Grading and Staging of Carcinomas

the future of staging?

Patients with the same tumor, grade and stage can have variable outcomes There is a *need to better subclassify tumors* so as to personalize treatment *Biomarker expression will likely be used as a complement to tumor classification*, grade and stage in the future - Especially as more biologically targeted therapeutics become available Staging will undoubtedly be refined more going forward and we do need to improve how we subclassify tumors. After all not all Gleason score 7 prostate carcinomas behave in the same fashion and not all stage IIIA breast cancers behave exactly the same, so there is a need to understand this variability in more granular detail, although currently we don't know what accounts for this variability in tumor behavior and biology. I feel that *additional biomarkers will be revealed in the future as we learn more from molecular and gene testing*. The results of these ancillary studies will likely be taken into account in future grading and staging protocols. This is already happening in brain tumor grading to a degree. This additional subclassification will also be important in the future for *tailoring patient treatment* because it can identify potential therapeutic targets as these new therapies become available

how is grading and staging largely done?

by pathology! clinical and imaging features are used in some tumors too

what types of cancers is the grading system heavily used in?

*BAP BRO* - prostate carcinoma - breast carcinoma - ovarian carcinoma - renal carcinoma - astrocytomas and other types of brain tumors - B cell lymphomas That was a generic grading system in reality there really is no uniform grading system and different tumors are graded using different systems. Treatment decisions that incorporate tumor grading are heavily used in carcinomas of the prostate, breast, ovary, and kidney, as well as certain lymphomas and astrocytomas of the brain. The pathologist is the physician who actually grades the tumor by looking at slides of tumor tissue in the microscope Grading tumors is not easy and it requires specialized training and a lot of experience. This is because tumor grading is subjective and there can be sampling error. For instance what if the high grade part of a tumor was small and slides weren't made from it, then we would never see it in the microscope and it would be missed. Pathologist have to be sure to perform a detailed and careful examination of the tumor to ensure that this does not happen. I believe that these factors have driven, at least in part, the specializations in surgical pathology that we have today

system used to grade breast carcinoma?

*Bloom-Richardson Grading System* (USA)

Breast Cancer - N Status histology?

*Lymph nodes can be involved by tumor to varying degrees and the N status also reflects this*, although I won't get into those details, but I will show some histopathology to demonstrate this *Panel A shows a lymph node with no metastatic disease* and you can see the *prominent germinal centers as pale little islands*, an arrow indicates one of them (N0) *Panel B shows a lymph node that is essentially replaced by eosinophilic staining tumor cells*, with the *remaining normal lymphoid cells in the dashed circle*. When this happens tumor can invade outside of the lymph node into the adjacent fat so lymph nodes and fat can get matted together *Panel C shows a lymph node that is partially replaced by multiple deposits of eosinophilic staining tumor cells in the cortex (T)* *Panel D shows a microscopic focus of tumor cells* (dashed circle). These are referred to a *micrometastases* since you *need a microscope to detect them*. The pathologist needs to do a careful and detailed histological examination to detect these lesions What is the bottom line, just be aware that *the extent of lymph node involvement by breast cancer and other carcinomas can be highly variable* and this is also reflected in N status, even though we did not go into details about it here

Grade and Prognosis: Prostate Cancer

*Prostate and breast carcinomas are common tumor types* and grading these tumors imparts important prognostic information. Lets start with prostate cancer This is a *Kaplan Meier survival curve* that looks at cumulative survival over time. So the plot starts at 1.0 on the y-axis because everyone diagnosed with cancer is still alive at the time they are diagnosed, which is when x=0. The curves then trickle down overtime as patients die of cancer. I have a simple trick to reading these that doesn't use any of the fancy statistics you will be learning about. Here it is: I *draw a line across the plot at y=0.5, (red) which is the time on the X-axis when half the patients who were diagnosed remain alive.* This method is easy and it is a *good approximation of how aggressive the tumors are* in each group I'll explain the basics of Gleason grade soon, but for now look at the result. Approximately 50% of patients with high grade cancer are still alive about 7 years after diagnosis, while patients with low grade tumors haven't even crossed my red line at 50% when they are 18 years after diagnosis, which is the end of our x-axis here. As expected, the intermediate grade cancers are somewhere in between with 50% of patients remaining alive about 14 years after diagnosis

Lung Cancer Staging Systems are staging and grading criteria static?

