has been always been developed based on evidence-based medicine and helps to classify the patient in terms of the size of the tumor and the extent of the involvement of the lymph nodes and whether there are distant metastases or not.
According to the older staging system, it has shown to be very useful and classified patients into stage zero, stage 1, 2A, stage 2B, stage 3A and 3B as well as stage 4. This older system helped to differentiate the patients into groups that separate very well on survival curves, as you see on this slide indicating that stage 1 does very much better than stage 2 or stage 3 and the poorest outcome follows stage 4 where you have metastatic disease.
Also lymph nodes separate the patients very clearly in terms of survival and all this depends upon the number of lymph nodes-whether there is no lymph node involvement at all versus 1, 2, 4, 6, 11 or more and therefore as you see then, the curves are very close together and further separation of these curves is needed for better evaluation of prognosis in the future clinical trials.
Because of this, a new TNM staging was put in place a few years ago and the major changes were in terms of evaluation of the lymph nodes as well as addition of a stage 3C that was not present before. To make things more illustratable for you here is an illustration of the staging diagrammatically: Stage 1 which did not differ from the classical staging in which the patient is called stage 1 (if the tumor is less than 2 centimeters and it is node negative). However stage 1 is divided into T1A if the tumor is less or equal to half a centimeter, T1B if the tumor measures half a centimeter to 1 centimeter and T1C if it is between 1 centimeter and 2 centimeters.
Stage 2A also looks at tumors that are between 2 and 5 centimeters, and the patient can be either node negative or N1, that is lymph node involvement on the ipsilateral axilla. Stage 2B, when we have T2 or T3 tumors with N- zero for T3 and N1 for T2, this makes stage 2B.
Stage 3 however is divided into three categories, A, B, and C as is illustrated here. Stage 3A is T3 with N1, or N2 with any T including T1, T2 and T3. Stage 3B is when the tumor is T4-that is involving of the skin or the chest wall and with any N, however no evidence of metastases. Stage 3C would include ipsilateral supraclavicular lymph node, infraclavicular lymph node and the combination of internal mammary or axillary adenopathy. Then obviously stage 4 which is considered as any evidence of metastases outside the local regional confinement of the tumor, index tumor.
As I noted earlier, the tumor size remains one of the major prognostic features and that's why the staging system stresses very much the size of the tumor and as you see as these studies projected on the slide that 5 and 10 year survival will differ significantly when you account for the size of the tumor, whether it is a T1, T2 or T3. Also the number of lymph node involvement will reflect significantly on the prognosis of the patient in terms of 5 and 10 years, especially when you divide the patients into node negativity, 1 to 3 positive lymph nodes, and 4 or more positive lymph nodes.
How does the new staging system differ from the old one that most of us were trained on? In the previous system, clinical N2 would represent ipsilateral axillary nodes fixed to one another or to other structures, and N3 however, on the previous system, will look at ipsilateral internal mammary lymph nodes. Now these entities have changed in the current system in use, and divide the N2 into N2a and N2b, whereN2a looks at the ipsilateral axillary nodes fixed to one another and to other structures and N2b when you have discovered in the patient ipsilateral internal mammary nodes in absence of other clinical evidence of axillary node metastasis. So N2a axillary lymph nodes to be internal mammary lymph nodes. However N3 is divided the new system to N3a, which is ipsilateral and infraclavicular nodes, and N3b ipsilateral internal mammary nodes and axillary nodes, and N3c would represent ipsilateral supraclavicular lymph nodes.
Pathological lymph node assessment also changes between the previous and the current system. With the previous system PN1 represents metastasis to ipsilateral axillary lymph nodes. PN1a would represent micro-metastasis, none larger than 0.2 centimeters. In the current system PN1 represents metastasis in 1 to 3 axillary lymph nodes and/or internal mammary lymph nodes detected by sentinel node biopsy but not clinically apparent.
PN1-mi for micro-metastasis represents involvement of the lymph node that measures more than 0.2 millimeters and less than 2 millimeters. The previous system calls for PN1bi and PN1bii which represents metastasis in 1 to 3 lymph nodes, any of which is greater than 0.2 and all are less than 2 centimeters, and the second entity would be metastasis in 4 or more axillary lymph nodes, any greater than 0.2 centimeters and all less than 2 centimeters respectively. The current system made significant differentiation between these entities by calling PN1a, which is metastasis in 1 to 3 axillary nodes, PN1b-metastasis in internal mammary nodes detected by sentinel node biopsy but not clinically apparent, and PN1c- metastasis to 1 to 3 axillary nodes and internal mammary nodes detected by sentinel node biopsy but not clinically apparent. PN2a and b represent metastasis in 4 to 9 axillary lymph nodes or in clinically apparent internal mammary nodes without axillary node metastasis.
