Flashcards in Hematologic Malignancies IV Deck (64):
What is the basis of myeloproliferative diseases?
chronically proliferating clones which DIFFERENTIATE AND PROLIFERATIVE to MATURE circulating blood cells. So, for some reason you have a proliferation of a certain lineage of cells out of the BM
Two major myeloid lineage myeloproliferative diseases?
1) CML- chronic myelogenous leukemia
2) CMML- chronic myelomonocytic leukemia
Some characteristics of CML:
-All stages of granulocyte maturation end up in blood
Some characteristics of CMML:
-High WBC, monocytes, and promonocytes
-Weird hybrids between monocytes and granulocytes
What are two types of rare myeloproliferative neoplasms which present with an elevated eosinophil count?
CEL and PDGFR-related neoplasms.
REMEMBER: the two types respond differently to different therapies.
What two myeloproliferative diseases often present with thrombosis?
1) polycythemia vera (form erythroid line)- elevated red cell count
2) Essential thrombocythemia or Primary myelofibrosis - elevated platelet count
What things would make you suspect sepsis vs. myeloproliferative disease ?
A high WBC with toxic granulation and no left shift
If the typical symptoms of pneumonia are present, it’s easy to tell that the patient is unlikely to have a myeloproliferative disease. But what if the clinical signs of infection are weak, or ambiguous?
A review of the peripheral smear can help. Toxic granulation and a “left shift” composed of progressively fewer cells representing the more immature precursors (bands > metamyelocytes > meylocytes) supports an infectious etiology.
i.e. bands=20, metamyelo=15, myelocytes=10
What things would make you suspect myeloproliferative disease vs sepsis?
A patient with the same total white count, no evidence of toxic granulation, and more myelocytes than metamyelocytes (a “myeloid bulge”) is more likely to have a myeloproliferative neoplasm.
i.e. bands=15, metamyelo= 10, myelocytes= 20
What does the bone marrow of CML patients look like?
-many myeloid precursors,
-little in the way of dysplasia
-no increase in blasts.
How is CML diagnosed?
-RT-PCR positive assay for the BCR-Abl1 fusion protein, and you can do that with peripheral blood.
-follow up with BM biopsy to gauge progression
Because CML is treatable, you need to have a low threshold of suspicion for sending the RT-PCR assay. You should send enough of them that you get more negative results than positives, because the cost to the patient of missing the diagnosis is high.
How is treatment efficacy in CML determined? What is the treatment?
Treatment is Imatinib.
whether the fusion transcript is detectable by RT-PCR (a “complete molecular response”, down to levels at which the abnormal transcript is present at less than 0.001% of the normal parent transcripts).
Molecular diagnostics are excellent, but you still need to get a bone marrow biopsy when you diagnose CML. Why?
Because CML patients can progress to an accelerated phase (via more mutations), with increased blasts in the marrow, and then to a “blast phase” that is essentially the same as an acute leukemia (usually myeloid, sometimes lymphoid). At diagnosis, and occasionally during treatment, you need to make sure they’re not progressing.
If you miss the diagnosis, or let the condition slip by for a year or two before making the diagnosis and checking the status of the bone marrow, you increase the risk that the patient will progress to an acute leukemia.
So, what is the overall workup order in suspected CML?
1) CBC and manual diff
2) Suspect CML
3) RT-PCR of peripheral blood sample for BCR-Abl1
4) Bone marrow biopsy
What is Polycythemia Vera?
myeloproliferative disease resulting in increased red cell counts
What is the pathogenic basis of Polycthemia vera?
Activating Jak2 mutations in >95% of cases mimics the presence of EPO in a clone of committed erythroid progenitors– detectable in peripheral blood leukocytes.
Some patients have mutations in the Epo receptor instead (Mpl)
Precise designation for the PV mutation?
Molecular testing for this mutation is standard of care in suspected P vera cases and, and finding the mutation is diagnostic of P vera.
Clinical presentation of PV?
-Elevated red cells
-Thrombosis/hypertension/stroke or MI.
Increased RBC’s can also be due to lung disease!
How do you differentiate between increased red cells in PV and lung disease?