*Staging and grading criteria are far from static*. These criteria undergo periodic review and careful revisions. Basically, committees are established that examine, review and discuss the data available and then they come to a consensus about grading and staging criteria. These *discussions can become heated* and, since the resulting guidelines come about by the process of consensus, no one neuropathologist leaves completely happy with the product. Still this *peer review is very important and it helps check biased data and ensure objectivity*. The revisions that are done have clinical implications and this slide shows an example. *These plots include the same data on lung carcinomas that were staged using old and revised staging criteria*. Notice that *the more recent criteria are better at stratifying patients in terms of survival* than the old criteria. How can you tell? Well in the plot that used the revised staging criteria the yellow, blue and purple lines are distinct and don't cross over each another at the end of the plot, as they did when plotted using the former staging criteria. This means that the revised staging criteria provide better information in terms of patient survival than the old staging criteria or, stated another way, the revised staging criteria are more predictive than the old criteria Notice that even the revised staging criteria have room for improvement. The purple and black lines meet at about 20 months, same for the green and yellow lines. It is really not until after 30 months that all of the lines are well separated. Perhaps future editions of the staging manual will help resolve this issue

grading and staging is used in...

*treatment decision making*: in fact, some types of therapy can only be used if a patient's tumor is not above or below a certain threshold stage. For example, a given therapy may be totally ineffective in high stage disease or a particular treatment method could be considered overtreatment in low stage disease *estimating prognosis*: the higher the tumor grade and stage, the more biologically aggressive the tumor, the less favorable the prognosis becomes *ensures variables in clinical trials are reproducible and standardized; allows comparisons to be made*: It provides reproducible, standardized means to compare variables in clinical trials, which allows comparisons to be made. This is important because it lets us make sure that we are comparing apples-to-apples. Without grading and staging one clinical trial cohort could have more patients with more extensive disease than another, which would confound your ability to translate the results of one clinical trial study to another

how does this translate into a predictor of tumor aggressiveness?

A well differentiated tumor proliferates/ grows more slowly than a poorly differentiated tumor and they are less likely to spread, so the prognosis is relatively favorable. Undifferentiated or poorly differentiated tumors tend to be aggressive and they tend to spread more frequently, so they have a worse prognosis. Moderately differentiated tumors fall somewhere in between

stage? what's the major staging system in use?

American Joint Committee on Cancer Staging is the major staging system in use, *employs the TNM system* Based on *size of primary lesion (T)* -- This refers to the size of the primary lesion, typically the maximum dimension measured in centimeters *Extent of spread to lymph nodes (N)* *Presence/ absence of blood borne metastases (M)*

examples of prostate cancer grading?

Appreciate that the low grade (1 and 2) cancers have fairly well formed glands, so they are considered to be well differentiated. Compare them to the grade 3, which are forming glands, but they are more complex and the nuclei in the glands are bigger making the glands appear more blue, these are moderately differentiated. Notice the grade 4 tumors form glands but they are becoming back-to-back with little intervening eosinophilic (pink) stoma

example of grade in the thyroid gland?

Each of these images are taken from neoplasms including carcinomas of the thyroid gland and this figure will allow you a chance to compare and contrast thyroid tumors of various grades The follicle is the basic unit of the thyroid gland; you will learn more about this in future blocks, but for now I indicated a follicle in panels A, B and C with an arrow. In panel A the normal thyroid resembles the follicular adenoma (a benign thyroid tumor) that pushes it off to the upper left and they are separated by the dashed yellow line. Notice the follicles (arrows) in the normal thyroid and adenoma. *The carcinoma in panel B is very similar in appearance to the normal thyroid (and even the follicular adenoma), based on the presence of follicles and this is what makes it well differentiated or low grade* Look at the *carcinoma in panel C. It is mostly a dense mass of cells, but the arrow shows one small runt of a follicle*. This shows that the tumor is *not recapitulating the normal morphology of the normal thyroid gland all that well, so it is not well differentiated*, but it has *at least one tiny follicle so it is not poorly differentiated or undifferentiated* either. Taken together this makes the tumor in panel C *moderately differentiated* Based on our discussion of the tumor in panel C you would think that poorly differentiated or undifferentiated tumors might be challenging to classify, because if they don't recapitulate the tissue they arise in then could be difficult to recognize their origin. This can certainly be the case at times. Notice that *there are no follicles in the tumor in panel D* and the tumor is just a *patternless mass* of cells. The *anaplastic thyroid carcinoma in panel E is even worse*, these *cells are very pleomorphic and dyshesive*. The poorly differentiated (D) and anaplastic (E) tumors are *high grade*

Grade 1 breast carcinoma?