As you notice, now we start seeing the break down of patients who have more than 4 lymph nodes into 4 to 9 lymph nodes and as we see later, to patients who may have more than 10 lymph nodes. PN2 metastasis to the ipsilateral axillary nodes fixed to one another or other structure did not change very much however PN3 in the previous system represented metastasis to ipsilateral internal mammary nodes and it changed to represent metastasis in 10 or more axillary nodes or infraclavicular nodes or clinically apparent ipsilateral internal mammary nodes with at least one positive axillary node or ipsilateral supraclavicular lymph node. So this is one of the main changes in the system.
Therefore the consequences of changes is looking at patients in separate categories, now we have a category 4 to 9 nodes and another category, patients who have more than 10 nodes. We have stage 3C in addition to stage 3A and 3B. Also stage changes may appear to alter prognostic categories and therefore we need reconciliation with prior staging editions. We should always be aware of these changes, particularly when we read numerous studies and compare it to literature.
How does this change? If you look at these two clinical categories and according to 1988 staging system then both would be called stage 2A, T1N1. One patient had 1.5 centimeter tumor and has one of ten positive lymph nodes. The second patient had 1.7 centimeter tumor. Both are a T1 but (the second) has 15 of 17 possible lymph nodes. It's no brainer that these patients are going to behave differently and are going to have different prognoses, however the staging system does not distinguish between the two. According to the older system the first patient is considered stage 2A and according the new system which was devised in 2003, it continues to be called stage 2A, so there's no change in the staging of the first patient. However, the second patient has changed significantly to stage 3C now because of the involvement of multiple lymph nodes in excess of 10.
Also in the 1988 system N1 is mobile but in the 2003 system N1 is only 1 to 3 lymph nodes, N2 is 4 to 9 lymph nodes and N3 is more than 10 lymph nodes and this is what we need to remember when we look at the patient's evaluation. So mobility of the lymph nodes may not necessarily be an important issue however the number of the lymph nodes is more important.
And if you look at 454 patients with stage 2A and devise their staging according to the new system, you'll see that there is a 31% change in this stage of that patient from 2A to 3A and 3C. And this different staging will have a different prognosis and different overall survival indicating that this is a very legitimate separation. Stage 2 patients also can be changed in over 50% of the time from 2B to 3A and to 3C and as you see now that you're going to see more 3A and 3C moved up from stage 2A and 2B, and the survival curves also reflect the adequacy of this separation according to the new system.
Overall survival therefore has changed significantly between the 1988 staging system and the 2003 staging system when we look at 10 year overall survival, particularly when you compare the stage 2 and stage 2B, and it's quite statistically significant because now we move more of the poorly prognostic features into the higher stages. And stage-specific survival now, according to the new staging system, appears to be looking better for the stage 2B compared to the older system.
Therefore evidence for staging categories are categorized as follows: first, high level evidence-number of lymph nodes. This is something that we cannot argue. It is very clearly demonstrable with the survival curves and therefore now patients should be looked at as 4 categories: node negative, 1 to 3 positive lymph nodes, 4 to 9 positive lymph nodes and 10 or more positive lymph nodes. Next, some evidence—we are looking at immunohistochemistry for cytokeratinpositive cells. Evidence is needed to look at the RT and PCR and its significance. IHC and/or RT-PCR positive but less than 0.2 millimeters of disease are considered node negative disease, however significant research is being done on this entity and we are not really sure at this present time whether these tumors should be considered negative or not, and if we are not going to consider them negative then where are we going to draw the line to distinguish between negative lymph nodes and positive lymph nodes? And micro metastasis, which is defined as any tumor that measures between 200 microns or 0.2 millimeters and 2 millimeters, should be treated as node positive.
Therefore the new staging system provides a basis for analyzing additional data, so to be meaningful it provides a framework for deriving information about the relevance of the nodal and micro metastasis, and may enhance the derivation of evidence of clinical oncology.
Where does the future lie? It lies in molecular diagnosis and cDNA staging, in tumor specific treatment and improved evidence. I believe the future will rely more on the molecular diagnosis and prognostication but still we are not yet ready to give up on any histological features of the tumors and I think the future will lie by integrating both systems. Molecular diagnosis and molecular profiling of the tumors will also help us targeting the tumor in a better way which we like to call personalized oncology or personalized medicine.
I would like to thank you. I know that there is a lot to be talked about this topic, which can be very complex and I know that many of you may have a lot of questions and I will look forward to look at your questions and address it in a follow up session so that all your personal issues or questions can be addressed in a customized way. Thank you very much again for your attention and wish you a good day or evening.
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