If an increased red cell count occurs due to lung disease, it will be associated with increased serum EPO levels. In P vera, it will not.
Immunophenotype of PV?
No known features (no red cell markers)
Prognosis of PV? Progression?
-10+ yr survival is common (14yr survival average)
-can progress to myelofibrosis, MDS, acute leukemia
What is an important fact about the morphology of PV?
megakaryocytes as well as the erythroid precursors are increased in number in P vera (normally myeloid precursors outnumber the erythroid ones by better than 2:1).
What is the pathophysiology of PV?
Constitutively active mutants of the Type 1 hematopoietic growth factor receptor complex with is a JAX/STAT system
Note on JAX/STAT system
For example, if the cytokine/receptor complex EPO and EPO-R, the transcription pattern generates red cell precursors.
For TPO and its receptor (Mpl), the result is proliferating megakaryocyte precursors.
Why you need to know this: acquired mutations in the receptors, or in the Jak-2 kinase, are clinically relevant – paticularly when they result in constitutive activation of these signal transduction pathways. If that were to occur in a self-sustaining clone of CFUs, you ought to be able to predict the result: excess, unregulated production of red cells, or platelets, or both.
What is the major cause of Essential Thrombocythemia?
Jak2 V617F mutations in ~50% of cases– detectable in peripheral blood leukocytes;
Mutations in another gene (calreticulin) occur in ~25%.
What is the clinical presentation of ET?
increased platelet counts (thrombosis risk)
When else are platelet counts elevated?
Increased platelets can also be due to iron deficiency, infection, chronic inflammation.
Much more common in these situations than in ET.
What is a major difference in the morphologic of ET vs. P. vera?
The Megs in ET look very abnormal and large
Prognosis of ET? Progression?
Prognosis: > 10 yr survival is common;
-can progress to myelofibrosis, MDS, acute leukemia
What is Primary myelofibrosis caused by?
see mind map (neoplastic and non-neoplastic common)
Jak2 mutations in ~50% of cases- detectable in peripheral blood leukocytes
Why is PM hard to diagnose?
This condition can be hard to diagnose because the CBC findings are quite variable: anemia is common, as is thrombocytosis, but they can also show a leukocytosis OR a leukopenia.
Review of the peripheral smear is usually the critical diagnostic step because it will show leukoerythroblastic findings (as discussed in my first presentation on blood cells). That in turn will inspire you to biopsy the bone marrow (as it always should).
What are the key findings in the marrow in PM?
An increased number of megakaryocytes (often bizarre looking) and fibrosis.
The latter can be hard to pick up until a special stain (called a reticulin stain) is used.
Prognosis of PM?
Usually shorter survival than ET; can progress to marrow failure, acute leukemia
Increased platelet counts would lead you to think of what if you knew you were dealing with a myeloproliferative neoplasm?
ET or PM. Not polycythemia vera
Increased RBCs would lead you to think of what if you knew you were dealing with a myeloproliferative neoplasm?
What else would lead you to suspect PM if you knew you were dealing with a myeloproliferative neoplasm?
hypertension (with thrombosis)
Are mast cells circulating?
What mitogen plays a big role in mast cell growth and migration?
Neoplasms of mast cells usually present as what?
benign cutaneous lesions in kids (the most common is “urticaria pigmentosa”, aka itchy pigmented skin lesions).
They usually don’t spread beyond the skin. (Except when they do)
What happens if mast cell neoplasms spread beyond the skin? Most common site affected in this case?
In that case they release lots of histamine and other mediators, causing systemic symptoms (flushing, abdominal pain, tachycardia, hypotension) that can can really confuse the clinician.
The bone marrow is the most common site of systemic involvement, but multiple organs (lymph nodes, spleen, liver) can be involved
Whats a good diagnostic tool for mastocytosis diagnosis?
serum tryptase level.
Tryptase is one of the major mediators secreted by mast cells - but hyperactive normal ones can secrete it too.
What is the root cause of most mastocytoses?
