I've written about 17p deletion in CLL previously. You may recall that this is the chromosomal home of TP53 - the gene which encodes the p53 protein- one of the most important determinants of chemotherapy success. P53 is mutated with lower frequency in many of the lymphoid cancers than it is in solid tumors (such as pancreatic, esophageal, etc) which may partially explain the success we enjoy in treating diseases like DLBCL.
A recent paper has evaluated the impact of p53 mutations on survival of patients with DLBCL treated with R-CHOP chemotherapy. They found a mutation in about 1/5 patients. It was important! Those without a mutation survived about twice as long as those in whom it was not mutated.
I've attached a link to an editorial / summary I wrote on behalf of Clinical Oncology News for the interested reader: p53 Is a biomarker in patients with DLBCL on R-CHOP. Below is a copy of the text. It is written for an audience of oncologists so the writing might be a little more technical than what I usually put here in the blog. Hopefully it is still worth the read.
Personalized medicine is the goal of detecting unique characteristics of an individual’s cancer and appropriately modifying therapeutic interventions to maximize efficacy and minimize side effects. A growing number of molecular diagnostics offer multiplex analysis of many oncologic targets bundled within one commercial assay. With the explosive progress in genome sequencing technology, a thorough understanding of molecular biomarkers is imperative if the goal of personalized medicine is to be reached.
p53 is one of the most important molecular markers in cancer. Known as the “guardian of the genome,” p53 determines cell fate in response to a variety of cellular stresses by regulating transcription of important proteins resulting in cell cycle arrest or activation of pro-apoptotic machinery. Loss of p53 activity is therefore a common mechanism by which cancer cells avoid cell death in response to chemotherapy.
The article by Xu-Monette et al highlights the importance and complexity of p53 analysis in patients with DLBCL. Despite histopathologic similarities, patients with DLBCL can be clustered into distinct subgroups based on gene expression profiling. Beyond RNA expression differences, DNA mutational analysis adds further insight into the prognosis of these patients.
This study evaluates a large multi-institutional cohort of patients with de novo DLBCL (excluding patients with transformed disease), treated in uniform manner according to p53 status, using a variety of molecular techniques including sequencing, expression profiling, fluorescence in situ hybridization and immunohistochemistry.
p53 mutation is shown to be an adverse molecular finding in the 21.9% of patients with abnormalities. Overall survival in patients with wild-type p53 was nearly twice as great as it was for those patients with mutated p53, with similar effect on PFS. This effect was independent of germinal center (GC) or activated B-cell subtype, which differs from the prior analysis of DLBCL patients treated with CHOP alone (pre-rituximab) where the effect was limited to patients with GC subtype DLBCL. This highlights the importance of re-evaluation of prognostic markers as standards of care change.
One concern is the incredible complexity of p53 alterations. This study highlights the multitude of ways p53 can be altered in gene sequencing. Although there are hotspots for recurring abnormalities, not all mutations are created equally. Some mutations may not affect amino acid sequence, whereas others cause an amino acid substitution or premature termination of the coding sequence.
It is tempting to consider p53 changes in a binary “yes/no” manner but that probably oversimplifies the biology. As personalized diagnostics emerge, the interpretation of such abnormalities may be as important as the detection of the change in the first place.
Identification of a high-risk cohort may enable therapeutic intensification, but such trials are difficult to design and execute. As the molecular taxonomy of cancer advances more quickly than our ability to know what to do with the data, clinical research remains a vital link in advancing the care of these patients.
Sunday, January 6, 2013
Friday, January 4, 2013
Richter's Syndrome / Histologic Transformation
Patients with CLL or indolent NHL occasionally experience a significant clinical change in their disease where it becomes a lot more aggressive. When this happens, the formerly "slow growing" cancer becomes a lot more nasty and in many cases the prognosis gets a lot worse. In a number of publications, NHL, CLL) the average survival when this happens is about a year. A number of those are older articles (retrospective / in pre-rituximab era) which may have been confounded by patient selection bias. My own impression is that many patients do quite a bit better but that is at least what the literature reports.
In CLL/SLL this is called "Richter's Transformation (RT)" while in the indolent NHL's this is called, "Histologic Transformation (HT)." Sometimes docs jumble these terms and call it "Richter's Syndrome" or "transformation" regardless of which disease it started out as. There is a different discussion about what we call Grade 3 follicular lymphoma. Sometimes these can be confused by the patient. I will save the discussion of Grade 3 until an upcoming post. In follicular lymphoma HT occurs at a rate of about 3%/year. While that is a pretty small number, it is cumulative so by 10 years it may be as high as 30%. In CLL the rate appears to be a fair bit lower so that the cumulative risk is only about 10-15%.
