Pathology - Dr



Pathology - Dr. Morgan Sneha Patel

P040509 Ashis Barad

WHITE CELL DISORDERS

He started off with some jokes about hematology and then started on page 535 of the notes. I tried to keep the outline format that Dr. Morgan used in his notes, but there are spots where he just goes off for a long time (these are the bulleted areas in the scribe). I tried to make it as easy to read as I could, but if you have any questions just ask.

I. Leukopenia

A. Neutropenia

1. Decrease in the absolute number of neutrophils below the normal range of 2,500-7,000 neutrophils/mm3. You will notice however, that some of these normal ranges will vary a lot depending on the patients age, especially in pediatrics. However, for the purposes of this class we will only be concentrating on the normal adult range of 2500 -7000.

• He stressed that it is very important to know the absolute numbers of the different types of WBC's. This is especially important when looking at a CBC report that often gives percentages of the different WBC's . A normal percentage of neutrophils might be about 60 -70 %, but it doesn’t really mean a lot because when the WBC count increases or decreases, the percentage may increase or decrease with it. The percentage is only important when the WBC count is within the normal range.

• For example: A patient can have a WBC count of 50,000 (which is very high) and a %age of neutrophils of only 10% (which is a whole lot below the normal %age range). This low percentage does not however mean that a patient has neutropenia because 10% of the total WBC count is 5,000, which is within the normal range of 2500-7000.

• The point: IGNORE percentages. The first thing to do when interpreting a CBC report is to multiply the WBC count (Segmented + Band Neutrophils) by the different percentages of cell types to give an absolute number.

a. Cyclic Neutropenia: a benign syndrome of low neutrophils that is more common in blacks. It has no clinical significance, other than the fact that their neutrophil count is low. They do NOT have an increased risk of infection. You diagnose this when a patient comes in with an absolute neutropenia and their past medical records show no history of repeated infections. To make sure of the diagnosis, you should have the patient come back again in a couple of weeks and see if their neutrophil level has returned to normal. If it has then you are probably dealing with a cyclic neutropenia.

b. Severe Persistent Neutropenia: aka-Agranulocytosis – which is usually a misnomer, because you hardly ever see an absolute neutrophil count of 0. Syndrome in which the neutrophil level is 100,000). Also see immature granulocytes (also a sign of leukemia, particularly chronic granulocytic leukemia, which has maturing granulocytes). However, the big difference between a leukemoid reaction and a leukemia is that a leukemoid reaction is reactive. The main differential diagnosis of a leukemoid reaction is chronic granulocytic leukemia.

d. Leukoerythroblastosis: the presence of immature precursors (not necessarily blasts) of the WBC’s, especially neutrophils and erythroid cells in the peripheral blood. Therefore, there is an increase in granulocytic band cells and also nucleated blood cells are present on the peripheral smear. This also tells us that there is either hyperplasia in the bone marrow of neutrophils and erythroid precursors or that there is an extramedullary hematopoeisis where the immature precursors are leaking out into the blood. DDx of leukoerythroblastosis includes chronic granulocytic leukemia, which can also have circulating red cell precursors.

Slides of examples of reactive changes in neutrophils:

-Cytoplasmic vacuolization: This is often not seen until there is sepsis. In other words, when the microorganisms or the bacteria actually are circulating in the blood. Many times, you may actually see the microorganisms in the cytoplasmic vesicles of the neutrophils. This is a much better indicator of bacterial infection (especially sepsis) than just an increase in band forms because we know that the cells are actually reacting to something.

-Toxic granulation: See pretty normal looking bands and neutrophils with faintly staining cytoplasmic granules. When these cells react to an antigenic stimulation such as a bacterial infection, the granules increase in number and they become darker. This is because they are becoming more metabolically active. (Similar to Robbins, Fig 15-3, pg 649)

-Dohle body: blue blobs usually found at the periphery of the cells are clusters of rough endoplasmic reticulum and ribosomes. This only tells you that these cells are synthetically active. (Similar to Robbins, Fig 15-3, pg 649)

So, there are 3 main signs of a Bacterial Infection: cytoplasmic vacuolization, toxic granulation, and Dohle bodies.

B. Eosinophilia: the absolute increase in the number of eosinophils above 500/mm3. There is no such thing as eosinophilopenia – because normally it is possible to not see any eosinophils on a blood smear when a 100 cell differential count is done. With a machine count it is possible however, to get a low eosinophil count, but there is no clinical significance in having a low eosinophil count.

