OC (Study No. 30089) is a 5-year-old boy referred on account of a 2-week history of severe pallor and high grade fever. Examination revealed pallor, significant peripheral lymph node enlargements and hepatosplenomegaly (6 and 10 cm BCM respectively). Blood counts showed PCV - 13%, WBC – 920,000/µl (lymphoblasts 97%, neutrophils 3%, slides 3 - 6), Plt – 124,000/µl. Lymphoblasts were uniform, with cleaved nuclei, open chromatin and deeply basophilic vacuolated cytoplasms. Similar cells were found constituting >95% of the nucleated bone marrow cells. CSF samples also revealed significant malignant pleocytosis (slides 1 & 2). Features were in keeping with acute lymphoblastic leukemia (FAB L3, i.e. Burkitt-type).
 
Serum chemistry was essentially normal. He was then commenced on hydration, allopurinol, supportive red cell transfusion, and the 14-day-cycle COM regimen (as used for Burkitt lymphoma: IV cyclophosphamide 1.2 g/m2, IV vincristine 1.4 mg/m2 and IV methotrexate 75 mg/m2 on Day 1; IT methotrexate 12 mg days 1 & 8, and IT cytarabine 50 mg day 4). By day 6, repeat blood counts were now PCV - 32%, WBC – 600/µl (mature lymphocytes 80%, neutrophils 20%), Plt – 40,000/µl. Platelet concentrates and prophylactic antimicrobials were commenced. At the end of the 1st cycle, blood counts were PCV - 24%, WBC – 1,600/µl (mature lymphocytes 85%, neutrophils 15%, no blasts), Plt – 55,000/µl.
 
Second cycle had to delayed for 10 days, until absolute neutrophils counts reach 1,040/µl. Repeat marrow aspirate at the time of starting 2nd cycle showed normal myeloblasts <1%. He is presently stable and doing well in remission, and is scheduled to receive 6 cycles of the COM+IT regimen.