The best clue that a patient has undergone RT/HT is when the disease acquires a bad attitude. Instead of just involving blood and lymph nodes, you see it in new places like liver, lung, intestine, bone nodules, sometimes even brain. Patients might experience increasing fevers, night sweats, weight loss. Laboratory changes are notable for a significant rise in a blood marker known as LDH (we are not talking about subtle changes, but 2-4x higher). If you get a PET scan (which measures metabolic activity of tissues), you might get one spot which is disproportionately "hot."
Traditional risk factors for developing this in CLL include an increasing number of prior therapies, CLL diagnosis at a younger age (longer exposure to risk), and more advanced disease. A number of newer studies show that pre-existing NOTCH mutations, "stereotyped B-cell receptors (a topic for a future post)," 17p deletions etc. also increase the risk. In indolent NHL, risk factors include the diagnosis of grade III follicular NHL, advanced disease, high flipi scores, and several lab variables (LDH, B2 microglobulin).
Under the microscope, the new disease most commonly resembles the "intermediate grade" Diffuse Large B Cell Lymphoma. Less commonly it can look like Hodgkin's Disease, and extremely rarely it may look like Burkitt's or Lymphoblastic Lymphoma. In any case, it goes from "indolent" to aggressive, or even the highly aggressive.
Because it is so easy to get samples of cancer cells from patients with CLL (blood draw), we know a lot more about transformation in CLL than we do in low grade lymphoma. It is probably worth while therefore writing about what occurs in CLL and then highlighting the differences that we know about in NHL.
In CLL there are two main and one uncommon way of experiencing RT. The most common way (80%) is for the dominant CLL clone to acquire more and more genomic mutations over time. Typically these involve several important genes including p53, Myc, and NOTCH. The second most common way (20%) is for a patient with CLL to "spontaneously" develop an entirely new diffuse large B cell lymphoma that is clonally unrelated to the original CLL. You might think no patient should ever have such bad luck, but in a prior post about 13q, I detailed how some genomic deletions can predisopose to lymphoid malignancies. Some patients who develop CLL may in fact be predisoposed to the spontaneous development of DLBCL.
The difference is significant. In the first case, you have a highly resistant clone - often with a p53 mutation - giving rise to an aggressive lymphoid malignancy. When p53 mutations are present, chemotherapy often does not work well. Just like every other cancer we have ever studied, p53 is a BAD THING to have mutated in DLBCL. Conversely, when DLBCL develops spontaneously, it is often a curable cancer. This plays out with regard to prognosis of the transformation. In the former, survival averages about a year, whereas in the latter a good number of patients are cured. Once again, I would point out that it is frustrating that we have no way to tell which one a patient has with testing that we would consider readily available. In indolent lymphoma, it seems far more likely that the new DLBCL is clonally related and p53 mutations are as high as 80%!
Treatment often consists of R-CHOP chemotherapy regardless of which sort of RT you have. While this is typically a well tolerated treatment, it is harder on the patient if they have already been exposed to a bunch of chemotherapy previously. You only get to beat up the bone marrow so many times (chemo) before it starts telling you it can't accept more flogging. It is not uncommon to run into dose delays, or reduced dosing, etc. Add this to more resistant disease and you can probably figure why it is less effective. Furthermore, a lot of patients with follicular lymphoma have been previously treated with the "H" in R-CHOP and you can only give so many doses of that drug before the heart starts to complain. Since treatment is less effective, some patients will be treated with an "auto" stem cell transplant but a lot depends on how robust the patient is at that point and how well they responded to therapy.
In the future, I think this may be one situation where the "engineered T cells" could become an important therapy. NOTCH antibodies have recently entered clinical trials and might be appealing. We have used brentuximab vedotin in one clinical trial and been pleased with the results for some of our patients. Hopefully these newer approaches will give a more favorable outlook to patients with RS/HT sometime soon.
Here is a video I did with Brian Koffman describing it all: Richters Transformation
In CLL/SLL this is called "Richter's Transformation (RT)" while in the indolent NHL's this is called, "Histologic Transformation (HT)." Sometimes docs jumble these terms and call it "Richter's Syndrome" or "transformation" regardless of which disease it started out as. There is a different discussion about what we call Grade 3 follicular lymphoma. Sometimes these can be confused by the patient. I will save the discussion of Grade 3 until an upcoming post. In follicular lymphoma HT occurs at a rate of about 3%/year. While that is a pretty small number, it is cumulative so by 10 years it may be as high as 30%. In CLL the rate appears to be a fair bit lower so that the cumulative risk is only about 10-15%.
