Pathology Student

Q. If the chronic leukemias have lots of mature cells, and the acute leukemias have immature cells, then how come chronic myeloid leukemia has lots of immature cells? Seems like it belongs in the acute leukemia category!

A. I think the best way to look at it is to oversimplify it a little, to get at the basics, and then put in a little detail.

The oversimplified version is this: Acute leukemias are composed of immature cells (usually blasts), whereas chronic leukemias are composed of mature cells (mostly the ones you normally see in peripheral blood).

The problem with that definition is that it doesn’t quite cover every chronic and acute leukemia. For example, AML-M2 is an acute leukemia that has at least 20% myeloblasts – but there are also a fair number of maturing neutrophils too (promyelocytes, myelocytes, metamyelocytes, and segmented neutrophils). So that doesn’t quite fit. The important thing in this AML, though, is that it does have at least 20% blasts. So you have to call it AML, even though it doesn’t quite “fit” our nice little definition.

Another example that doesn’t quite fit our neat little definition, as you noted, is CML. In CML, most of the cells are pretty mature (segmented neutrophils, metamyelocytes)…but there are some less mature ones too (myelocytes, promyelocytes). The important thing in CML is that there really aren’t very many blasts around at all; certainly not 20% or more like you’d see in AML. So even though it doesn’t quite fit, we put it into the chronic category (and it certainly acts a lot more like a chronic leukemia than an acute one!).

The underlying reason you see all these mature (and maturing) cells in CML (and in the other myeloproliferative disorders) – rather than a bunch of blasts – is that the problem has to do with a mutated, constitutively activated  growth receptor. In CML, the mutated growth receptor is produced when bcr and abl are joined together. In PV (and to some extent in ET and MF), the Jak part of the Jak-Stat pathway (a signal transduction system) is mutated. In either case, the tyrosine kinase is permanently in the “on” position, which means that growth and proliferation signals are constantly being sent to the nucleus. So the cells are dividing and proliferating even when they shouldn’t be.

These mutated tyrosine kinases don’t impair differentiation (or maturation), though, so you get uncontrolled growth of stem cells, and these bad stem cells are able to mature and progress through the normal stages of development! This is in contrast to many other leukemias, where there is increased growth but the cells are “stuck” at a certain stage of maturation (like the malignant cells in promyelocytic leukemia, which remain stuck at the promyelocyte stage).

Q. I was wondering what the difference was between labeling something as a “leukemia” vs labeling it as a “chronic myeloproliferative disorder.” I understand that leukemias are neoplastic proliferations of hematopoietic stem cells in the bone marrow, but aren’t myeloproliferative disorders the same thing? In particular, what category would chronic myelogenous leukemia be placed into? I have been grouping it with the MPDs, but then I get confused when I start to compare it to acute myelogenous leukemia, which is just labeled as a leukemia, and not a myeloproliferative disorder…?

A. You are right: leukemias are neoplastic proliferations of hematopoietic stem cells in the bone marrow. There are two big categories of leukemias: acute leukemias and chronic leukemias. The acute leukemias are divided into acute myeloid leukemia and acute lymphoblastic leukemia; the chronic leukemias are divided into chronic myeloproliferative disorders and chronic lymphoproliferative disorders.

Under these big acute and chronic categories, there are many different types of leukemia. Acute myeloid leukemia is divided into five main types: AML with genetic abnormalities (like t[8;21]), AML with FLT3 mutation, AML with multilineage dysplasia, therapy-related AML, and AML not otherwise categorized. ALL is divided into three main types: T-cell ALL, B-cell precursor ALL, and B-cell ALL (same as Burkitt lymphoma). The main chronic myeloproliferative disorders are: chronic myeloid (or myelogenous) leukemia (shown above), chronic (or idiopathic) myelofibrosis, polycythemia vera, and essential thrombocythemia. The main chronic lymphoproliferative disorders are: chronic lymphocytic leukemia, hairy cell leukemia, prolymphocytic leukemia, and large granulated lymphocyte leukemia.