hurwitz 2011-01-19 21:34	Thanks for sending the images. The Giemsa stain on images 4,5 and 6 is very nice. Images 1,2 and 3 seem to have been taken from the thick end of the smear and are difficult to read. The blasts are quite pleomorphic. Some of the larger blasts show Burkitt like features. I think the blasts are too pleomorphic and the Burkitt like features are not prominent enough to call it ALL, Burkitt type.The findings are consistent with an ALL; probably B-ALL, which cannot be further classified by morphology.   Do you have a chest x-ray ? If yes could you please upload it?   We will ask for additional opinions.
leoncini 2011-01-20 13:35	I completely agree with the ommentsof Dr Hurwitz
hurwitz 2011-01-24 20:31	As an amateur pathologist I would comment that I can see why this might well be called L3-ALL (BL) - there are frequent cells with cytoplasmic vacuoles and the cytoplasm often appears dark blue in color. Vacuoles, however, do not define BL and can be seen in many rapidly growing lymphoid and even non-lymphoid tumors. There are, on the other hand, quite a few small and intermediate size tumor cells (i.e., much greater pleomorphism as mentioned by Dr Hurwitz)with pale cytoplasm and no vacuoles, which look like typical ALL cells. To me, the chromatin pattern is too dense for BL, without clear fenestration and nucleoli are difficult or impossible to see in the majority of cells. As one can see by looking at the granulocytes, the staining is not perfect, which makes an absolutely definitive diagnonsis impossible, but primarily because of the pleomorphism and chromatin appearance, I too would weigh on the side of ALL - probably what would have been once called FAB2 ALL. The clinical findings are consistent with either disease. The initial good response to therapy would also be expected with both. This is, however, a rapidly growing tumor with a two week history. I presume the statement of "cleaved" cells is a mistake - I don't see any, and BL is a NON-cleaved lymphoma, but it could be that these were visible on the microscope. If so, this would actually favor a T cell ALL. Immunohistochemistry would have been useful, and higher quality of staining and photography would have permitted a more definitive diagnosis. If multiple slides are available, it might be worth send one for direct microscopy.
hurwitz 2011-01-24 20:37	The previous comment was by Ian Magrath, not Nina Hurwitz
Githanga 2011-01-24 20:54	The blasts look too pleomormorphic for typical BL even though in some smears it is at the thick end. I favour a B-cell ALL although immuno would certainly help.
imagrath 2011-01-25 10:47	I wonder whether we should not either universally use the WHO classification, or indicate alternative nomenclature. The reason I raise this point is that pediatric oncologists use the term B cell leukemia for L3 or Burkitt leukemia. In the WHO classification it is used for precursor B cell ALL. While it is regretful that the pediatric oncologists have used this term, it is scattered throughout the literature. It is a rare ALL (otherwise typical morphologically for ALL that expresses surface Ig. I am sure the pathologists are using the term B cell ALL in the WHO classification sense, but pediatric oncologists may not be aware of this difference in terminology - unfortunately, as part of the modern disease, few specialists read what other specialists write. Would anybody like to comment on this?
leoncini 2011-01-25 15:20	[comment sent by email on Tue, 25 Jan 2011 14:03:48 +0000 (GMT)] I agree that the terminology of the WHO classifiaction would be adopted both by pathilogist and pediatric hematologist
mdurosin 2011-01-25 19:17	The diagnosis is very much like B-cell ALL (L3) , which some of us take as Burkitt ALL, and we often treat as such.     This child has done very well on the Burkitt regimen, he is into 2nd cycle. We will watch him very closely however, and change his therapy as required. From our experience, the patient may not require the maintenamce therapy as 6-mercapto and methotrexate as for other ALL. We would rather give six cycles of the COM regiment, with IT prophylaxis.     I do not aggree we are dealing with a T-cell ALL. Immunohistochemistry would be most useful in this case
hurwitz 2011-01-26 17:12	I agree with Ian Magrath's suggestion that this case does fit into the category formerly called ALL FAB2. Of course it would be ideal to prove the immonophenotype with immunostains, but we are not dealing with an ideal situation. Considering the clinical presentation, I think we have enough arguments to feel comfortable with the diagnosis of an acute lymphoblastic leukemia FAB L2, which corresponds to Precursor B Lymphoblastic Leukemia in the WHO Classification.   I also agree with Ian's and Lorenzo's suggestion to try to use the WHO Classification, but I think we should use both, the FAB together with the WHO Classification,since in particular in African countries, the WHO Classification has not been widely used yet.
Githanga 2011-01-27 20:32	I agree it would be ideal to use the WHO classification, however, as Nina pointed out it is not as widely used in our set-up as is the FAB classification due to unavailability of flow/immuno stains. It would be advisable to use the two.
mproytch 2011-01-28 16:44	Thank you for this interesting case that pose such a difficult diagnostic dilemma. Morphologically the blasts vary in size, have oval to irregular nuclear contour and moderate to abundant amount of cytoplasm. Cytoplasmic vacuoles are present, but as many of you had pointed out, those are non-specific. No immunophenotyping, cytochemistry, or cytogenetic studies were possible to determine the nature of these blasts. If unstained peripheral blood smears are available, FISH for t(8;14) would be helpful to exclude BL. I wonder whether it is not possible such study to be done outside of Nigeria.   The major diagnostic dilemma is lymphoblastic leukemia, B or T, versus Burkitt leukemia (BL). Based on the morphology, such a distinction is not possible. However, the clinical presentation and laboratories may be more helpful to make such distinction. T-lymphoblastic leukemia can present with hepatosplenomegaly (HSM) and lymphadenopathy (LA), though mediastinal mass is more characteristic, and may present with such a high WBC and normal chemistry. B-lymphoblastic leukemias present with HSM, LA, peripheral blood cytopenias and blasts, but such a high WBC would be very unusual and the LDH or other chemistry most likely will be abnormal. On the other hand, for Burkitt leukemia such a high WBC would be very unusual. Furthermore, BL with such high tumor burden will most likely present with renal failure by the time the WBC is so high.   Thus, based on the morphology and clinical presentation of this child, I more favor lymphoblastic leukemia than BL. Either way, this is a high risk leukemia due to the high WBC that will require a proper therapy.
diane.c.farhi 2011-01-28 17:35	I apologize for the lateness of this comment. I don't see any report of flow cytometry. Without that, we don't know whether this is AML or ALL. Some AML cases do show these morphologic features. This needs to be resolved before assigning a definite diagnosis. Otherwise, the diagnosis is simply acute leukemia.
SergeyN 2011-01-29 20:32	I wholeheartedly join Dr.Farhi's comment, you cannot be too careful with childhood AL.   First, cytologically it is not a typical Burkitt, there is a well seen small blast cell population without vacuoles, vacuoles themselves are much less conspicuous, the nucleus structure is evidently blastic.   Second, if flow is absent, a simple myeloperoxidase stain (that costs about 50 cents) should have been performed before the treatment. It seems that in this case the stars were on the child's side, for 85% of childhood AL's are lymphoid. Still, the next time might be not so lucky.
diane.c.farhi 2011-01-30 01:07	I agree with SergeyN (I'm sorry I don't know your full name; please send it).
hoellers 2011-01-31 10:08	I understand the concerns of Dr. Farhi and Dr. Nikulshin, however, we have to keep in mind, that we, as Dr. Hurwitz pointed out, don't have access to additional examinations. That meens the clinicians have to make a decision based on what we have here.
hurwitz 2011-01-31 13:40	Thanks Sylvia, for your pragmatic comment hitting the heart of the matter. The circumstances we are faced with force us to compromise. The big question is when, where and the extend of the compromise.
SergeyN 2011-01-31 15:32	Dear Nina, myeloperoxidase actually is probably cheaper than cytological stain. It is extremely simple technically, though products are toxic (simple precautions will be necessary). There is no need of a special staining kit, for all components are easily obtainable.     PAS is the second simplest thing, though it isn't so informative, particularly in children.     Esterases are more difficult, but still manageable.     What I see from the patient's history is that the clinic in question has access to automatic hematology analyzer, bone marrow and CSF cytology, chemotherapy, antibiotics, red cell and platelet transfusions; that indicates availability of some funds and expertise. So, to try to save several cents on diagnosis or not to bother with easily obtainable crucial information is a wrong approach.
hurwitz 2011-01-31 15:56	Dear Sergey, I completely agree with you. In fact we are trying to introduce MPO, PAS and Sudan black at one African center. These classical stains should be much more widely used. Unfortunately it is not easy to persuade people to use such simple and cheap methods, if there are more impressive methods around
diane.c.farhi 2011-01-31 22:48	I agree that the MPO, and to a lesser degree PAS, are cheap, easy, and usually answer the question. If no access to these stains is possible and no Auer rods are present, then one must resort to treating for the statistically most common possibility. In a child of this age, the most common possibility is ALL. However, the diagnosis is still acute leukemia until more specific methods are used.
hoellers 2011-02-01 11:01	To sum up the case:     Acute leukemia, most probably acute lymphoblastic leukemia (cytologic criteria and clinical presentation only).     For further discussion I refer to some excellent comments.
raphael 2011-02-04 20:23	My opinion is very late, but I agree with all the very good comments     I favor the diagnosis of acute ALL (which is not FAB L3) and I also emphasize the comment from Nina to introduce MPO at least, that would be very useful inthe diagnosis of acute myeloid leukemia with minimal differentiation as it is describe in the WHO classification
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