Jorge Romaguera,
M.D.
Professor
Lymphoma/Myeloma
The
University of Texas MD Anderson Cancer Center
Hello. I am Dr. Jorge Romaguera. I am Professor of the Department of Lymphoma and Multiple Myeloma at the University of Texas MD Anderson Cancer Center. I will be speaking to you today about the diagnosis of staging of lymphomas and multiple myeloma.
Upon completion of this part of this talk, you will be able to define lymphoma, both Hodgkin's and non-Hodgkin's lymphoma as well as multiple myeloma. You will be able to discuss clinical presentation of the cases of these diseases --- [I apologize] --- as well as hematologic, radiographic, and pathologic findings for classification and staging of each.
We will start first with lymphoma. This is a group of malignancies that originates in the lymphatic system. It is broadly divided in two categories, the Hodgkin's lymphoma and the non-Hodgkin's lymphoma or malignant lymphoma. Here in North America, 85% of the malignant lymphomas are of the B-cell type and 15 are of a T-cell type. We will be discussing in this presentation mainly the B-cell type, which is the most common.
The cause of non-Hodgkin's lymphoma is not known. It is not accepted to be inherited as other cancers are, although there is a suspicion that there might be some familial inheritance risk. There are environmental factors that have been associated, mainly herbicides. Also the Agent Orange which was used in the Vietnam War, also the creosol that was applied to the telephone posts several --- a decade or two ago. There is a suspicion that high-dose radiation exposure might predispose to non-Hodgkin's lymphoma. It is known that immune deficiency states such as AIDS, acquired immunodeficiency disease --- syndrome, is a risk factor for developing lymphoma. It is also known that Helicobacter pylori predisposes in a very small population of patients to the development of indolent lymphoma in the stomach. There is also a suspicion of Epstein-Barr virus being behind the lymphomagenesis of several lymphomas. The one that is mostly discussed is the child --- childhood Burkitt's lymphoma, the African type.
You will know or suspect lymphoma if you have a --- an enlarged lymph node that does not disappear after two weeks and is not responding to antibiotics. Usually this lymph node will be non-tender. And it might or not be associated with unexplained weight loss or unexplained fever or drenching night sweats so that you have to change your clothes or your night spread --- sheets.
To diagnose lymphoma, you will need a biopsy. It could be incisional or excisional. And fine-needle aspiration is also recommended in order to do some of the additional markers and recent studies that have been added to the armamentarium. But you do have a --- you do need a biopsy. This will be able to make --- make you able to subclassify the lymphoma. You will need a bone marrow, both for staging purposes, to see how advanced the disease is. And, in some cases where you present with symptoms but no enlarged lymph nodes, this might be the only place where you have lymphoma. As part of the initial tests, once you have a diagnosis, you will have to evaluate for other prognostic factors, such as elevated levels of lactate dehydrogenase in the serum. You will also want to know how the blood count is to see if there has been an effect of the lymphoma in the platelet count as well as the hemoglobin. You will also want to do imaging studies as part of the workup to find the extent of disease. This will include a chest x-ray, computed tomographies of the neck, chest, abdomen, and pelvis, and more recently a positron emission tomography in the cases that have large cell non-Hodgkin's lymphoma or Hodgkin's lymphoma.
There have been many classifications of lymphoma. The most recent one, the World Health Organization Classification from a year or two ago, is mainly a pathologic classification. Although for the clinician it helps to separate them into the slower indolent growth lymphomas, the more aggressive lymphopro --- lymphoproliferative processes, and the very aggressively fast-growing lymphomas. The indolent lymphomas are those mentioned in the table: small lymphocytic lymphoma; Waldenström's, which is intermediate between lymphoma and a plasmacytic process; the marginal zone lymphomas; the follicle center cell lymphoma follicular grades I and II, which are by far the most common indolent lymphomas; and the follicle center primary cutaneous lymphomas. Other aggressive lymphoproliferative disorders, multiple myeloma is included, but I will discuss this separately. Mantle cell lymphoma is one of the aggressive lymphomas. The follicle center cell follicular grade III is considered aggressive and should be treated as such. The diffuse large B-cell lymphoma is one of the two most common lymphomas along with the follicle center follicular grade I and II, and other more unusual presentations such as primary mediastinal large-cell lymphoma, lymphomatoid granulomatosis, primary cutaneous large-cell lymphoma of the leg type. Under the very aggressive group, the fast growing lymphomas with also a predilection for extranodal presentation are the Burkitt's and the intervascular large B-cell lymphoma.
This pie chart gives you an idea of the frequency of distribution. Like I said before, the most common lymphoproliferative malignancies, non-Hodgkin's lymphomas are the large B-cell lymphomas and the follicular lymphomas.
This is an example of how a researcher would evaluate and what he would see under regular electron --- [I'm sorry] --- under regular microscopy on low-power field. This would be a follicular lymphoma, so-called follicular because it respects the follicular active texture of the lymph nodes. The areas that are less dense are the areas that are involved by the lymphoma: and that is the center of the follicle, so-called germinal center of the follicle. The areas in between the follicles are not involved by lymphoma.
This is how a diffuse large B-cell lymphoma would present. As the name states, it's a diffuse effacement of the architecture of the lymph node. And it is mostly composed of large cells whether they are centroblastic or whether they are the immunoblastic cytologic variants, which in some papers is reportedly more aggressive behaving.
You will also want to stage the disease. You will want to know if this is an early presentation or a more advanced presentation. We still use the Ann Arbor Classification devised for Hodgkin's lymphoma decades ago, but it is now not the only way to predict prognosis of the disease.