I don’t know why they don’t just call the chronic myeloproliferative disorders and chronic lymphoproliferative disorders “chronic myeloid leukemias” and “chronic lymphoid leukemias,” but they don’t. Maybe it’s because one of the chronic myeloproliferative disorders is chronic myeloid leukemia, and to call the whole group of them “chronic myeloid leukemias” would be confusing. In fact, the term “chronic leukemia” isn’t really an official term either. But I like to use it because it shows that the chronic myeloproliferative and lymphoproliferative disorders really are leukemias, not some sort of benign proliferative disorders.

Here are some real student questions about myeloproliferative disorders. You should always ask questions when you don’t understand something – preferably in lecture. If you don’t understand something, at least 5 other people are having the same problem.

Q. Can chronic myelofibrosis lead to anemia?

A. Yes! It can lead to anemia because the marrow eventually get so full of fibrosis that there is no room for the red cells (and all the other cell types) to grow. The cells try their best to grow elsewhere, but it’s never as good – and patients eventually get anemic.

Q. With polycythemia vera, are both the bone marrow and blood full of red cells?

A. Yes! In polycythemia vera, there is a panmyelosis (like in all myeloproliferative disorders), but the line that’s dominant is the red cell line. The marrow is stuffed with them, and they spill out into the blood as mature red cells. The RBC goes way up, and the blood gets more viscous and sludgy. One way to treat these patients is to do periodic phlebotomy to get rid of the excess red cells.

Q. In essential thrombocythemia, are there an increased number of megakaryocytes seen in marrow and blood too? Do megakaryocytes escape the marrow since there is a malignant proliferation?

A. Yes, there is an increased number of megakaryocytes in the marrow! They end up making a TON of platelets, which spill into the blood. The megakaryocytes do not spill into the blood because they are HUGE – too big to get out.

Q. Would essential thrombocythemia be considered an underlaying cause of DIC? Is the high count of platelets consistent or does it fluctuate?

A. Essential thrombocythemia is not considered a cause of DIC. There are definitely a ton of platelets around – and sometimes they can sludge up into little vessels – but they don’t really initiate the coagulation cascade, like DIC does (in DIC, the problem is not only that you have platelet clots all over, but you’re sealing them up with fibrin. When the red cells try to go through, they get snagged on the fibrin strands). The high count remains pretty consistently high, unless you treat the patient. By the way, patients with essential thrombocythemia can either have abnormal clotting or abnormal bleeding (they can actually develop a secondary (or “acquired”) von Willebrand disease! Weird! So can some of the other myeloproliferative disorders.).

Q. Are chronic myeloproliferative disorders incurable?

A. All chronic leukemias – myeloproliferative disorders and lymphoproliferative disorders – tend to be slowly-progressing, incurable disorders. The exception is chronic myeloid leukemia, which is a relatively (compared to the other chronic leukemias) faster-progressing disorder. It also has a really, really good treatment now – a drug called imatinib (or Gleevec) that can essentially halt the progression of the disease. It doesn’t really ”cure” CML, but it does turn it into a chronic disease that people can live with for many many years.

Image credit: Stefan Baudy (http://www.flickr.com/photos/-bast-/349497988/)

The four main myeloproliferative disorders share several similarities such as a hypercellular marrow, a high white count with a left shift, and splenomegaly.  But there are distinct morphologic and clinical differences too; that’s why they have been separated into four distinct entities.  

Take chronic myelofibrosis for example. In this disorder, the myeloid cells proliferate like crazy early on. If you looked the blood and bone marrow at this early stage, you’d see a high white count with a left shift, and a hypercellular marrow, features common to all myeloproliferative disorders. But as the disease progresses, the marrow becomes replaced by fibrous tissue. The hematopoietic precursors have nowhere to grow, so they start setting up shop outside the marrow, in places like the liver and spleen. The spleen, in particular, becomes massive – even bigger than it does in the other chronic myeloproliferative disorders.

