So peripheral T cell lymphomas are a very challenging group of diseases to see and treat and diagnose, and there are many challenges into um treating these patients. I think the first initial challenge that clinicians face is the challenge of diagnosis. So many of these um. Diseases are quite rare. There's only about 2000 cases of peripheral T cell lymphoma annually per year in the United States, which means, uh, pathologists who work in the community usually only see this this group of diseases once a year or once every other year, and, um, and that makes that diagnosis itself quite challenging to make while they're more com more comfortable with making diagnosis of more common forms of B cell lymphoma. These lymphomas require a different diagnostic workup. Furthermore, there's multiple types of peripheral T cell lymphoma, which then makes the classification more confusing. Um, so patients who have anaplastic large cell lymphoma, which presents with large anaplastic cells that universally express CD30 look very different from the diagnosis of T follicular helper phenotype lymphoma, uh PTCL, um, which can look like. Uh, the more traditional form of angioimmunoblastic T-cell lymphoma, where you see these atypical lymphocytes around venules and, and blood vessels, um, and who are um encompassed by this inflammatory milieu, um, where the, the abnormal T cell is only a part of the whole biopsy, not replacing the lymph node in sheets like we would see in diffuse large B cell lymphoma. And then um there are other um follicular help or phenotype lymphomas that don't necessarily have that same immuno phenotypic appearance histologically, but have the same cell of origin. Um, and so all of these lymphomas are connected by the presence of a by. Having the origin of the lymphoma from a T follicular helper cell, those cells are usually CD4 positive, and they tend to have two of the following 5 markers be positive. That's CD 10, BCL-6, PD1, ICAS, and CXCL 13. And having positivity in two of the 5 markers in the atypical cells represents a TFH phenotype lymphoma, and then of which there are multiple types. There's follicular T-cell lymphoma, peripheral T cell lymphoma, not otherwise specified of angioimmunoblastic type, peripheral T cell lymphoma, not otherwise specified of T follicular help or phenotype, but in general we think about all those entities of the T-ollicular helper phenotype lymphomas as one big chunk. And then there's peripheral T cell lymphoma, not otherwise specified, which used to be the most common form of peripheral T cell lymphoma. Now maybe um the second most common behind the TFH phenotype lymphomas, and that's really all the rest of them, um, that are not um either anaplastic large cell lymphoma, TFH phenotype lymphomas, and there are um there are some more even more rare forms of peripheral T cell lymphoma that we won't get into um right now, but that also makes the diagnosis confusing. So in a world where most of the times we start with a um a corneal biopsy for lymphoma diagnostics, sometimes the architecture of the um atypical cells relative to the other cells ends up becoming quite critical in the diagnosis of these diseases, kind of like we think about in Hodgkin lymphoma, and sometimes it takes an excisional biopsy to make the diagnosis. Then beyond that, even when you have an excisional biopsy or you have a very good, very good core needle biopsies, the atypical cells can be um underwhelming compared to the rest of the cells that are present, um, like histiocytes and eastinophils and other and other groups of cells, and even groups of B cells that sometimes are clonally associated with these T cell lymphomas. So that leads to another era of complexity in terms of the diagnosis. And therefore, it's not uncommon that the um diagnosis then hinges on doing um these stains that we talked about um and then also doing um molecular analysis for the um T cell receptor or doing T cell receptor gene rearrangement studies to assess if there's a clonal T cell population in this in the population of the lymph node. Um, and that test can take a couple weeks to come back, depending on which institution you're working at. It is therefore very common for a community pathology center to then send um these cases for a second opinion, and so it takes time to make the diagnosis, and these patients are often very sick at present. Some of them present um in the hospital um with acute renal failure, or malignant hypercalcemia, or a terrible rash, um, and, um, they often can't always wait to start treatment of some sort because they feel systemically quite ill with fevers and night sweats and, and weight loss and fatigue. So I think that clinically poses a big challenge because here you are with a disease that needs more urgent treatment, but it takes time to make the diagnosis and the diagnosis that impacts your therapeutic decisions. Um, and, um, you know, there, there, um, we know that the average time to make a diagnosis for these diseases is many weeks, not many days, um, and, and that's part of this whole process, um. So it's not, and on top of that, you know, studies that were published by Alex Herrera now almost a decade ago suggested that when biopsies were reviewed at community centers, there was, there was an adjustment of the diagnosis and up to 25% of the cases of T cell lymphoma than one reviewed in an academic center. And so again, articulating the difficulty in making these diagnoses and the difficulty in arriving at the most at the most appropriate um diagnosis.
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