LT TELEPATOLOGIJA

Appologies: I cannot paste info up to the moment into case due to strange technical problems...

All things are placed there.

I do not understand this case: there is CD3 positivity and clonal TCR beta which would indicate T-cell origin and also clonal IgH but no clear cut B-cell markers. Light chaon restriction difficult to evaluate - can you test light chain retriction by PCR? Did you check plasmacell markers such as CD138 and/or MUM-1?

Dear Ugnius,  
 
a difficult case. In my opinion there is no doubt about the CD3 positivity. I completely aggree with Dr. Porwit, that there must be some more arguments for a B-cell origin of the lesion. Maybe ISH of light chains may help (IHC hard to interpret) and also markers of terminal B-cell differentiation (MUM1p and CD38).

Dear Ugnius,  
I agree with the diagnosis of undifferentiated EBV+ lympho-epithelial carcinoma of the stomach.  
In the lymph nodes there is  
(1) hemophagocytosis (EBV-drvien? would you check for replicative ibfection by performing EBNA-2 staining? clinical paramteres of hemophagocytosis?),  
(2) Castlemann-like follicles (would you perform IgM/IgD/IgA/IgG and cyclin D1 stainings? Plasmablast are often IgM+/cyclin D1+) and  
(3) sheets of "plasmablast-like" with expression of CD3. Considereing the latter, there are still too few argumants to call them plasmablasts; stainings like Cd138, MUM1, CD38, vs38c, CD56, heavy chains, cyclin D1 might add arguments considering their lineage.  
Considering the clonalites, especially in productive EBV infection you can detect T-cell clones, this might explain why you detect the Beta, but not the Gamma.

Thank you for comments. Add IH are in progress (Cyclin/CD56/IgM/IgD/Mum1). Only I have. The first idea was about CD3+ folliculotropic T NHL, but you never find a definite variant for that (so called folliculotropic T lymphoma related to AILT has typical "non-immunoblastic" appeareance). So I begun to think, that CD3+ (medium level dispresed) reaction is SINGLE positive in T panel and most probably ABBERANT. After that I've found dim CD79a and single cells Ig lambda. Additionaly I jus made a proposal regarding EBER in gastric tumor and congruentally in NHL. Both was positive. And HHV8 positive too. So in the moment I cannot find ANY nosology, except mentioned above, to group these findings. We will procede further soon. Thank you one more time.

look at PMID: 12384445  
KSHV- and EBV-associated germinotropic lymphoproliferative disorder  
looks similar to what you have...

Yes, I mean the same:  
"AFTER REVIEW COMPLEX DIAGNOSIS: .... High grade B plasmablastic lymphoma in peripheral and perigastric nodes: so called "germinothropic lymphoma", Possibilities: HIV asociation? extracavitary PEL? DLBCL, plasmablastic, multicentric Castlemann disease asociated?"  

and this  
 
PMID: 17613780  
KSHV- and EBV-associated germinotropic lymphoproliferative disorder: a rare lymphoproliferative disease of HIV patient with plasmablastic morphology, indolent course and favourable response to therapy

the only "problem" with the phenotype is CD3, therefore I would wait for the additional stains (heavy chains etc.)

I will follow all recomendations with IH I have there. Thank you a lot for "targeting" and support.

Plasmablasts: Mum1+ 100%, IgD(-), IgM+ 60%, CyclinD1(-). IF IgA/IgG will be later as Castlemann like follicles. Really I think that plasmblastic lymphoma (extracavitary PEL) diagnosis is argumented enough? The patient is HIV(-) and quite well now (rehabilitation after gastro-resection). Hematologists are thinking about future therapy...

would you be so kind to upload one MUM1 and IgM image?

Today all things will be uploaded. I'm sorry for delay.

Please find interestingle S100+, scattered cells CD23+ and faint Bcl2+ in virtual slides.

Please find the lats Mum1, IgM, CyclinD1 virtual slides.

Bravo Ugnius, nicely done, IgM+/Lambda+/MUM1+/(CD3dim+) - I think, you (we) can solve the case now, this is the picture of an (HHV8?)/EBV-associated germinotropic lymphoproliferative disorder.

Thank you, Alex. But: if we have ePEL- it's aggressive/probably fatal. "Germinotropic" plasmablastic is not part of WHO classification, but after words of published case reports (I cannot reach "Leukaemia and lymphoma" full text one)- respond to classic (RCHOP now) therapy well. Clinically: he is well now (not critical at all). So I think even hemophagocytosis (due to cytopenia threpine was done at first) disapear... WHAT THE FORMAL DIAGNOSIS MUST BE? Thank you.