The best clue that a patient has undergone RT/HT is when the disease acquires a bad attitude. Instead of just involving blood and lymph nodes, you see it in new places like liver, lung, intestine, bone nodules, sometimes even brain. Patients might experience increasing fevers, night sweats, weight loss. Laboratory changes are notable for a significant rise in a blood marker known as LDH (we are not talking about subtle changes, but 2-4x higher). If you get a PET scan (which measures metabolic activity of tissues), you might get one spot which is disproportionately "hot."
Traditional risk factors for developing this in CLL include an increasing number of prior therapies, CLL diagnosis at a younger age (longer exposure to risk), and more advanced disease. A number of newer studies show that pre-existing NOTCH mutations, "stereotyped B-cell receptors (a topic for a future post)," 17p deletions etc. also increase the risk. In indolent NHL, risk factors include the diagnosis of grade III follicular NHL, advanced disease, high flipi scores, and several lab variables (LDH, B2 microglobulin).
Under the microscope, the new disease most commonly resembles the "intermediate grade" Diffuse Large B Cell Lymphoma. Less commonly it can look like Hodgkin's Disease, and extremely rarely it may look like Burkitt's or Lymphoblastic Lymphoma. In any case, it goes from "indolent" to aggressive, or even the highly aggressive.
Because it is so easy to get samples of cancer cells from patients with CLL (blood draw), we know a lot more about transformation in CLL than we do in low grade lymphoma. It is probably worth while therefore writing about what occurs in CLL and then highlighting the differences that we know about in NHL.
In CLL there are two main and one uncommon way of experiencing RT. The most common way (80%) is for the dominant CLL clone to acquire more and more genomic mutations over time. Typically these involve several important genes including p53, Myc, and NOTCH. The second most common way (20%) is for a patient with CLL to "spontaneously" develop an entirely new diffuse large B cell lymphoma that is clonally unrelated to the original CLL. You might think no patient should ever have such bad luck, but in a prior post about 13q, I detailed how some genomic deletions can predisopose to lymphoid malignancies. Some patients who develop CLL may in fact be predisoposed to the spontaneous development of DLBCL.
The difference is significant. In the first case, you have a highly resistant clone - often with a p53 mutation - giving rise to an aggressive lymphoid malignancy. When p53 mutations are present, chemotherapy often does not work well. Just like every other cancer we have ever studied, p53 is a BAD THING to have mutated in DLBCL. Conversely, when DLBCL develops spontaneously, it is often a curable cancer. This plays out with regard to prognosis of the transformation. In the former, survival averages about a year, whereas in the latter a good number of patients are cured. Once again, I would point out that it is frustrating that we have no way to tell which one a patient has with testing that we would consider readily available. In indolent lymphoma, it seems far more likely that the new DLBCL is clonally related and p53 mutations are as high as 80%!
Treatment often consists of R-CHOP chemotherapy regardless of which sort of RT you have. While this is typically a well tolerated treatment, it is harder on the patient if they have already been exposed to a bunch of chemotherapy previously. You only get to beat up the bone marrow so many times (chemo) before it starts telling you it can't accept more flogging. It is not uncommon to run into dose delays, or reduced dosing, etc. Add this to more resistant disease and you can probably figure why it is less effective. Furthermore, a lot of patients with follicular lymphoma have been previously treated with the "H" in R-CHOP and you can only give so many doses of that drug before the heart starts to complain. Since treatment is less effective, some patients will be treated with an "auto" stem cell transplant but a lot depends on how robust the patient is at that point and how well they responded to therapy.
In the future, I think this may be one situation where the "engineered T cells" could become an important therapy. NOTCH antibodies have recently entered clinical trials and might be appealing. We have used brentuximab vedotin in one clinical trial and been pleased with the results for some of our patients. Hopefully these newer approaches will give a more favorable outlook to patients with RS/HT sometime soon.
Here is a video I did with Brian Koffman describing it all: Richters Transformation
Monday, December 31, 2012
The Slow (Indolent) Lymphomas
In my prior post "Understanding The Different Types of Lymphoma" I spent a bit of time explaining how there were three main categories of B cell NHL; slow, medium, fast. I encourage readers of this post to review the prior post if coming to this for the first time.
The slow lymphomas probably have the greatest number patients falling into different disease categories. I've had a lot of traffic on my website for the intro post so I thought it was time to go deeper into detail for some of the "indolent - aka: slow" lymphomas.
