A difficult case. Did I understand correctly, if all histopathologic diagnoses are right, the patient had a B-ALL, a PTCL, not nearly defined EBV-associated LPD and the tumor now? If this is the case, a common immune- or genetical defect should be excluded! Familial history? HIV? Ethnical background? How was ALL treated? Allo-SCT? Considering the actual case, did you stain for ALK, CD30 and EBV?

1. I have no histological data about B-LBL.  
2. I'm not quite sure about PTCL-NOS, because the survival is long and any treatment was administered (except steroids). ALL node biopsies were formulated as granulomatous lymphadenitis and in 2007 after clinical pressure (they ask about B-LBL recidive for sure) 2007 diagnosis was changed.  
3. I had no possibility to apply EBER in these years (2004-2007), but EBV LMP1 was negative.  
4. In bronchial biopsy EBV LMP1+ cells are in necrotic debris only.  
5. I was restricted in IH typing of the last tumor. But for sure I will insist my collegues to apply all deficient stains on re-biopsy material. The first step was to repeat line markers as PanCK/LCA, etc and try CD68.

CD30 was negative in node biopsies.

I'm sorry for mistyping (old story): primary disease T-LBL. About treatment: "induction chemotherapy only, high dose therapy or transplantation were not carried out".

I would recommend to have a look at all biobsies ever done, even at the LBL... does the patient have any congenital or acquired immune defects?

The patient is oligophrenic and microcephalic. Maybe the solution of this situation may be a hypothesis of Nijmegen breakage or other syndromic possibility...  
Please find some external photos of the last biopsy: the tumor seems to be ALCL (ALK1 negative). The further subtyping (T line) in progress...

Hopefully the patient will continue the treatment in our hemato dept- I will inform about future evaluations...

The puzzling picture begins to become more clear with the information on microcephalia and the detection of CD30 and at least focally of LCA. Nijmegen-Breakage-Syndrom will be an elegant common denominator, but this is not a histological diagnosis. Did you re-evaluate the T-LBL? Could you once again recapitulate, at which time which organ showed tumorous involvement? Does the patient actually have two tumors - "paraspinal" and "rebiopsy 2010", or is this a rebiopsy of the paraspinal tumor?

The last 2 episodes (biopsy and rebiopsy) deal with paraspinal tumor compressing medulla.  
The primary cannot be reviewed (any threpine or node biopsy was taken). Maybe diagnosis was made on flow and aspirate only.  
At the moment I guess NODE 2004-2007 with prominent granulomatous response diagnosis as PTCL, NOS. Because atypical CD3+ lymphoid infiltrate was scarse enough (T clonality was proved). If we confirm an existance of 3 tumours we deal with very unusual case, even in case of NBS...

His familly name shows possible slavic genesis, as I know, dominating in NBS studies.

Another problem: focal necrotic changes in the lung...

Please find: the last tumor (paraspinal): CD2+; CD3(-); CD30+; CD4(-); ALK1(-). So ALCL, ALK1 negative.

So far all histo- and cytomorphology and phenotype indicate an anaplastic T-cell lymphoma, ALK-negative in the paraspinal region. As the patient had anemnestic two previous T-cell lymphomas (T-LBL and PTCL) one should compare the T-cell clones through the three maligancies, since they might be related, particularly the assumed PTCL from 2007 and the ALCL from 2010...

Theoretically you can have Hodgkin in this setting. Though it is a bit far-reaching, could you stain for CD15 and cytotoxic molecules just to be sure?  
 
I am not completely sure, but lymphomas in Nijmegen BS are likely to be fatal, aren't they? But there must be a common determinator, by all means.

It is not easy to work yourself through all these data. I will try to summarize and give my impression:  
 
1998 T-ALL diagnosed on flow cytometry treated.  
2004/05 /07 Lymph node biopsies: similar appearance consistent  
with: peripheral T-cell lymphoma NOS, lymphoepitheloid (Lennert)  
variant  
2010 bronchial biopsy: necrotic material, no tumor.  
2010 paraspinal tumor (re-biopsy): ALCL ALK-  
 
One million dollar questions:  
1. are all these malignancies clonally related?  
2.Are only the PTCL NOS and ALCL related ? If yes, are they  
therapy related ?  
3.What is the role of an assumed genetic disorder such as  
NBS ?  
I wonder is anyone can help to solve this puzzle.

Thank you. I will compare all 3 (4? including lung biopsy) clones. In 2007 PTCL cone was detected (beta/gama). I get back the last biopsy, repeat IH. Interestingly, it seems, that the tumor has difuse CD15+: it means that it may be better to keep the last diagnosis as "PTCL NOS" after WHO criteria of ALCL ALK1(-)? I will append all "new" IH data...

