Myeloproliferative disorders: Pathology review

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Case Study0:00–0:50

A 70 year old female named Jenny is brought by her husband to the emergency department complaining of blurred vision and headache.
Her face appears plethoric and her husband says that Jenny has been complaining of extreme itchiness after showers for the last few days.
She has no significant past medical history. CBC shows increased hematocrit and slightly increased platelets.
Uric acid is also increased. Next to Jenny, there’s a 65 year old male named Seth that came in with fatigue and progressive weight loss due to early satiety.
Past medical history is unremarkable. Clinical examination reveals a very enlarged spleen.
CBC shows pancytopenia and peripheral blood smear shows teardrop cells. Both Jenny and Seth suffer from myeloproliferative neoplasms.

Pathology0:50–2:22

These are a group of malignant neoplasms characterized by proliferation of the bone marrow cells from the myeloid lineage.
That includes RBCs, platelets, as well as granulocytes, which include neutrophils, basophils, mast cells, and eosinophils.
Each disorder can potentially cause proliferation of all of the myeloid cells, but they’re classified based on the dominant cell line involved.
So there’s polycythemia vera, for RBCs, essential thrombocythemia for platelets, chronic myeloid leukemia, or CML, for granulocytes, and the odd one out, primary myelofibrosis, which doesn’t really have a dominant cell line, but instead is characterized by bone marrow fibrosis.
Okay, now CML is associated with the 9:22 translocation, which is when there’s fusion of the BCR gene on chromosome 22 and the ABL tyrosine kinase gene on chromosome 9.
This is called the Philadelphia chromosome. Now, in this video, let’s focus on the myeloproliferative disorders that are not associated with Philadelphia chromosome, or the “Philadelphia chromosome negative myeloproliferative disorders,” like polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
Alright, so let’s take a closer look at these myeloproliferative disorders, starting with polycythemia vera, where there’s an increase in RBC production.

Polycythemia Vera2:22–4:23

It typically begins with a mutation in a single hematopoietic stem cell, which gives rise to RBCs, WBCs, and platelets. In 90 percent of the affected individuals there is a mutation of the gene that encodes for a non-receptor tyrosine kinase called Janus Kinase 2 or JAK2, and that’s something you absolutely have to remember for the exams.
Normally, the kidneys produce erythropoietin, which is a hormone that binds to receptors on the hematopoietic stem cells and activates JAK2.
When that happens, it causes the cell to divide and thus produce more blood cells. However, when there’s a mutation, it keeps JAK2 activated all the time, and these cells are able to divide even in the absence of erythropoietin.
This results in massive RBC production. The interstitial cells of the kidney sense the high levels of RBCs, so they decrease erythropoietin production to keep the RBC levels normal.
However, as the mutated cells proliferate, they rapidly become the predominant hematopoietic cells in the bone marrow and this will keep increasing RBC levels.
In time, these cells start to die out and lead to fibrosis of the bone marrow. At that point, the bone marrow can no longer produce blood cells, leading to anemia or low RBC levels, thrombocytopenia or low platelet levels, and leukopenia or low WBC levels.
This is known as the spent phase. And once the disease is in the spent phase, it’s really a different disease altogether.
At that point it’s secondary myelofibrosis. The treatment of polycythemia vera include phlebotomy, hydroxyurea or a JAK inhibitor like Ruxolitinib.
Okay, next up is essential thrombocythemia, where there’s an increase in platelet production. It can be caused by a genetic mutation in the JAK2 gene like in polycythemia vera.

Essential Thrombocyth.4:23–5:30

Normally, the liver and kidneys produce a hormone called thrombopoietin which binds to hematopoietic cell receptors. When it binds, those cells activate the JAK2 gene which makes them divide and mature into megakaryocytes, which are responsible for creating platelets.
But unlike polycythemia vera, only 50 percent of patients have a JAK2 mutation. They can have mutations in the thrombopoietin receptor, MPL, or in the chaperone protein, Calreticulin or CalR.
CalR mutations are present in 25 percent of patients. Okay, whatever the mutation, the signalling pathway remains active all the time, and that means that platelets keep getting produced even in the absence of thrombopoietin.
In rare cases, essential thrombocythemia can develop into myelofibrosis and acute leukemia. Alright, let’s talk about primary myelofibrosis which unlike secondary myelofibrosis, is not caused by another disease.

Myelofibrosis5:30–6:38

This is why it’s also called chronic idiopathic myelofibrosis. Okay, although primary myelofibrosis is a myeloproliferative neoplasm, it doesn’t always cause a cell count elevation.
That’s because it results from an abnormal proliferation of megakaryocytes that, instead of making platelets, make cytokines and a very high yield one is platelet derived growth factors, or PDGF.
This cytokine stimulate excessive collagen deposition in the bone marrow, which replaces the hematopoietic stem cells, causing anemia.
The WBC and platelet counts are variable, and can be increased, normal or decreased depending on how much of the bone marrow is fibrosed.
For the exams, remember that 50 percent of patients with myelofibrosis have a JAK2 mutation, and 25 percent have a CalR mutation and that’s exactly the same as in essential thrombocythemia!
Alright, now most patients with myeloproliferative disorders don’t have symptoms and are discovered incidentally when a CBC is done for another reason.