1. Etiology

a. Allergies such as hayfever and asthma. At this time of year a lot of people have eosinophilia.

b. Allergic drug reactions

c. parasitic infections (textbooks make a big deal about this, but in the US it is rare to find eosinophilia due to parasitic infections, because we don’t have problems with parasites like they do in 3rd world countries. When there is eosinophilia associated with parasitic infections, it is usually diagnosed very early on. However, it does need to be included in the DDx for eosinophilia).

d. Many skin disorders

e. Idiopathic eosinophilic syndromes include Loeffler’s syndrome which presents with endocarditis, eosinophilic infiltrates in the lungs and GI tract, and eosinophilic gastritis. Not very common.

f. Eosinophilia can also be seen with acute and chronic leukemias.

C. Basophilia: an increase in the absolute number of basophils above 100/mm3. This is rare.

1. Etiology

a. Myxedema

b. Chronic Myelogenous Leukemia (CML): Basophilia is used to distinguish between a leukemoid reaction and CML because basophilia is not seen with leukemoid reaction.

c. Ulcerative colitis, . . .(He said to read the rest)

D. Monocytosis: greater than 1000 monocytes/mm3

1. Etiology

a. chronic infections such as TB and bacterial endocarditis

b. chronic inflammation such as chronic vascular disease, inflammatory bowel disease, metastatic tumors, and myelodysplastic syndromes.

Monocytosis is nonspecific but can be an indicator of chronic infections or inflammation.

E. Lymphocytosis: greater than 4,000 lymphoctes/mm3 in adults and greater than 8,000 in children.

1. Etiology

a. chronic inflammation.

b. many viral infections such as hepatitis, CMV, and especially infectious mononucleosis. The increase in lymphocytes is where the term infectious MONONUCLEOSIS comes from.

III. Morphologic abnormalities of WBC’s: Whenever, you look at peripheral blood smears you want to look at all the leukocytes. However, when a person has an infection, you especially want to look at leukocytes for reactive changes. These changes tell whether it is likely to be due to a bacterial infection.

A. Reactive changes

1. Reactive changes in Neutrophils

a. Toxic granulation

b. Toxic vacuolization

c. Dohle bodies.

2. Reactive changes in Lymphocytes

a. Reactive lymphocytes are often referred to as variant or atypical lymphocytes or transformed lymphocytes (the name Dr Morgan likes to use).

i. In a reactive situation, such as a viral inflammation, the transformed lymphocytes are morphologically heterogenous (very important). This is important in differentiating between a reactive lymphocytosis and a malignant lymphocytosis like chronic lymphocytic leukiemia. With a malignancy, there is a problem with the cloning process so that the lymphocytes all look the same. In a reactive process, you see a heterogenous population (small and large cells) of cells.

Slides of transformed lymphocytes:

-Very large cell with lots of blue cytoplasm. Small mature lymphocytes are about the size of a red cell. However, this lymphocyte was huge. One thing that must be considered with a cell that looks like this is “is it a blast?” To differentiate a transformed lynphocyte from a malignant cell you must:

-Look at the cytoplasm: a transformed lymphocyte has lots of cytoplasm, while a blast has little cytoplasm and a high N:C ratio. -Look at the nucleolus: both transformed lymphocytes & reactive cells have prominent nucleoli.

-Look at the chromatin: If it is coarse, smudgy and heavily clumped, then it is probably the mature chromatin found in a reactive cell. If the chromatin in immature then the cell is probably a blast.

-Look at the platelet count: If you see something that looks like a blast and the platelet count is either normal or high, it is probably a transformed lymphocyte, especially if there are a lot of cells that look like this one and a lot of other heterogenous cells around as well. If the platelet count is low then it is probably a blast. This is because with acute leukemias, when you start seeing blasts in the blood, it almost always means that the bone marrow is full of the leukemic blasts and other precursor cells, like the megakaryocytes are rapidly being wiped out (especially because megakaryocytes make up the lowest number of bone marrow precursors). Also, if there are lot of cells that look like the “blast”, then it is probably a blast.

-Another transformed lymphocyte. It is big with lots of blue cytoplasm (blue cytoplasm can indicate a blast or a metabolically active cell). It is probably not a blast because of the large amount of cytoplasm and the heavily clumped chromatin.

-Smaller cell, but you see mature chromatin.

-Cell not much bigger than a small mature lymphocyte. It doesn’t have the perfectly round nucleus of a normal mature lymphocyte though.

-Looks like plasma cells.

Where do these transformed cells come from?

• In the lymph nodes there are follicles, which have very large cells interspersed with smaller cells. Around the follicle is a mantle zone, which consists of just small mature lymphocytes, which are memory B cells or virginal B cells that have never been exposed to any antigenic stimulus, but are ready to be exposed. When an antigen from a bacterial infection comes along, it is first exposed to histiocytes (macrophages) in the lymph nodes. The histiocytes then process the antigen and send a signal to the lymphocyte, which responds by transforming.