Grade 1 tumors are well differentiated and consist of well formed tubules

Grade 2 breast carcinoma?

Grade 2 tumors are moderately differentiated and have intermediate features

as size of primary lesion increases, how does T change?

Increased size of primary lesion increases T1-T4 T0 = no evidence of primary tumor As size/local extent of primary lesion increases from T0 to T4 the stage increases and prognosis worsens.

what is a better predictor of tumor behavior and prognosis: stage or grade?

It turns out that *for solid tumors, staging is a far better predictor of tumor behavior and patient prognosis,* especially in terms of survival, than grade. Why should this be? Well, consider that *grading only really takes the microscopic appearance of the primary tumor into account*, which is *limited compared to all of the parameters assessed in staging according to the TNM system*. Yes, *staging also takes the primary tumor into account, but it does not focus on the microscopic appearance*, instead it *focuses more in terms of the primary tumor's size and, in some tumor types, like breast, the presence of adjacent tissue infiltration* (i.e. skin). In addition to the primary tumor, *staging also takes the presence of lymph node and distant organ involvement into account*, which are *very strong predictors of tumor behavior and clinical prognosis*. Why is stage a better predictor? Well, quite simply *staging takes more aspects of the tumor into account than grading, so it is a more accurate overall than grade*

Gleason numbers are used to grade prostate cancer. what about breast cancer grading?

Let move from prostate cancer grading to breast cancer grading. This is a *different kind of plot than the Kaplan Meijer curve* we looked at previously. Instead of survival, this *curve looks at tumor grade as a function of distant failure*, i.e. distant tumor metastasis over time (years). Notice that at *5 years after diagnosis there is a distinct separation between grade 1, 2 and 3 breast cancers and metastasis*, with the grade 3 tumors having the highest percentage (27%), grade 1 tumors (8%) the least and grade 2 tumors an intermediate percentage (22%). No surprise there, huh? However, at *10 years after diagnosis the story changes*, notice that the *grade 2 and grade 3 tumors at this time point have equal percentages of metastasis* and this remains the case pretty much from that point on. So the *meaning of grade for a patient can change over time and this guides clinical care*. At 10 years grade 2 and 3 breast cancer patients are monitored and followed in similar fashion for this reason, start to behave in similar fashion

M?

M0: no metastatic lesions in non-lymph node tissues M1 (occasionally M2): metastatic lesions are present in non-lymph node tissues

N?

N0: no nodes are involved N1-N3: denotes increasing numbers and ranges of nodes involved Generally speaking the more nodes involved and the more distant the involved lymph nodes are from the primary tumor, the higher the stage and the worse the prognosis

A 49 year old female complains of back pain and a sudden onset of right leg weakness. While taking her medical history she tells you that about 1 year ago she was diagnosed with breast cancer that went to her lymph nodes. What is your chief clinical concern now?

She has Stage IV disease This is alarming in breast cancer patient because her back pain and neurologic involvement could be due to a spinal metastasis. Alternately a brain metastasis could be the cause of the neurological issues, but it would be unlikely to cause back pain.

Stages of Breast Cancer how are T, N, and M brought together?

T, N and M status are brought together to determine various tumor stages Once T, N and M are determined the book or website of the American Joint Committee on Cancer Staging is consulted and a table like this will be used to stage the patient. For example, a tumor with a T score of 1 and N and M scores of 0 is stage IA, these patients have a highly favorable prognosis. In contrast, *note that stage IV patients have any T score and any N score with an M score of M1*. These are the *patients who have metastatic disease and this illustrates the incredible impact metastasis has on prognosis*, because these patients have the worst prognosis. Notice that *stage IV disease basically means that there are distant metastases*. Patients with stage II and stage III tumors have intermediate prognoses that are more variable and, as you may expect, most cancer patients will fall within this range. It is generally in this range where the most refinements are made with each new edition of the American Joint Committee on Cancer Staging manual

difference between Gleason system (prostate) and Bloom-Richardson system (breast)?

