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Leukemia, Lymphoma, Wilms Tumor, Neuroblastoma and Other Solid Tumors

Acute lymphoblastic leukemia. So it’s not just leukemia but it’s acute lymphoblastic leukemia. For this kind of leukemia, the peak age is four-years-of- age and half of all the patients have each one of these things; fever, pallor, lymphadenopathy, and bleeding. There’s organomegaly and hepatosplenomegaly in two-thirds of the patients and they can often have bone pain in the long bones. You can see these leukemic lines at the metastases. Now the bone pain is because of the leukemia. The marrow cavity is growing so fast that it actually pushes on the periosteum and these patients have tenderness when you press on their leg. Prognostically, a day 7 bone marrow is very highly prognostic. So even after seven days, if you’ve managed to clear your leukemia from the bone marrow, even though the therapy goes on for 2-3 years, those patients will end up doing better. The other thing is age. Between 2-10 years of age, that’s like the golden years of ALL. Like if you had to have ALL it would be best to have it during 2-10 years of age. The worst is less than one-year-of-age and these patients are bi-phenotypic, they have CNS, bulky disease.

In terms of the facts and little things they will pump you with, ataxia telangiectasia patients have an increased risk of ALL, but the way that I would remember it is, all these other things have an increased risk of ANLL, or the non-lymphocytic leukemia. Things like Klinefelter’s, Fanconi’s anemia, Costmans granulocytopenia, Schlockman, neurofibromatosis and Bloom’s syndrome.

T-cell malignancy. They can have massive hepatosplenomegaly or massive lymphadenopathy. That’s the lymphoma part. But they also have circulating blasts just like leukemia.

Other presentations of ALL is the aplastic presentation. Here this girl presents with a two-week history of pallor, weakness and petechiae, and her white count is only 3.1. Actually, although you might think of leukemia as having a high white count, half of all patients with ALL have either a normal or low white blood count. But the tip-off is that these patients are usually neutropenic. The other thing they have is low hemoglobin in 80%. And three-quarters of patients with ALL also have low platelets.

Here we have tumor lysis syndrome. A six-year-old girl starts chemotherapy with a high white count and now her kidneys are shutting down and her EKG is going nuts. Usually starts within 24 hours of therapy and lasts 4-5 days. In the olden days, when

AML is where you really see a high white blood count. Not just greater than 100,000 but easily 8, 900,000, 1.2 million is about the highest I’ve seen for AML. They get this thing called hyperleukocytosis. See, blasts are really big and fat and they don’t squeeze through the tiny capillaries as well as regular white blood cells. And then when your white count gets to be about 900,000 the blood is very viscous so it sludges and that’s why you get a headache because that’s like a little stroke basically, blurred vision, respiratory distress from the sludging of these white blood cells.

All right, case three is CML and it turns out - this is that 14-year-old boy with splenomegaly, just isolated splenomegaly - they say in the western hemisphere that CML is the most common cause of isolated splenomegaly. Well, if you have mono or something then you have a sore throat, fever, lymphadenopathy, but if you just have splenomegaly then that’s CML most likely. Mean age is in the mid-40’s but in the pediatric age group we can see this in teenagers. The key diagnostic point is persistent neutrophilia without infection. If you do a dip on these people you see peaks at segs and also the myelocytes. And we call that the myelocyte bulge. The other thing you can see is absolute basophilia. We can draw this X here, and see these cells here? This is a metamyelocyte but all these guys here, they are all myelocytes. This is peripheral blood, by the way. So it’s full of myelocytes and segs and bands. This is what we call the myelocyte bulge, and here is a basophil even. How obliging. Unlike acute leukemias, CML patients don’t have low platelets. They actually have high platelets. They have a chronic phase. CML is kind of interesting in that you can go around, walk around with CML and not have that bad of a life. You may take a little oral medication, you may not need anything. Your spleen might be big, it may not, but you can’t be distinguished just by physical exam from somebody who is sick. It’s just like there is this clock inside of patients with CML so that after about 3-5 years the alarm bell rings and then they change. They enter this thing called the accelerated phase and then they turn into acute leukemics. All of a sudden they will have a high white count, they will have low platelets, and then at that point their disease is untreatable.

How do you diagnose this stuff? There is something called a leukocyte alkaline phosphatase score, or LAP score. It is low in the chronic phase. Patients with leukemoid reactions - you know, left shifts common with Down’s - they have normal to elevated LAP scores. The other thing is CML patients may have increased serum B12, and I actually don’t know why that is. Now these are the prognostic indicators and these sort of say how long it will be before that alarm clock rings. Is it going to be shorter than three years, or longer than three years? Massive hepatosplenomegaly, high white count, blasts, nucleated red blood cells, or a platelet count that’s either really high or really low, if you have those things, those things tend to indicate that your alarm clock will ring sooner rather than later.

Like I said, the median survival is 3-5 years, usually ends in blast crisis. And there you have thrombocytopenia. The treatment of this is allogeneic bone marrow transplant in the chronic phase, and you need a bone marrow transplant to fix this. The reason is that CML is a stem cell disease. That is, every single cell in this bone marrow is part of the leukemic clone. Even if it’s a red cell precursor, it’s still part of the leukemic clone. I mentioned isolated splenomegaly, the Philadelphia chromosome is diagnostic of CML. This 9-22 reciprocal translocation involves oncogenes called BCR-abl. It forms a fusion gene. This gene is tyrosine kinase that has a very promiscuous function, and right now in clinical trials there are tyrosine kinase BCR-abl inhibitors for the treatment of CML and they’ve been showing really great promise. So we can actually molecularly target these things now. Again, if it doesn’t have this, either by chromosomes or molecular, then it’s not CML. And like I said, because this is a germ cell problem, if you looked at a red cell precursor in the bone marrow in somebody with CML, you will find a BCR-abl 9-22 translocation, even though this is a myeloid malignancy.

A twist on CML is juvenile CML. Usually these patients are less than two-years-of-age. They do not have the Philadelphia chromosome. They do have hepatosplenomegaly, lymphadenopathy, but unlike adult CML these guys right off the bat are thrombocytopenic. A diagnostic factor for juvenile CML is fetal erythropoiesis. They can have increased hemoglobin F, so that in these patients they will have persistence of hemoglobin F even beyond the neonatal period. Normally once you are past the neonatal period every one of us makes capital I antigen, but these people still make little-i antigen. And there’s a differential diagnosis of Langerhans cell histiocytosis, which I’ll cover at the end. Oh, what does this guy have? Burkitt’s.

Burkitt’s lymphoma. This is that boy with the right lower quadrant mass. This is the sporadic Burkitt’s. The guy with the big cheek, that was African Burkitt’s. But about sporadic Burkitt’s, abdominal pain and right lower quadrant mass is seen in 50% of these patients. Often presents with inguinal adenopathy, and remember with Burkitt’s lymphoma, this kind of lymphoma.