• As they transform, the lymphocytes move to the germinal center where they proliferate and go thru a series of transformations. We don’t really know which of the transformed cells comes first, but we do know what each of them look like. There is a small cleaved transformed lymphocyte, a large cleaved transformed lymphocyte, a small non-cleaved transformed lymphocyte with a prominent nucleolus and a large non-cleave transformed lymphocyte with a prominent nucleolus.

Small immat. lymphocyte(transforms to small/large cleaved OR small/large non-cleaved lymphocyte(plasma cell

• The whole purpose of this transformation in the B-cell lineage is to end up with a plasma cell, which produces immunoglobulins. T-cells also undergo similar transformations which end up becoming peripheral T-cells such as helper T-cells or suppressor T-cells.

• So, within the germinal center, there is a variety of transformed lymphocytes involved in a reactive process. Some of these cells get out into the peripheral blood. This is the reason that in a reactive process, such a spectrum of transformed lymphocytes and even some plasma cells are seen.

How does transformation differ from a malignant process such as a leukemia?

• All of the different types of leukemias and lymphomas are cells that have gotten stuck in a certain stage of maturation or transformation; therefore they all look alike. For example, you may get a leukemia in which cells are stuck in the stage of small immature lymphocytes and thus you will seen many of these cells. This is called chronic lymphocytic leukemia or small cell lymphocytic lymphoma. If cells get stuck in the germinal center follicles, they are called small cleaved, small non-cleaved, large cleaved or large non-cleaved or a combination of two depending on which stage they can stuck in. If cells are stuck as plasma cells, then you get multiple myeloma or Waldenstrohns macroglobulinemia. Malignancies associated with cells stuck at the mature T-cell phase are usually skin diseases, although a few may be lymphomas. Therefore, in a malignant processes, the cells are stuck at a certain cell type.

Dr. Morgan says that the main thing we need to know is that with reactive processes you see heterogenous populations of these cells and with malignancies you see a predominance of only one particular cell type.

3. Reactive changes in Monocytes

a. Large cell with light blue cytoplasm with a few granules and often times you will see vacuoles because monocytes are phagocytic cells.

-Slide of reactive changes in monocyte: Monocyte with a microorganism in a vacuole that is difficult to see. This monocyte is from an AIDS patient. Can see lots of vacuoles with little blue dots, which is the histoplasmosis.

B. Syndromes

1. Pelger-Huet anomaly: see Pince-Nez neutrophils (French for pinched nose. It refers to the appearance of wire-rimmed glasses that pinch your nose).

a. Inherited anomaly: Autosomal dominant and is found in 1/6000 individuals, therefore is not that Uncommon. See an increase in band forms with very mature chromatin. This is because this disease is an abnormality in nuclear segmentation. We may also see mononuclear neutrophils with mature chromatin. These things can easily be mistaken for actual granuloctye precursors or an increase in band forms.

i. For example, Dr. Morgan may get a call from a doctor of a patient that has just delivered a baby and wants to send the patient home, but the lab keeps reporting 30% bands in the peripheral smear. This is usually a patient with Pelger-Huitt anomaly. They are not really bands, but rather mature neutrophils without a nuclear segment and therefore are mistaken for bands. It is clinically insignificant except for the fact that it gets confused with evidence of infection.

b. Acquired Pelger-Huet anomaly: Often seen with severe infections, such as TB. The changes are similar. These changes can also be seen in leukemias, myelodysplasias and in patients with bony metastases or colchicine therapy. Therefore, we must look at clinical symptoms to help differentiate between these abnormalities.

-Slide of Pelger-Huet: Bilobed nucleus w/ a tiny string of nucleus connecting both lobes.

The following syndromes, Dr Morgan says were “just for fun and I don’t expect you to remember all of these”.

2. May-Heglin anomaly: these patients have lots of Dohle bodies in their neutrophils all of the time. This can be confused with a patient that has a bacterial infection. The clue is that these patients also have giant platelets and thrombocytopenia. A giant platelet is a platelet that is larger than a normal red blood cell precursor. The patients may have a mild leukopenia, but are usually asymptomatic. There is no clinical significance. DDx for May-Heglin: infection, acute leukemia, or another cause of thrombocytopenia.

-Slide of a Dohle body.

3. Alder-Reilly Syndrome: see Congenital Hypergranulation of granulocytes. These patients always have toxic granulations. This can be confused with an infection. We see the toxic granulations with monocytes and lymphocytes as well. It may be associated with Gargoylism, which is a very strange and rare disease where the patient is of very short stature and the kids are just hideous looking.

4. Chediak-Higashi Syndrome: also rare and also involves congenital granulation of granulocytes. The granulocytes tend to be even bigger than those found in Alder-Reilly. Again the granules can also be found in monocytes and lymphocytes. This disease is associated with albinism, peripheral neuropathy, neutropenia with frequent infections, and bleeding due to platelet dysfunction.

-Slide of lymphocyte with large granules.

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