The *Gleason system looked at gland formation and architecture*, while the *Bloom-Richardson system takes nuclear grade, mitotic count and tubule (duct) formation* into account.

Breast Cancer - M Status

The *M status of breast cancer assesses distant metastases* and includes: *Mx*, designates that the *M status cannot be assessed*, typically because no distant tissue was biopsied or imaging scans could not be performed *M0*, designates a patient with *no evidence of metastasis* *M1*, denotes patients who have *distant metastasis* Panel A shows a longitudinal section of vertebral column with a metastatic carcinoma indicated. Observe that the lesion appears to be a cavity. *Metastatic cancer often destroys bone*, which can cause pain and in this case spinal instability is a possibility. Panel B shows *multiple metastatic deposits in the brain* as round, white lesions of various size. In *both of these images the patient's M status would be M1*, which would *correspond to stage IV because metastatic lesions like these are the hallmarks of stage IV disease*

Breast Cancer - N status

The *N score refers to the lymph node status for breast cancer* and it often *takes into consideration whether the lymph nodes involved are local or distant from the primary tumor*. This figure is simplified but it will do for our purposes. Lymph from the breast drains via lymph vessels to the lymph nodes so tumor cells can reach lymph nodes this way. Generally speaking *the farther the involved lymph nodes are from the primary tumor or the more lymph nodes involved the greater the N score*. N status for breast cancer is complicated so I am simplifying this for our purposes: *Nx*, indicates that *regional lymph node status cannot be assessed* (can occur when surgeons do not remove lymph nodes for pathologists) *N0*, indicates that there are *no regional lymph node metastases* *N1, 2 and 3, indicates that there are metastases to ipsilateral regional lymph nodes*. This is further subdivided based on *additional criteria such as which lymph node chain is involved and how far away the involved lymph nodes are from the primary tumor*. For example, low axillary (arm pit) or *level I lymph node involvement by tumor has a lower N status* than if the high axillary (arm pit) lymph nodes in level III are involved by tumor. *Level III involvement is a higher N status, because the tumor cells had to disseminate farther* in the lymphatics to reach axillary level III than they would need to in order to reach level I. Likewise, if tumor is present in supraclavicular (meaning "above the clavicle", clavicle is the collar bone) nodes then the N status goes up. To reach the supraclavicular nodes the tumor cells had to disseminate even farther in the lymphatics, beyond axillary level III, so the N status increases to reflect this

what is key in determining tumor grade?

The *degree of tumor cell differentiation* is key in tumor grade; however, *some additional features are also considered* in determining grade in some tumor types such as the *presence mitoses or certain architectural features* of the tumor cells

when breast cancer spreads, where does it usually spread to?

The *organs breast cancer spreads to are taken into account in the patient's clinical record* because it *does impact their clinical management*, but *the M status does not change depending on the organ involved by tumor*. For instance, *when breast cancer metastasizes it tends to reach the liver, lungs, bones and brain*, but these organs do not have different M status, so a *metastatic lesion or lesions to any one of them is M1* and if *more than one organ is involved, as is often the case, the M status remains M1*

You are a third year medical student and you're asked to talk to a pathologist who reviewed a biopsy from a tumor mass that was sampled from a patient you are following. The pathologist tells you that the tumor cells are growing in sheets with no pattern and they have little recognizable cytoplasm. She does not know what the origin of the tumor is and is awaiting the results of special studies for guidance. What does this tell you about the tumor?

This tumor is grade 3 (poorly differentiated grade 3 tumor that fails to recapitulate the morphologic features of the tissue it arose from)

Summary

Tumor Grading: - Well (1), Moderate (2), Poorly Differentiated (3, 4) - Uses guidelines, subjective - Scores in place for some tumor types - Based on guidelines, attempt to increase reproducibility and enhance objectivity TNM Stage: - Well established guidelines, periodically revised - Criteria vary with tumor type - Biomarkers, genetic, molecular information will likely be incorporated in the future

Gleason numbers?