For now, I am going to restrict the discussion to the B cell cancers. Many of the T cell disorders that affect the skin are also considered "indolent" but they are really an entirely different discussion probably best saved for later.
Follicular lymphoma
(read this even if it isn't the type you have)
The most common indolent lymphoma is follicular lymphoma. In fact, this is the second most common type of NHL. In a number of important ways, you can generalize from follicular lymphoma to many of the other indolent subtypes of lymphoma. I've got a few blog posts that outline what I think is the current approach I use to treat the disease (low risk & high risk).
Follicular lymphoma comes in many shapes and sizes - there is considerable diversity in terms of patient presentation. It can range from an asymptomatic enlarged lymph node that does not require any treatment - all the way to life threatening cause of marrow or organ dysfunction. I have a number of patients in my clinic who have carried the diagnosis for many years never requiring any therapy. In fact, I have one patient originally diagnosed in the 1950's still chugging away - pretty remarkable.
Pathologists determine the diagnosis of follicular lymphoma in several ways. In fact, if you simply hold a microscope slide of a lymph node up to the light, you can often have a pretty good idea that you are dealing with follicular lymphoma. They look for a particular growth pattern (nodular), cell size (mostly small), and can use a handful of special stains (CD10, 19, 20 positive, CD5, 23 negative) or DNA probes (translocation of chromosomes 14:18) to verify the diagnosis.
The name "follicular" comes from the "cell of origin." When a b cell runs into the bacteria or virus it was born to fight it goes into the "follicle" of the lymph node. There it undergoes a number of changes to make it a better infection fighter and spits out a bunch of copies of itself. It is a genomically unstable time in the life of a b cell (see my post: why did I get lymphoma) and can give rise to a lymphoma. When lymphoma starts here it is typically either a follicular lymphoma or a diffuse large b cell lymphoma.
When I consider a new patient with follicular lymphoma, there are several key features I want to know about before making my management decisions: 1) What stage is the patient? 2) How much disease do they have? 3) How aggressive does it look? Though you might think these three characteristics are all the same, I actually think they are quite different.
Stage is fairly straight forward in NHL terms but often misunderstood by a patient who is already shellshocked by the diagnosis. It is quite common for follicular lymphoma to be stage 4 at diagnosis but that is very different than a lung cancer that is stage 4. Since lymphoma is a cancer of the immune system, it is pretty much everywhere to begin with. In contrast, a lung cancer that has spread beyond the confines of the lung and lymph nodes has "metastasized." We don't think of lymphoma as undergoing "metastasis." While stage 4 follicular lymphoma is typically worse than stage 2 follicular lymphoma, I would still take it over stage 4 lung cancer any day. Stage 1 is a single lymph node, stage 2 is lymph nodes confined to one side of the diaphragm, stage 3 is lymph nodes on both sides of the diaphragm and stage 4 involves the marrow.
Embedded within "stage" though is a consideration of how much disease a patient has. If a patient has an 18cm lymph node in their abdomen and nothing in their marrow - I still worry more about that patient than the one with a handful of 2-3 cm nodes in the chest and abdomen and a little bit in the marrow. We refer to this as tumor "bulk." It is often a subjective evaluation but one that is important. If there is a single disproportionately large node we begin to worry about transformation. Sometimes a PET scan or additional biopsy is necessary.
Aggressiveness is another qualitative / semi-quantitative evaluation. Pathologists will assign a "grade" to the lymphoma that is either 1, 2, 3a, or 3b. This is a measure of how many "large cells" are visible. Large cells are bad as they tend to be more proliferative. The lower the grade the better. Unfortunately there is a lot of variability between pathologists when they try to sort out the 3a/3b's. We are taught to think of the 3b's as the same thing as diffuse large B cell lymphoma. Pathologists can also use a marker known as Ki-67 that indicates how many cells are in the cell division process. Once again, the lower the better.
There is a score that does a pretty good job integrating a lot of this known as the FLIPI score. It looks at patient age, stage, number of nodal sites, marrow function (hemoglobin), and a blood test known as LDH. The higher the worse. FLIPI is helpful for allowing us to evaluate results across trials and getting a sense of an individual patient but I still take the other measures as important as well.
Anyhow, that is the basics of follicular lymphoma. See my other posts for treatment etc.
Marginal Zone Lymphoma
Marginal zone lymphoma is a lot like follicular lymphoma in terms of how it shows up, behaves clinically, gets treated, etc. There are a few key differences though that are worth pointing out.
