CASE IS OPEN FOR DISCUSSION:  
 
33 yrs old male with some teeth irregularities.  
CLIN HISTORY: non healing anal fissure, oral infections (post extraction of teeth), mediastinitis.  
EPISODE 1: In 2018 bone marrow biopsy taken: MDS-EB1. CD34+ blasts elevated 7-8% and visible in IH.  
Molecular: Karyotype normal. No defining AML mutations found.  
Clin: Fever, oral ulcerations, in flow/aspirate: MDS changes + ~8% blasts: CD45+ dim; CD34+; CD38+ het; CD117+ het; HLADR+ CD13+ CD33+ CD11c+ het; cMPO+ het; CD5+ dim; CD7+ dim; CD4/CD11b/CD14/CD36/CD56/CD64/sCD3/cCD79a(-).  
TREATMENT: transfusions only.  
 
EPISODE 2: After treatment another threpine was taken with DIAMETRALLY other picture: expansile NASDE+ immature atypical granulopoiesis with depressed or extinct erythros and megas (as in AML cases).  
But IH anonymous:  
MPO+ immature granulopoiesis with majority WT1 (++), CD99(+/++); p53 (+++); CMYC(++/+++) 70%; ERG1 (+++) 100%; CD2(-); CD30(-); CD14(-); CD15(-); CD2/CD5(-); CD56(-); CD4(-); CD11c(-).  
 
FLOW: to be contd (NO DEFINITE BLASTS in the window, but immunophenotype atypical); ~32% young, myeloid cells with abberrant phenotype: CD45+dim, CD34-/+dim (nonspec), CD13+, CD33-/+dim, CD11a+het, CD15+het, CD38+het, HLA-DR-/+ partial, CD56+dim, CD99+dim, CD123+dim, CD133-/+dim, cMPO+ strong, CD7-/+ dim (nonspec?), CD117-, CD11b-, CD14-, CD36-, CD64-, CD96-, CD2-, NG2-, TdT-.  
Not expressing blastic promyelocytic Ags (CD117), abberrantly express CD56, CD99, abberrantly diminished maturation Ags CD33, CD64.  
Additionally ~5,8% CD34+/CD117+ abberrant myeloblasts.  
 
PB:  
WBC (*10^9/l) 1,17 (4,0-9,8)  
NEU (*10^9/l) 0,10 (1,5-6,0)  
RBC (*10^12/l) 3,00 (Male 4,3-5,8)  
HgB (g/l) 90 (Male 128-160)  
Plt (x10^9/l) 52 (140-450)  
 
VULSK aspirate:  
Blasts (threpine) 7,5  
Blastai (marrow.) 5,0  
Siderocytes and sideroblasts 30%, ringed ones 8.  
 
MOLECS: Complex karyotype (7 abberations): 3q, 5q, 6p, 7q deletions, 8 trisomy, 19 monosomy and 15q duplication.  
Bad prognostic group.  
Telomere length NORMAL. Chromosome breakage: NO.  
NGS TSM: TP53 c.857A>C (p.Glu286Ala) mutation.  
 
2 pathogenic mutations of SBDS gene found (Schwachman Diamond anemia): to be more specified soon.  
 
DIAGNOSTIC QUESTIONS:  
1. How interpret EPISODE 2 (AML? Immaturity? No MDS features; depressed mega/erythro) especially comparing with "classic" MDS EB1 in EPISODE 1.  
2. Do immunophenotype CD99+ WT1+ ERG1+p53+CMYC+ only is specific/enough for " NASDE+ BLASTS"/AML or possible in "immature" inherited SD hematopoiesis?  
ThankYou.  

tzankov 2019-06-20 09:38	What kind of treatment has been given between episode 1 and 2?   Can you sequence TPT53 at episode 2?   Was the complex karyotype obtained at 1. or 2.?   Independet of our considerations donor search shuld be considered...
ugnius 2019-06-20 10:08	1. I will check out therapy mode asap.   2. At first 2018 karyotype was normal, no defining AML mutations found.   3. Complex karyotype found on my "immature granulopoiesis" (episode 2).   4. They are preparing alo Tx.   5. I will chek with p53, not sure.
ugnius 2019-06-20 10:54	No specific treatent, except transfusions. Because: non healing anal fisure, oral infections, previously mediastitis, etc.
ugnius 2019-06-20 12:27	p53 NGS was not sucessfull- 'll be repeated.
tzankov 2019-06-25 11:45	well we can assume form what we know that we are dealing with a MDS arising in the background of Schwachman Diamond syndrome
ugnius 2019-06-25 12:57	Please find FLOW and TP 53: NGS TSM: TP53 c.857A>C (p.Glu286Ala) mutation.     Additional quest: a quality of MDS-EB is changing and no signs of erythroid or mega dysplasia, EXCEPT massive "left shifted" and abberant myeloid expansion.     something happens and slightly MORE than MDS by my eyes (in NEW molecular context)....
ugnius 2019-06-25 13:04	If we count ALL abberant cells by flow- "young immature 32%"+ blasts ~7%, easily got 40%- practically the same number visible NASDE+ MPO+ immature cells occupying BM....
tzankov 2019-07-01 08:37	I think we have to consider the "hard facts":     Schwachman Diamond syndrome with komplex karyotype and pathoegenic TP53 mutation as well as 7-8% blasts: all these quailify the patient for the diagnosis of a high-risk myeloid malignancy in the backgroudn of an inherited BM failure disease, at the moment MDS-EB1.     In addition in the CD45dim gate there is a population with a monoblastic differnetiation that appears immture and atypical on histopathology, as there is a Delta between the CD34+ "blasts" and the TP53+ atypical cells. The question is if these cells are "blast-equivalents" or part of the MDS clone... this should be judged in an integrative way taking into consdieration the aspiration smear (atypical monocytes? monoblasts? pro-monocytes?) and additional stainings for CD11c and CD56 on the biopsy. How do the FACS people interprete the flow results?
ugnius 2019-07-01 08:48	ON HISTO "blasts": CD4/CD56(-).     FLOW Comment: "Cells immature, but without blastic/promyelocyte early Ags as CD117, abberantly expressing CD56, CD99. Abberrantly diminished maturing myelocytes Ags as CD33, CD64.   Additionally detected ~5,8% CD34+/CD117+ abberrant myeloblasts, which vey similar to immature cells.   Without typical blastic markers, immature immunophentype more close to abberrant promyelocytes."     So I gues they MAY BE be counted as "blast equivalents"... (due to DIFFERENT picture comparing with classic RAEB presentation earlier and molecular shift...
tzankov 2019-07-01 10:28	Difficult issue. The question is what the difference in the clinical management will be if you designate the case "AML in the context of inherited cytopenia sydrome" or "MDS-EB1 in the context of inherited cytopenia sydrome": more intesnive induction prior to allo-SCT? In the case of "usual AML" this will be the case...I am not sure if this is also optimal in inherited cytopenia sydromes, esepcially if we are not 100% convinced how to classify the immature cells...would this increase the chances of cure or select an induction-resistant clone? I don't know. Please discuss these issues with theh treating physicians. I am curious to hear their thoughts.
ugnius 2019-07-02 10:41	Last IH: immature population CD11c(-).
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