USED FOR PROSTATE CANCER GRADING *Gleason 4-6 are low grade cancers, Gleason 7 cancers are intermediate grade tumors and Gleason 8-10 cancers are high grade tumors*.

Breast cancer T status?

We can *use breast cancer to illustrate the TNM* system *T refers to the primary tumor* so it is associated with *tumor size and, in the case of breast cancer, the presence of tumor extension* into adjacent tissues is also considered. The T status is broken down into Tx, T0, T1, T2, T3, and T4. There is also a *Tis designation that represents carcinoma in situ* *Tx* = primary tumor cannot be assessed *T0* = no evidence of a primary tumor Yes these scenarios do occur, although very rarely. Cancer and cancer care are complicated *T1* refers to a tumor that is *less than or equal to 2 cm in greatest dimension*. There are some additional size variables we will skip that further subdivide T1 (A) *T2* denotes primary tumors that are *over 2 cm to less than 5 cm* in greatest dimension (B) *T3* denotes tumors that *exceed 5 cm* in greatest dimension (C) *T4* refers to a *tumor of any size that extends to chest wall and/or skin* and there are some additional criteria that subdivide T4. In panel D and you see the red-orange discoloration of the skin on this mastectomy specimen, this due to the skin being infiltrated by tumor Many students have asked me in the past, why does size and local infiltration of the primary tumor matter, so much for T status? It turns out that *the bigger the tumor or the more extensive its local spread, i.e. the higher its T status, the more likely the patient will have lymph node involvement or metastatic disease*. Lets move onto those parameters now T1 <2cm. T2 2-5cm. T3 >5 cm. T4 extends to chest wall/skin

Which of the following tumors would you expect to most likely have the worst prognosis?

Well differentiated stage IV Stage IV have distant metastasis and the least favorable prognoses of all tumors. Metastasis trumps the well differentiated nature.

Tis?

carcinoma in situ (has not spread)

what is grade based on?

degree of tumor cell differentiation, number of mitoses (some cancer types) and architectural features (some cancer types) By tumor cell differentiation I am referring to how closely the cancer cells in the tumor mimic the morphologic appearance and function of normal cells. Basically, grade can be thought of as how abnormal the tumor cells look under the microscope, the more abnormal the tumor cells look, the higher the grade. I want to differentiate in my grades! With grade think differentiation.

grade?

describes potential aggressiveness

stage?

describes spread/extent

how are the 3 variables in the Bloom-Richardson grading system scored?

each variable scored on a 1-3 scale low grade 3-5 intermediate grade 6-7 high grade 8-9

Grade 3 breast carcinoma?

grade 3 tumors are poorly differentiated and consist of crowded cells with no tubules The cells in the grade 3 lesions have larger nuclei than those in grade 1 lesions

Grade 3/4 tumors?

high grade or poorly differentiated / undifferentiated - High growth rate and tend to spread Grade 3 and grade 4 tumors are poorly differentiated or undifferentiated. These tumors do not resemble normal cells and tissue and they tend to grow rapidly and spread (metastasize) more frequently than lower grade tumors. This means that these tumors are aggressive and these patients have a less favorable prognosis. These tumors are often referred to as high grade tumors, because they have a high score for grade

Grade 2 tumors?

intermediate grade or moderately differentiated Grade 2 tumors are moderately differentiated. The tumor cells somewhat recapitulate the organization and morphology of the tissue they arise in. These tumors tend to grow and spread at rates that are intermediate to grade 1 and 3 (or 4) tumors, so they clinically behave in an intermediate manner and have an intermediate prognosis. These tumors are sometimes referred to as intermediate grade tumors, because they have an intermediate score for grade

is TNM staging the same for each specific form of cancer?

no! it varies!