Symptoms6:38–10:41

But sometimes symptoms can occur and you have to remember them for the exams since they are very high yield! In polycythemia vera, all those extra RBCs in the blood can make it sludgy and highly viscous.
Hyperviscosity causes stasis in the circulation, which augments the formation of blood clots in different tissues, causing various symptoms.
In the brain, they can cause blurred vision, headache, or strokes. Or in the heart, they can cause angina or myocardial infarction.
Blood clots can also form in unusual locations, such as the stomach where they can lead to peptic ulceration, or in the hepatic veins, they can result in Budd-Chiari syndrome; characterized by the triad of abdominal pain, ascites and an enlarged liver.
Also, the face can appear plethoric, which means a constant blush, because more RBCs means more redness. Now, since myeloproliferative neoplasms can cause an increase in all myeloid cells, mast cells can also be increased in polycythemia vera.
Therefore pruritus, or itching, occurs after warm showers, and this is thought to be due to increased histamine release from mast cells in response to the heat.
Now, the plethoric face and the itching after a hot shower are probably the best clues you can get on the exams for polycythemia vera!
Okay, now a rare but characteristic presentation of polycythemia vera is erythromelalgia; which are episodes of redness and intense warmth and pain in the palms and soles, caused by small blood clots in the distal extremities.
These blood clots can manifest from the hyperviscosity that predisposes patients to thrombosis, but can also be related to an increased platelet count in polycythemia vera patients.
More RBC proliferation means means more DNA and RNA synthesis, which results in more purine metabolism. Purines are metabolized into uric acid, and this increased metabolism can result in hyperuricemia, which can potentially cause cause gout.
Gout usually presents with acute joint pain, particularly in the big toe. The spleen, which is a bit like a nursing home for old RBCs, starts to get really filled up, resulting in splenomegaly.
The enlarged spleen can push against the nearby stomach wall, causing early satiety and eventual weight loss. Moving onto essential thrombocythemia, some patients can have symptoms like fatigue, headache, dizziness, nausea, tinnitus, and numbness in the hands and feet.
Also, they can get complications that are similar to polycythemia vera, like thrombotic complications, erythromelalgia, and splenomegaly because the spleen gets infiltrated by platelets.
But pruritus is uncommon in essential thrombocythemia and this can help you differentiate between the two on an exam. Also, if the platelet count exceeds one million, the platelets aren’t able to function in such a crowded environment, and the patient becomes paradoxically predisposed to bleeding!
Now, in myelofibrosis, all those extra cytokines produced by megakaryocytes can be released into the blood, triggering constitutional symptoms like fever, weight loss, and a decreased appetite.
Additionally, once the bone marrow becomes fibrotic, it stops doing its job of producing new blood cells like RBCs, causing symptoms of anemia like pallor and fatigue.
Also, another high yield fact is that backup hematopoietic organs like the liver and especially the spleen can get massively enlarged as they try to pick up the slack, a process called extramedullary hematopoiesis.
Like in polycythemia vera, splenomegaly can lead to early satiety and weight loss. Alright, now let’s switch gears and talk about diagnosis.