This is a difficult issue. I think that the clincial context of the patient should be studied more detailedly. Is there an obvious reason for immunosuppresion? Is there still replicative EBV infection? At least in that case Gancyclovir could be an issue. Is there evidence of persistent malignancy? Liver metastases? Distant metastases? Pleural effusion? Ascites? The decision to treat and what to treat first, the metastasizing gastic cancer or the EBV-associated germinotropic lymphoproliferative disorder should be made by the oncologist, who knows the patient, not by us. In Basel a patient with pN1 gastric cancer will be given in not neoadjuvant, then at least adjuvant chemotherapy. Her2Neu testing of the gastric cancer would be an issue as well, but nobody knows what to do with the EBV... Considering the lymphoma, at least from what is reported germinotropic lymphoproliferative disorders are not as aggressive as PEL (interestingly we have here a HIV+ patient with PEL, who is still alive 2.5 years after being given aggressive therapy). One can speculate here that for whatever reason of immunosuppression and lost control over virus, EBV triggered a gastric cancer and probably for the same reasons an EBV-associated germinotropic lymphoproliferative disorder, which might also become controlled, while decresing the gastric tumor load, as obviously hemophagocytosis did. Nevertheless the clinicians have too look for the parameters mentioned above to make a decision. By the way, since the EBV-associated germinotropic lymphoproliferative disorder is CD20, what will be reason to add R? To prevent further EBV B-cell infection?

Thank you once more time. All interested med-persons was informed about.

Although for some reason I could not open many images to review the findings, I agree that findings are compatible with KSHV- and EBV-associated germinotropic lymphoproliferative disorder. The only comment I have is that the CD3 positivity appears to be cytoplasmic only in diagnostic cells while it is membranous in normal T cells. If this is really the case there are two possible explanations: 1. cCD3 is not lineage specific and should not be interpreted as definite evidence of T cell differentiation, and 2. cCD3 positivity is in my experience not so unusual as a non-specific background with some rabbit monoclonal CD3 Abs (cannot remember the clone name right now). I have seen it with carcinomas, sarcomas, and B-cell lymphomas.

Thank you. Fortunatelly I have only single cases with such CD3 "positivity", usually it works "correctly". The patient arrived for hemato evaluation: I will inform you about future therapy tendentions and situation.

HIV status: negative.

The last point: gastric tumor HER2(-). It was decided not treat with chemo gastric one (possibly good prognosis) but discuss about possible treatment of PL. The patient is in hemato dept and quite well. We are not sure about aggressive chemo. He had hemophagocytosis close to another 2 diseases at time of diagnosis.  
Thank you all for discussions.

Thanx, Sylvia reminding me: HHV8 was positive (PGR) from perigastric LN sample (with lymphoma). Infortunatelly I have not HHV8 marker (IH).

Dear Dr. Michys, dear Ugnius  
 
Thank you very much for sending me this very interesting case. Considering the lymph node one can detect a folliculotropic and perifollicular infiltration by plasmablast. The plasmablasts are all positive for Epstein-Barr-virus RNAs in the insitu hybridisation as well as for the LANA antigene of HHV8. There is no productive EBV infection since the EBNA2-staining remains negative. At least in the submitted lymph nodes there is no infiltration by cytokeratine positive tumour cells. Considering the lacking history of previous Castlemann's disease as well as the morphology in the huge proliferative activity of those plasmablasts as documented on the Web, I would suggest diagnosing here a diffuse large B-cell-lymphoma. Formally the present disease does not fit any of the WHO suggested entities since plasmablastic lymphomas should be consistently negative for HHV8, while large B-cell lymphomas arising in HHV8 associated Castlemann's disease should arise in the setting of a multicentric Castlemann's disease. Considering the describtion of Qu et al. Blood 2000, Vol. 100, Page 3415, the present case does not fit the diagnosis of EBV and HHV8 associated germinotropic lymphoproliferative disorder since it is monoclonal by PCR.  
 
Even more interesting in this patient - the second preparation you have send - namely a moderately and poorly differentiated gastric carcinoma with infiltration of the submucosa. At least from the pictures on the Web all tumour cells appear to the infected by EBV, which fits to the original data for EBV association in gastric cancer. HHV8 is not present in the gastric cancer. The lymph nodes above are devoid of cytokeratine positive tumour cells. Considering this issue I kindly refer to Fukojama, Pathol Int. 2010, Vol. 60, Page 337.  
 
It is tempting to speculate how the sequence of events in this patient should be understood. Considering the co-infection of HHV8 and EBV in the lymphoma cells and the infection by EBV only in the carcinoma cells a common cellular origine of both tumours seems to be excluded. A common denominator of both tumours would be immuno-suppression or an immuno-genetic defect in the host defence against viruses. Interesting in that consideration would be the clinical history in the family anamnesis of the patient.  
 
Final diagnosis:  
963:  
Lymph node:  
Infiltration by an HHV8 and EBV positive plasmablastic large B-cell lymphoma, reminiscent of EBV and HHV8 associated germinotropic lymphoproliferative disorder.  
 
Final diagnosis:  
964:  
Stomach:  
EBV-associated, poorly differentated gastric carcinoma.  

Dear Alex. Thank you for the "final cut" of the case.