3 variables of Bloom-Richardson Grading System?

nuclear grade mitotic count tubule formation percentage

grade 5 prostate carcinoma?

poorly differentiated and high grade. Note that there are essentially no glands, instead the tumor cells grow in patternless solid sheets of cells and there are areas of necrosis (arrow)

TX, NX, MX?

primary tumor, regional lymph nodes, or distant metastasis cannot be evaluated

differentiation?

refers to how closely cancer cells look and function compared to normal cells - well-differentiated cancer cells look and behave like the normal cells in the tissue they started to grow in - undifferentiated or poorly differentiated cancer cells look immature or undeveloped; often do not resemble the tissue of origin at all - moderately differentiated cancer cells look/behave somewhere between - *most types of cancer!!* - a tumor may contain cells of different grades! For example, a *squamous cell carcinoma that makes keratin is a well differentiated tumor*, while *one that lacks keratin production is an undifferentiated or poorly differentiated squamous cell carcinoma*. So, *well differentiated cancer cells look and behave more like the normal cells* in the tissue they started to grow in. In contrast, *undifferentiated or poorly differentiated tumors tend to appear immature* or undeveloped and often do not resemble the tissue of origin much, if at all Moderately differentiated cancers are intermediate to well differentiated and poorly/undifferentiated cancers and as you might expect the tumor cells in moderately differentiated tumors look and behave somewhere in between poorly- and well-differentiated tumors. Most tumors actually fall into this moderately differentiated category. Grading a tumor can be challenging because a *tumor may contain cells of different grades. When this happens the tumor is often classified along the lines of the worse component*, since it is the *one that will likely dictate* the clinical course

what does grading and staging allow us to do?

semiquantify the potential aggressiveness (*grade*) of a tumor and its extent/spread (*stage*) in a patient it also allows us to use a uniform system to compare one group of patients to another

what are the numbers used in the tumor grade?

semiquantitative description uses a number (1-4) that refers to the degree of differentiation *the lower the number, the lower the grade* *the higher the number, the higher the grade* The descriptive designations of well, moderate, and poorly then get numbers applied to them (1-3 or 4), which yields the semiquantitative aspect to this process. The lower the number, the lower the grade and the higher the number, the higher the grade. You have probably surmised by now that grade must be a spectrum with poorly differentiated and well differentiated tumors representing the ends and moderately differentiated tumors falling in between. Yes, this is the case and if you think of it that way then it makes sense that most tumors that arise are moderately differentiated because they make up the big middle of what is a pretty wide spectrum

how does the Gleason scoring system work?

takes the *most common tumor grade and assigns it a grade of 1-5*. Pathologists do this by *comparing tumor cell morphology to the patterns which are shown in the shaded area on this slide*. Then the Gleason system *does the same for the second most common tumor grade*. The *two grades are added together to form a pattern*, so the *highest Gleason score is 10 and the lowest is 2*, although grade 2 tumors are really pretty rare That shaded area is what the pathologist sees in the microscope. If the *pathologist sees discrete glands it is scored a 1 or 2* or well differentiated. If the *glands start spreading out a bit then it is a 3* or more moderately differentiated because you still see glands. *Grade 4 and 5 tumors show tiny glands or glands growing in a back-to-back fashion* as represented by the black blobs) or the *tumor grows as single cells, represented as tiny dots* in the shaded area

Grade 1 tumors?

the tumor cells and the organization of the tumor tissue appear close to normal (aka - low grade, well differentiated) - Slow growth rate and slow to spread Grade 1 tumors are well differentiated. The tumor cells tend to recapitulate the organization and morphology of the tissue they arise in. These tumors tend to grow and spread slowly, so they tend to be relatively less aggressive, and therefore they have a relatively favorable prognosis. These are often referred to as low grade tumors, because they have a low score for grade

why is grading and staging important?

treating a *well differentiated (i.e. low grade)* breast cancer that is *localized to breast (i.e. low stage)* is considerably different that treating a *poorly differentiated (i.e. high grade)* breast cancer that has *metastasized to lymph nodes and bone (i.e. high stage)* The low grade, low stage breast cancer is likely curable by surgery, whereas the high grade, high stage breast cancer is not, since the tumor has spread beyond the breast to distant sites

most critically important aspect of clinical cancer care?

tumor grading and staging, it's performed more/less together! provide critically important information that guides patient treatment and can forecast a cancer patient's prognosis

high-grade cancer cells?

usually poorly differentiated or undifferentiated, and the tumors are faster growing and spread earlier

low-grade cancer cells?

usually well differentiated and the tumors are slower growing