The first difference is seen by the pathologist. It arises from a different part of the lymph node architecture (any guesses - yes - the marginal zone - which surrounds the normal follicle areas). They often do the same panel of stains on the sample but in contrast to follicular lymphoma, it is negative for CD5, 10, 23, and positive for CD19, 20. They don't necessarily look for the translocations common to other lymphomas like 14;18 in follicular or 11;14 in mantle cell - largely because they are not there.
Marginal zone lymphoma comes in three main varieties, nodal, primary splenic, and extranodal mucosal associated lymphoid tissue (Aka MALT). The nodal variety may as well be follicular lymphoma in terms of treatment, prognosis, etc. Some of these can make really highlight how slow these lymphomas can be.
Primary splenic marginal zone lymphoma is a little interesting. It can be closely related to hepatitis C. In fact, treating hepatitis C in these patients can even lead to remissions of the lymphoma. Hep C probably gives some growth signals to B cells - so if you get rid of the hep C the lymphoma can go away. It is certainly worth an attempt at Hep C treatment and it should be noted that Hep C treatment is getting a lot more effective. This disease is often also often confused with CLL to a doc unfamiliar with lymphoid cancers. Sometimes you see an elevated lymphocyte count in the peripheral blood, the flow cytometry shows a b-cell cancer, and the doc misunderstands this to be CLL. In the past this might not have been too big of a deal but now that there are some extremely effective CLL drugs, getting the diagnosis right might be more important.
Finally the extra-nodal varieties that are associated with mucosal tissues (the lining of the stomach, tear glands, etc) can be interesting because of their associations with paticular infections. The stomach version can be associated with the same H. Pylori bacteria that causes ulcers. Treating the bacteria is often effective at getting rid of the lymphoma. The eye version can be associated with a chlamydia infection (no not the sexual transmitted disease). Here too, treating the infection can cause remission of the lymphoma.
Small Lymphocytic Lymphoma
Small lymphocytic lymphoma (SLL) is essentially chronic lymphocytic leukemia (CLL) except it affects the nodes more than the blood and marrow. The two disases are so similar we often refer to them together as CLL/SLL. We arbitrarily define CLL as cases with lymphocyte count greater than 5000. In virtually all other ways the two disease are the same.
The pathologist will often look at a node and call it SLL/CLL when it stains positive for CD5, CD23, and CD19. The B cell receptor is characteristicly "dim" so any BCR markers such as kappa, or lambda or CD20 are present at lower levels than other B cell cancers. Translocations are not common. Unfortunately the same FISH tests that are so vital in CLL are often not obtained in SLL.
Staging can sometimes seem "unfair" to the patient because of how arbitrarily the distinction between the two diseases (CLL vs SLL) are defined. In SLL, staging is done in the same way as follicular lymphoma above. In CLL staging is different though. Stage 0 is elevated WBC, Stage 1 has WBC and enlarged nodes, Stage 2 has the above and an enlarged spleen, Stage 3 has low red blood cells and stage 4 has low platelets. Therefore a SLL patient who has a few nodes and some marrow involvement but a lymphocyte count of 4900 is stage 4 SLL, but if they had a count of 5100, their CLL would be stage 1. It is arbitrary and unfair because they are really the same biologically and calling it stage 1 or 4 sounds a lot worse than it really is.
The other thing about SLL that is important and sometimes overlooked is that it should be approached in the way one things about CLL instead of follicular lymphoma. A lot of docs will give lymphoma regimens for SLL when it probably makes more sense to use CLL regimens. I would tend to favor fludarabine based treatment instead of things like R-CVP. It is also important because the new drugs like CAL-101 and ibrutinib are quite active in SLL and should be considered.
Mantle Cell lymphoma
It isn't totally clear if mantle cell lymphoma belongs in a discussion of the "slow lymphomas." Mantle cell can take on the "incurable" clinical features of follicular lymphoma while sometimes having the growth rates of the more aggressive diffuse large B cell lymphoma. It gets the worst of both.
Our knowledge of Mantle cell lymphoma is clouded by the fact that we didn't even recognize this as a discrete type of lymphoma until the mid to late 1990's. Some of the early reports may have been biased by more aggressive cases. More recently, we've come to identify that some mantle cell really can indeed behave slowly.
The lymphoma gets started from yet another part of the lymph node - the mantle zone. It stains positive for CD5 but negative for CD23 in distinction to CLL/SLL. Mantle cell does have a characteristic translocation between 11:14 resulting in too much "cyclin D-1" Sometimes this test helps a pathologist determine whether it is CLL or mantle cell. In B cell biology mantle cells arise from B-1 b cells which are similar to CLL. It is therefore interesting to me that the research drugs ibrutinib and ABT-199 look very exciting in this disease since they are also so impressive in CLL.