In this staging system, which I will show in a more illustrative fashion, we have four stages depending upon the areas involved. Stage I is a region of nodes involved either above or below the diaphragm. Stage II are two regional areas both either above or below. Stage III has regions involved below and above the diaphragm. And Stage IV is when there is an extranodal presentation along with a region of lymph nodes or two extranodal presentations. In this illustration, the extranodal sites are the bone marrow and the liver, but there could be other extranodal sites.
As I have mentioned before, we have included in the most recent models of prognosis, not only the stage, which you see in the lower part of the graph --- of the table but other factors such as age, performance status, the level of the lactate dehydrogenase in the serum, and the number of extranodal sites. You can see that, according to the number of factors that you have, you will decrease your chances of being alive at five years, going from 73% chance if you have none or one of these five variables in the adverse category, all the way to 26% only if you have four to five of these variables on the adverse area. There is an age-adjusted model that also helps in specific groups of patients by age --- less or equal to 60 versus more than 60.
This previous staging model was for the diffuse large-cell lymphomas. We have since modified it also to be applicable for the follicular lymphomas. This model has five variables also, although two variables have been removed and two new ones have been added, mainly the number of nodal sites and the level of hemoglobin. And, as you can see, this model predicts, for better or worse, 10 year overall survival.
Another example where a recently introduced model is being applied is the mantle cell lymphoma. There is a Mantle Cell International Prognostic Index. And these are four variables that have been included in the model. Two of them are familiar because they have been included in the previous models, the age and the serum level of LDH, and the other two are particular to this lymphoma.
And based on the number of variables, you will have low, intermediate, and high risk of death from disease.
There are other models for T-cell lymphomas, but the T-cell lymphomas are not being discussed in this talk. Going into the Hodgkin's lymphoma, the World Health Organization Classification divides them into two major types: nodular lymphocyte predominant with or without diffuse areas. This is the least common and the classical types, which are by far the most common: predominantly nodular sclerosing but also mixed cellularity as well, and the lesser common lymphocyte-depleted and lymphocyte-rich subcategories.
This is an example of the Reed-Sternberg cell, which is a pathognomonic cell or used to be called pathognomonic for Hodgkin's. It is still [a] very reliable parameter to diagnosis Hodgkin's. As you can see in the center of the slide, there is a cell that has two nuclei. And this is a very typical cell that is present in Hodgkin's lymphomas.
The classification, as I stated earlier, is the Ann Arbor Classification. And it is still in use. We broadly divide them into the early stages, stage 1 and II. But even among the stage ones and twos, we further divide them into favorable and unfavorable. And any of these factors that you see here will make that person unfavorable and will have implications in terms of treatment: either a large mediastinal mass, or extranodal disease, or three or more involved areas of disease, or an elevated sedimentation rate.
For the Hodgkin's lymphomas that are advanced stage at presentation, this model has been devised with seven variables. And, as you can see, as the variable number increases, your chance of being alive without recurrence or any events will decrease in this case from 84% to 42%. Again, this is for patients with advanced stage Hodgkin's lymphoma, stages III and IV.
The last topic that I want to discuss is multiple myeloma. This is a malignancy of plasma cells which are mature B-cells. It is a very common hematologic malignancy. The main findings are lytic bone lesions, which could cause pain in the patient; anemia, which would give symptoms of fatigue; kidney failure due to precipitation of a protein produced by the myeloma into the kidney; elevated calcium because of destruction of bone and re --- re --- demineralization of the bone; and hypercalcemia would give symptoms of increasing urination; as well as somnolence and could be fatal if not treated soon. You could also present with recurrent infections, mostly urinary.
This is a smear of a --- it could be a bone marrow or peripheral blood, where you see the plasma cells which are the cells that have a basophilic cytoplasm with an eccentric nucleus.
And, in addition, you would want to know what --- how much serum protein, which is abnormal protein produced by T-cells, is present. For that you would test in the serum for protein electrophoresis and do immunofixation in these proteins. You would also do the same in the 24-hour collection of the urine.
If you do an x-ray of your skull, you will see the areas that are lucent. It means that there is less mineralization and these areas are devoid of bone.
You will do a complete blood count to see if your hemoglobin and platelets are adequate. You will test for the calcium and the kidney function tests in the blood. You will do a skeletal survey to see if you find any other areas in the body that have lytic lesions in your skull --- in your skeleton. You will do the bone narrow biopsy to document involvement by the increased amount of plasma cells. More recently, cytogenetics are becoming important in being able to predict how the patient will respond to therapy as well as survival. And also a blood test for the serum beta-2- microglobulin is becoming important in predicting outcome.
The Durie-Salmon staging system is an old system that is still --- can be applicable to a patient in order to predict how he will do and it is basically a tumor load system. As you can see between cycles --- stages I and III, the difference is that the hemoglobin is lower, the calcium is higher, the bone lesions are more, the amount of protein deposition is more, and this is the high tumoral mass stage.
An international system has been devised, which is easy to do. It involves doing two blood tests. It includes a beta-2-microglobulin and a serum albumin. And, as you can see, the survival will range anywhere from 62 to 29% depending upon how many of these two variables are in the poor risk category.
Cytogenetics, as I mentioned before, is important. The lesion 13, the lesion 17 among these that you see are important prognostic features...
....such that they have been combined with the international staging system. And this is a recent presentation with a combination of these two models that is a better predictor of how the patients will do at four years in terms of survival.
So, in summary, I have described the principle hematologic malignancies. As you see, they are quite diverse in their presentation and diagnosis. We have available ever-increasing tools to assist in diagnosis and staging. And we have developed newer models to try to help determine prognosis and arrange --- and decide what therapy is best according to the different subgroups. I hope this will help you evaluate patients who present in any of these presentations. And this concludes my talk. I hope that you have enjoyed the lecture and we welcome your feedback. Thank you.
Hematologic Malignancies: Diagnosing and Staging Part II video
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