Did you consider the possibility that the changes 2004-2007 and the pulmonary process now could be in the spectrum of lymphomatoid granulomatosis? that would explain dominance of T-cells and good response to steroids.  
The paraspinal tumor is probably a new event not related - did you stain for cytotoxic markers?

My dears, ALL CLONES from 2005, 2006 and 2010 both pulmonary and paraspinal biopsies preliminary are the same (beta/gama). New photos will be added soon. Due to CD15 positivity and simlarity of the clones I prefer to stay on "Peripheral T cell lymphoma NOS diagnosis"...

Dear Ugnius,  
 
this information is very important since it challanges the initial T-ALL diagnosis. With respect to the morphology of the actual lymphoma, I will designate it, despite CD15 as ALK-negative ALCL. Age and presentation would fit better with ALCL than with PTCL.

Yes, but:  
1. I have no material to prove or deny T LBL diagnosis, unfortunatelly...  
2. If we look ar "granulomatous" appearance in 2004, 2005, 2007 nodes and believe, that the clone is same, its difficult to find out ALCL histological features on that, except the last 2010 paraspinal material...

I am afraid it does not make too much sense to speculate about the real nature of the "TLBL" diagnosed in 1998. According to the flow results, the "blasts" were CD34 - and there is no information on TdT. What are the arguments for a precursor origin?

Please find molecular data (thw last word file): Nijmegen breakage sindrome was proven (first in LT). Thank you for your encouragement and influence to generate and solve the problems.

Short citation from molec's report (dr.R.Janavicius): "Sequencing data (ABI-3500): homozygous NBN gene 5 bp deletion (657del5/657del5) in proband.  
Heterozygous 657del5 deletion in probands mother (breast cancer risk allele, ~2-fold increased risk of breast cancer for heterozygous women carriers)"

Tha last photos from clinics demonstrate typical phenotype...

This is a fascinating case and your discussions so far are so helpful. I am not sure I understand the chronology of the case - was it known at the very beginning that this patient has NBS or your thoughtful questions helped to figure that out? Wow!  
 
In a normal individual such a story will be so buzzard. But in patients with underlying genomic instability often combined with immune deficiency, such as patients with NBS, developing cancers and particularly lymphomas is magnitudes more frequent. In addition to high rate of malignancies, such patient tend to have a high recurrent rate and/or can develop multiple unrelated neoplasms, lymphoma, MDS, etc.. Once treated, the role of therapy should also be considered. I think such clinical history should make us consider underlying germline mutation leading to malignancy, and should prompt to further investigation to confirm this impression.  
 
We know little about the lymphomas in such genetic instability syndromes - NBS, Bloom syndrome, AT, FA, etc. The problem is that they are so rare and very few people have experience with more than a few cases in their lifetime, if they lucky. Reports of morphologic aspects and genetics of hematologic malignancies in such patients are so rare and usually include a few patients with specific disorder. Another reason for the confusion is our constant changing of classifications and limitations of using archive material for molecular studies. But one thing we can do, as you did, think about such a possibility when a young patient develop unusual malignancy or multiple malignancy.  
 
Back to this patient – what makes him so fascinating is the fact that the lymphomas are clonally related and that there is a morphologic progression to frank anaplasia with time. This reminds me of a patient with heart transplant we had who developed 5-6 monomorphic PTLD, each subsequent one more and more anaplastic appearing. He ultimately died. Unlike this case, the PTLDs were B-cells and we have not compare the clones to see whether the lymphomas are related.  
 
Another interesting feature of this case is the patient’s responsiveness to, what I understood, limited therapy, please correct me if I am wrong. This is not uncommon in patients with cancer predisposing syndromes. Some of those also have high sensitivity and develop severe toxicity if they are treated with regular doses or radiation therapy. They are usually treated with lower doses, but the response is good. Thanks.

Dear dr.Proytcheva. Nice to hear from you. Playing as pathologist only I cannot comment on clinical course, which is sligthly atypical. Appologies for still complicated story from 1998. The main points:  
1. I have no enough documentation about primary disese (T-LBL) in 1998. Biopsy was no taken. So we cannot speculate about that. It might be PTCL with bone involvement?! But it easily might be T-LBL after published data.  
2. 2004-2005-2007 nodal biopsies originaly was diagnosed as "granulomatous lymphadenitis". After review diagnosis was switched to PTCL NOS due to impressive atypia and mollecular findings in T population between granulomas.  
3. I have no experience with NBS and cannot explain WHY the "avatar" of NBS become ALCL, ALK1(-) like...  
4. Additionally its interesting, that the same clone exists in pulmonary biopsy lacking "tumoral infiltrates" and resembling maximum "lymphomatoid granulomatosis like lesion".  
So a lot of questions left... Anyway I'm happy to deal with this first in our area case. Tyhank you.

I really think it is a facinating case and you have done a slended job putting it together all thes information together. Thank you for sharing. How is the patient now and what is the treatment plan? Thanks again.