Mantle cell has another few curiosities. It loves the colon. In order to fully stage a patient, it is sometimes necessary to do a colonoscopy and get "blind biopsies." GI docs are often unaware of this so sometimes it requires some physician education. Not every patient needs a colonoscpy but it is common in clinical trials or chasing down symptoms.
Treatment of mantle cell lymphoma is all over the map. It can range from transplant to observation. I should probably just save that for another post. Instead of using the FLIPI from follicular lymphoma, we use the MIPI (mantle cell international prognostic index). It uses age, functional status, WBC count, and LDH. The original paper did not use the proliferation rate called the Ki-67 but this is very important (<10%, 10-30%, >30%) and separates prognosis quite well.
Waldenstrom's (lymphoplasmacytic lymphoma).
Waldenstrom's is named after the Sweedish hematologist who characterized the disorder. It is often a marrow only disease that arises from a b-cell en-route to becoming a plasma cell (the type of B cell that gives rise to multiple myeloma). It can involve lymph nodes however so that should not give rise to diagnostic confusion.
One unique feature to this disease is that it secretes an antibody into the circulation that can cause a variety of problems. The particular form of the antibody (IgM) is a big / bulky molecule. If the concentration gets too high it can make the blood become too viscous (think olive oil in the refrigerator). In fact "hyper-viscocity syndrome" can be a life threatening situation that requires emergent "plasmapheresis" which is a lot like dialysis.
One odd consequence of using rituxan in this disease is that it sometimes leads to a sudden rise in the antibody levels. To the unsuspecting doc, this can be confused for progression. If patients start with a high level of protein, this spike can be dangerous and should be monitored.
The protein can cause other problems as well. Neuropathy is not uncommon and sometimes pushes a patient toward therapy they might have otherwise been able to hold off on.
Steve Treon M.D. is the guru of this disease and practices in Boston. In addition to being extremely helpful to patients and other docs managing these patients, he has done a fantastic job organizing a number of academic centers into a combined research effort. Since the disease is uncommon, it would never get much research attention if it were not for the combined effort of some of the major centers.
The slow lymphomas probably have the greatest number patients falling into different disease categories. I've had a lot of traffic on my website for the intro post so I thought it was time to go deeper into detail for some of the "indolent - aka: slow" lymphomas.
For now, I am going to restrict the discussion to the B cell cancers. Many of the T cell disorders that affect the skin are also considered "indolent" but they are really an entirely different discussion probably best saved for later.
Follicular lymphoma
(read this even if it isn't the type you have)
The most common indolent lymphoma is follicular lymphoma. In fact, this is the second most common type of NHL. In a number of important ways, you can generalize from follicular lymphoma to many of the other indolent subtypes of lymphoma. I've got a few blog posts that outline what I think is the current approach I use to treat the disease (low risk & high risk).
Follicular lymphoma comes in many shapes and sizes - there is considerable diversity in terms of patient presentation. It can range from an asymptomatic enlarged lymph node that does not require any treatment - all the way to life threatening cause of marrow or organ dysfunction. I have a number of patients in my clinic who have carried the diagnosis for many years never requiring any therapy. In fact, I have one patient originally diagnosed in the 1950's still chugging away - pretty remarkable.
Pathologists determine the diagnosis of follicular lymphoma in several ways. In fact, if you simply hold a microscope slide of a lymph node up to the light, you can often have a pretty good idea that you are dealing with follicular lymphoma. They look for a particular growth pattern (nodular), cell size (mostly small), and can use a handful of special stains (CD10, 19, 20 positive, CD5, 23 negative) or DNA probes (translocation of chromosomes 14:18) to verify the diagnosis.
The name "follicular" comes from the "cell of origin." When a b cell runs into the bacteria or virus it was born to fight it goes into the "follicle" of the lymph node. There it undergoes a number of changes to make it a better infection fighter and spits out a bunch of copies of itself. It is a genomically unstable time in the life of a b cell (see my post: why did I get lymphoma) and can give rise to a lymphoma. When lymphoma starts here it is typically either a follicular lymphoma or a diffuse large b cell lymphoma.
When I consider a new patient with follicular lymphoma, there are several key features I want to know about before making my management decisions: 1) What stage is the patient? 2) How much disease do they have? 3) How aggressive does it look? Though you might think these three characteristics are all the same, I actually think they are quite different.