Diagnosis10:41–16:55

Myeloproliferative disorders are diagnoses of exclusion. So for example, when you see an increase in RBCs, or polycythemia, you have to think through all of the other causes before considering polycythemia vera.
Polycythemia is when the hemoglobin level is more than 16.5 grams per deciliter in men or more than 16.0 grams per deciliter in women, or a hematocrit more than 49 percent in men, or more than 48 percent in women.
Women have a lower cutoff because they normally lose some blood through the menses. Now, on your exam, you might need to differentiate between polycythemia vera, which is also referred to as primary polycythemia, and secondary polycythemia, which is further subclassified into relative polycythemia, appropriate absolute polycythemia, and inappropriate absolute polycythemia.
To differentiate the causes of polycythemia, we’ll be looking at four laboratory parameters: plasma volume, RBC mass, oxygen saturation, and erythropoietin levels.
So, starting with secondary polycythemia, relative polycythemia happens when something like dehydration, diuretic use or a burn injury causes a decrease in plasma volume, resulting in an apparent increase of RBCs, but the RBCs are only increased relative to the plasma.
Therefore, we don’t expect any change in the RBC mass, oxygen saturation, and erythropoietin levels. Now, a key concept that’s frequently tested on the exams is appropriate absolute polycythemia which is the physiological response to any cause of chronic hypoxia.
That includes chronic obstructive pulmonary disease, or COPD, obstructive sleep apnea, which is characterized by recurrent episodes of asphyxia during sleep, congenital heart disease, or even hiking up a mountain.
In response to the decrease in oxygen saturation, the peritubular cells of the renal cortex make more erythropoietin, which signals to the bone marrow to produce more RBCs to compensate for the hypoxia.
Over time, the RBC mass increases, while the plasma volume remains about the same. Now, inappropriate absolute polycythemia, on the other hand, is not some sort of normal physiological response.
Instead, it occurs due to pathologic overproduction of erythropoietin from malignancies such as renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, leiomyoma or pheochromocytoma.
So, erythropoietin levels and RBC mass are increased, but the oxygen saturation and plasma volume are normal. Okay, so if you’ve excluded the secondary causes of polycythemia, it’s time to consider polycythemia vera.
The workup includes a CBC, which will show an increase in hemoglobin, hematocrit, and RBC mass, as well as a slight increase in white blood cells and platelets as well.
Additionally, uric acid levels can be increased, and erythropoietin levels are decreased. Also, a bone marrow biopsy is done, and the cells are tested for the presence of the JAK2 mutation.
So, for the exams you have to remember that the diagnosis of polycythemia vera hinges on having an increased hemoglobin or hematocrit and a bone marrow biopsy showing increased proliferation of all myeloid cells, along with either a decrease in erythropoietin levels or the presence of a JAK2 mutation.
Okay, onto thrombocytosis, which is defined as a platelet count of more than 450,000. The most common cause is reactive thrombocytosis, which is a reaction of the bone marrow to make more platelets when the body is experiencing something like bleeding, iron-deficiency anemia, or inflammation.
In inflammatory conditions like an infection, cytokines like interleukin-6 stimulate platelet production. In addition, since the spleen normally houses about one third of the peripheral platelet pool, there can be a thrombocytosis in individuals that have had a splenectomy.
Once these causes of thrombocytosis have been excluded, it’s worth considering essential thrombocythemia. Alright, so for essential thrombocythemia, a laboratory workup includes a CBC, which’ll show an increased platelet count, and possibly an increase in the WBC count and hemoglobin as well.
Iron studies including serum iron and ferritin levels can help rule out a reactive thrombocytosis due to iron-deficiency anemia.
The four major criteria for diagnosing essential thrombocythemia are an increased platelet count, a bone marrow biopsy showing an increase in megakaryocytes, identifying a genetic mutation like JAK2 or CalR, and not having an alternative diagnosis like polycythemia vera or CML.
A minor criteria is the absence of any indicator of reactive thrombocytosis. To diagnose essential thrombocythemia, either all four major criteria must be met, or three major and the one minor criteria have to be met.
Finally, myelofibrosis can be primary, and that’s the myeloproliferative neoplasm, or secondary, which is when it’s the complication of leukemia, autoimmune diseases like SLE, toxins like benzene, or even glycogen storage diseases like Gaucher’s disease.
Now once these secondary causes are excluded, primary myelofibrosis is considered. A peripheral blood smear characteristically shows teardrop cells, or dacrocytes, which are red blood cells that barely squeezed themselves out of the tight environment of the fibrotic bone marrow.
Also, when attempting to aspirate a sample from the bone marrow, sometimes none of the cells are able to get out because of fibrosis, and this is called a “dry tap”.
Okay, as a quick recap, Myeloproliferative neoplasms are a group of malignancies characterized by proliferation of the bone marrow cells from the myeloid lineage.

Review16:55–17:56

They’re classified based on the predominant cell involved, so there’s polycythemia vera for RBCs, essential thrombocythemia for platelets, and chronic myeloid leukemia for granulocytes.
There’s also primary myelofibrosis, which is characterized by bone marrow fibrosis due to increased megakaryocyte that leads to collagen deposits in the bone marrow.
In polycythemia vera, almost all patients have a JAK2 mutation, while in essential thrombocythemia and primary myelofibrosis 50 percent have a JAK2 mutation and 25 percent have a CalR mutation.
CML is characterized by the presence of the 9:22 Philadelphia chromosome. Most patients are asymptomatic and are discovered incidentally when a CBC is done for another reason.
Myeloproliferative disorders are diagnoses of exclusion. Now, back to the patients!

Summary17:56–18:46

Due to her symptoms of hyperviscosity, plethora, itchiness after showers, and the increased hematocrit, Jenny most probably has polycythemia.
Secondary causes must be excluded in order to consider polycythemia vera and erythropoietin levels will be low. To confirm the diagnosis a bone marrow showing increased proliferation of all myeloid cells or genetic testing for JAK2 mutation must be done.
Now, due to his symptoms of fatigue, massive splenomegaly and pancytopenia with teardrop cells on the peripheral blood smear, Seth most likely has myelofibrosis.
Bone marrow biopsy will be a “dry tap” and to diagnose primary myelofibrosis, secondary causes have to be excluded. ...And that’s the myeloproliferative disorders pathology in a nutshell.