Either cKIT mutants OR PDGFRA activation (FIP1 translocation)
prognosis is variable
What is the immunophenotype of mastocytosis?
tryptase, CD117 (cKIT, the SCF receptor), CD25 usually positive
Increased activity of a tyrosine kinase, whether in the form of a fusion protein or due to a point mutation, is getting to be a common motif in MPN’s (and in some non-hematologic malignancies), and more of them are likely to be discovered. By good luck, some of them turn out to be responsive to the same kind of drugs used to treat CML!.
That means you need to get molecular testing when an eosinophilia is thought to be myeloproliferative rather than reactive (there are many causes for a reactive eosinophilia, the most common being parasites and drug reactions).
More drugs which specifically inhibit particular kinases like Jak2 (like Imatinib) are also likely to emerge.
We have a poor understanding of myelodysplasias.
We diagnose these conditions based primarily on bone marrow morphologic findings in the context of unexplained cytopenias. Cytogenetic findings are often used as additional criteria. Describe these.
The cytogenetic findings in MDS cases are usually nonspecific, and we can’t point to any particular oncogenes as critical elements in the pathogenesis (although that could change in the next few years). There is a general sense of genetic instability as a root cause of some of them, but the details of that have not been worked out.
Clinical significance: MDS usually presents in elderly patients, and for some of them the condition does not affect actuarial survival – meaning that in some cases our therapies will harm rather than help. But for others the condition carries higher risks, and for some of those there are effective therapies available.
What are the five major adult forms of myelodysplasias? Best to worst prognosis.
-Refractory cytopenia with unilineage dyplasia
-Refractory anemia with ring sideroblasts
-Myelodysplastic syndrome with isolated del(5q)
-Refractory cytopenia with multilineage dysplasia
-Refractory anemia with excess blasts
Are there any other myelodysplasias?
Myelodysplastic syndrome, unclassifiable (Garbage can category)
Childhood MDS (Rare, complex diagnostic/prognostic issues)
What is Refractory cytopenia with unilineage dyplasia?
a relatively good player, although if it presents without cytogenetic findings there is wide variation in the proclivities of pathologists for diagnosing it.
In part that’s because some of the morphologic findings (megaloblastoid features) are nonspecific - they can also be caused by nutritional deficiencies, drugs, or HIV. And in part it’s because the morphologic features can be hard to recognize.
Diagnosis of Refractory cytopenia with unilineage dyplasia depends on what?
Clinical presentation of Refractory cytopenia with unilineage dyplasia?
unexplained cytopenia, usually elderly patients (65+)
Prognosis of Refractory cytopenia with unilineage dyplasia?
not much less than normal; rarely progresses to AML
same in refractory anemia with ring sideroblasts
What is diagnosis of Refractory anemia with ring sideroblasts dependent on?
morphologic findings and iron stain results
Is cytogenetic analysis normal in Refractory anemia with ring sideroblasts?
No, trisomies/monosomies may be present
Clinical presentation of Refractory anemia with ring sideroblasts?
unexplained cytopenia, usually elderly patients (65+)
What is unique about morphology in Myelodysplastic syndrome with isolated del(5q)?
all megakaryocytic are mononuclear
Are cytogenetics normal in Myelodysplastic syndrome with isolated del(5q)?
show ONLY loss of the large arm of chromosome 5
Clinical presentation of Myelodysplastic syndrome with isolated del(5q)?
- usually women, 65+ y/o
same in refractory cytopenia with multilineage dysplasia
Prognosis of Myelodysplastic syndrome with isolated del(5q)?
good median survival; 10% progress to AML
What can Myelodysplastic syndrome with isolated del(5q) be treated with?
What is unique about the morphology of refractory cytopenia with multilineage dysplasia?
affected granulocytes don't granulate normally; nuclei don't lobulate normally
Prognosis of refractory cytopenia with multilineage dysplasia?
median survival is 30 months- not good treatment options available
What is refractory anemia with excess blasts?
5% - 9% morphologic blasts (RAEB-1)
10% - 19% morphologic blasts (RAEB-2)
About half show nonspecific cytogenetic abnormalities
Clinical presentation of refractory anemia with excess blasts?
usually in 65+ y/o
Immunophenotype in refractory anemia with excess blasts?
blast population (CD34+, and/or CD117+) usually evident