You can see evidence of the marrow fibrosis and splenomegaly in the blood if you look closely at the red cells. In squeezing through the tight fibrosis in the marrow, and in navigating through a markedly enlarged and cellular spleen, the red cells take on an unusual, “teardrop” shape. You can almost see how they dragged themselves through tight spaces, stretching their poor little bodies into elongated, pinched shapes. Another word for these teardrop cells is dacryocytes. While not specific for chronic myelofibrosis (they can occur in any case of marked splenomegaly or marrow replacement), if they are present in large numbers and the clinical setting is right, teardrop-shaped red cells are strongly suggestive of chronic myelofibrosis. You’d need to do a bone marrow biopsy to be sure, of course.

There are four major types of myeloproliferative disorders: chronic myeloid leukemia, chronic myelofibrosis, polycythemia vera, and essential thrombocythemia. Each has its own particular morphologic and clinical characteristics, and we’ll discuss them individually (we’ve already talked about chronic myeloid leukemia a little bit).  

However, there are some similarities between all of them that bear mentioning.

1. All of the myeloproliferative disorders are characterized by a malignant, clonal proliferation of myeloid cells (hence the name myeloproliferative). “Myeloid” in this context means all the cell lines of the bone marrow: the neutrophilic, erythroid, and megakaryocytic series (and to a lesser extent, the monocytic, eosinophilic, and basophilic series) – basically, everything except the lymphoid series.

2. They all have a high white blood cell count with a left shift. 

3. They all may present with splenomegaly (especially chronic myelofibrosis, in which extramedullary hematopoiesis can produce a truly massive spleen). 

4. All of the myeloproliferative disorders are characterized by a hypercellular bone marrow (at least early on). This means that there are a lot more cells than usual – and, correspondingly, that the amount of fat (which normally increases with age) is decreased. Also, there are often many more megakaryocytes than usual, as seen in the above image (the megakaryocytes are the large cells with abundant, eosinophilic cytoplasm). In fact, if all you had was a bone marrow biopsy, it would be hard to tell the different myeloproliferative disorders apart in their early stages!

The differences between the myeloproliferative disorders lie primarily in the type of myeloid cell that is proliferating the most. In CML, the neutrophil series is the predominating cell line. Polycythemia vera is characterized by marked erythroid hyperplasia; essential thrombocythemia is characterized by marked megakaryocytic hyperplasia (resulting in tons of platelets in the blood); and chronic myelofibrosis is characterized by a proliferation of all myeloid cell lines early on (followed by progressive fibrosis of the marrow).

We’ve talked already about how you’d differentiate chronic lymphocytic leukemia from a benign lymphocytosis. So how about the same thing for the myeloid series, namely, how do you tell apart chronic myeloid leukemia from a benign neutrophilia?

Chronic myeloid leukemia (CML), a malignant disorder of myeloid cells, can resemble a benign neutrophilia with a marked left shift.  Here are the differences:

1. In CML, the shift to the left is usually much greater than you would see in a benign process.  In a benign left shift, you’ll usually see lots of band neutrophils, fewer metamyelocytes, and even fewer myelocytes. Rarely, you’ll see a promyelocyte. In CML, you see the entire spread (though you don’t see many blasts at all; if you do, it’s CML in blast crisis or some kind of acute myeloid leukemia), with a marked “bulge” at the myelocyte stage.

2. In CML, there is a basophilia; in a benign neutrophilia, there is not. 

3. In CML, there is always evidence of the Philadelphia chromosome; in a benign neutrophilia, there never is. This is one of the few times in pathology you can say “always” and “never” with complete confidence. The Philadelphia chromosome is the mutated chromosome 22 that you get from the balanced translocation between chromosomes 9 and 22 that you always see in CML. You must see this translocation, or it is not CML (if it looks like CML, but doesn’t have the Philadelphia chromosome, it’s probably some other chronic myeloproliferative disorder). You can either look for the Philadelphia chromosome using cytogenetics, or you can look for the bcr-abl transcript using molecular studies (like PCR). This is the only way to definitively prove that something is or is not CML.

Polycythemia vera (PV) is a chronic myeloproliferative disorder in which the red cells are the predominating lineage. Here are some typical student questions along with my answers.