Stage is fairly straight forward in NHL terms but often misunderstood by a patient who is already shellshocked by the diagnosis. It is quite common for follicular lymphoma to be stage 4 at diagnosis but that is very different than a lung cancer that is stage 4. Since lymphoma is a cancer of the immune system, it is pretty much everywhere to begin with. In contrast, a lung cancer that has spread beyond the confines of the lung and lymph nodes has "metastasized." We don't think of lymphoma as undergoing "metastasis." While stage 4 follicular lymphoma is typically worse than stage 2 follicular lymphoma, I would still take it over stage 4 lung cancer any day. Stage 1 is a single lymph node, stage 2 is lymph nodes confined to one side of the diaphragm, stage 3 is lymph nodes on both sides of the diaphragm and stage 4 involves the marrow.
Embedded within "stage" though is a consideration of how much disease a patient has. If a patient has an 18cm lymph node in their abdomen and nothing in their marrow - I still worry more about that patient than the one with a handful of 2-3 cm nodes in the chest and abdomen and a little bit in the marrow. We refer to this as tumor "bulk." It is often a subjective evaluation but one that is important. If there is a single disproportionately large node we begin to worry about transformation. Sometimes a PET scan or additional biopsy is necessary.
Aggressiveness is another qualitative / semi-quantitative evaluation. Pathologists will assign a "grade" to the lymphoma that is either 1, 2, 3a, or 3b. This is a measure of how many "large cells" are visible. Large cells are bad as they tend to be more proliferative. The lower the grade the better. Unfortunately there is a lot of variability between pathologists when they try to sort out the 3a/3b's. We are taught to think of the 3b's as the same thing as diffuse large B cell lymphoma. Pathologists can also use a marker known as Ki-67 that indicates how many cells are in the cell division process. Once again, the lower the better.
There is a score that does a pretty good job integrating a lot of this known as the FLIPI score. It looks at patient age, stage, number of nodal sites, marrow function (hemoglobin), and a blood test known as LDH. The higher the worse. FLIPI is helpful for allowing us to evaluate results across trials and getting a sense of an individual patient but I still take the other measures as important as well.
Anyhow, that is the basics of follicular lymphoma. See my other posts for treatment etc.
Marginal Zone Lymphoma
Marginal zone lymphoma is a lot like follicular lymphoma in terms of how it shows up, behaves clinically, gets treated, etc. There are a few key differences though that are worth pointing out.
The first difference is seen by the pathologist. It arises from a different part of the lymph node architecture (any guesses - yes - the marginal zone - which surrounds the normal follicle areas). They often do the same panel of stains on the sample but in contrast to follicular lymphoma, it is negative for CD5, 10, 23, and positive for CD19, 20. They don't necessarily look for the translocations common to other lymphomas like 14;18 in follicular or 11;14 in mantle cell - largely because they are not there.
Marginal zone lymphoma comes in three main varieties, nodal, primary splenic, and extranodal mucosal associated lymphoid tissue (Aka MALT). The nodal variety may as well be follicular lymphoma in terms of treatment, prognosis, etc. Some of these can make really highlight how slow these lymphomas can be.
Primary splenic marginal zone lymphoma is a little interesting. It can be closely related to hepatitis C. In fact, treating hepatitis C in these patients can even lead to remissions of the lymphoma. Hep C probably gives some growth signals to B cells - so if you get rid of the hep C the lymphoma can go away. It is certainly worth an attempt at Hep C treatment and it should be noted that Hep C treatment is getting a lot more effective. This disease is often also often confused with CLL to a doc unfamiliar with lymphoid cancers. Sometimes you see an elevated lymphocyte count in the peripheral blood, the flow cytometry shows a b-cell cancer, and the doc misunderstands this to be CLL. In the past this might not have been too big of a deal but now that there are some extremely effective CLL drugs, getting the diagnosis right might be more important.
Finally the extra-nodal varieties that are associated with mucosal tissues (the lining of the stomach, tear glands, etc) can be interesting because of their associations with paticular infections. The stomach version can be associated with the same H. Pylori bacteria that causes ulcers. Treating the bacteria is often effective at getting rid of the lymphoma. The eye version can be associated with a chlamydia infection (no not the sexual transmitted disease). Here too, treating the infection can cause remission of the lymphoma.
Small Lymphocytic Lymphoma
Small lymphocytic lymphoma (SLL) is essentially chronic lymphocytic leukemia (CLL) except it affects the nodes more than the blood and marrow. The two disases are so similar we often refer to them together as CLL/SLL. We arbitrarily define CLL as cases with lymphocyte count greater than 5000. In virtually all other ways the two disease are the same.
The pathologist will often look at a node and call it SLL/CLL when it stains positive for CD5, CD23, and CD19. The B cell receptor is characteristicly "dim" so any BCR markers such as kappa, or lambda or CD20 are present at lower levels than other B cell cancers. Translocations are not common. Unfortunately the same FISH tests that are so vital in CLL are often not obtained in SLL.
Staging can sometimes seem "unfair" to the patient because of how arbitrarily the distinction between the two diseases (CLL vs SLL) are defined. In SLL, staging is done in the same way as follicular lymphoma above. In CLL staging is different though. Stage 0 is elevated WBC, Stage 1 has WBC and enlarged nodes, Stage 2 has the above and an enlarged spleen, Stage 3 has low red blood cells and stage 4 has low platelets. Therefore a SLL patient who has a few nodes and some marrow involvement but a lymphocyte count of 4900 is stage 4 SLL, but if they had a count of 5100, their CLL would be stage 1. It is arbitrary and unfair because they are really the same biologically and calling it stage 1 or 4 sounds a lot worse than it really is.
The other thing about SLL that is important and sometimes overlooked is that it should be approached in the way one things about CLL instead of follicular lymphoma. A lot of docs will give lymphoma regimens for SLL when it probably makes more sense to use CLL regimens. I would tend to favor fludarabine based treatment instead of things like R-CVP. It is also important because the new drugs like CAL-101 and ibrutinib are quite active in SLL and should be considered.
Mantle Cell lymphoma
It isn't totally clear if mantle cell lymphoma belongs in a discussion of the "slow lymphomas." Mantle cell can take on the "incurable" clinical features of follicular lymphoma while sometimes having the growth rates of the more aggressive diffuse large B cell lymphoma. It gets the worst of both.
Our knowledge of Mantle cell lymphoma is clouded by the fact that we didn't even recognize this as a discrete type of lymphoma until the mid to late 1990's. Some of the early reports may have been biased by more aggressive cases. More recently, we've come to identify that some mantle cell really can indeed behave slowly.
The lymphoma gets started from yet another part of the lymph node - the mantle zone. It stains positive for CD5 but negative for CD23 in distinction to CLL/SLL. Mantle cell does have a characteristic translocation between 11:14 resulting in too much "cyclin D-1" Sometimes this test helps a pathologist determine whether it is CLL or mantle cell. In B cell biology mantle cells arise from B-1 b cells which are similar to CLL. It is therefore interesting to me that the research drugs ibrutinib and ABT-199 look very exciting in this disease since they are also so impressive in CLL.
Mantle cell has another few curiosities. It loves the colon. In order to fully stage a patient, it is sometimes necessary to do a colonoscopy and get "blind biopsies." GI docs are often unaware of this so sometimes it requires some physician education. Not every patient needs a colonoscpy but it is common in clinical trials or chasing down symptoms.
Treatment of mantle cell lymphoma is all over the map. It can range from transplant to observation. I should probably just save that for another post. Instead of using the FLIPI from follicular lymphoma, we use the MIPI (mantle cell international prognostic index). It uses age, functional status, WBC count, and LDH. The original paper did not use the proliferation rate called the Ki-67 but this is very important (<10%, 10-30%, >30%) and separates prognosis quite well.
Waldenstrom's (lymphoplasmacytic lymphoma).
Waldenstrom's is named after the Sweedish hematologist who characterized the disorder. It is often a marrow only disease that arises from a b-cell en-route to becoming a plasma cell (the type of B cell that gives rise to multiple myeloma). It can involve lymph nodes however so that should not give rise to diagnostic confusion.
One unique feature to this disease is that it secretes an antibody into the circulation that can cause a variety of problems. The particular form of the antibody (IgM) is a big / bulky molecule. If the concentration gets too high it can make the blood become too viscous (think olive oil in the refrigerator). In fact "hyper-viscocity syndrome" can be a life threatening situation that requires emergent "plasmapheresis" which is a lot like dialysis.
One odd consequence of using rituxan in this disease is that it sometimes leads to a sudden rise in the antibody levels. To the unsuspecting doc, this can be confused for progression. If patients start with a high level of protein, this spike can be dangerous and should be monitored.
The protein can cause other problems as well. Neuropathy is not uncommon and sometimes pushes a patient toward therapy they might have otherwise been able to hold off on.
Steve Treon M.D. is the guru of this disease and practices in Boston. In addition to being extremely helpful to patients and other docs managing these patients, he has done a fantastic job organizing a number of academic centers into a combined research effort. Since the disease is uncommon, it would never get much research attention if it were not for the combined effort of some of the major centers.
Subscribe to:
Posts (Atom)