General comment:  clinicopathologic features of NHL as a consequence of immunosuppression

 

 Assessment of EBV in malignant cells is critical in determining whether or not a biopsy represents a lymphoma secondary to immunosuppression.  At most academic centers, EBER staining is the standard (RNA probe bound to peroxidase, resulting in “brown stain”), with high sensitivity and specifity.  Other ways of assessing EBV include EBNA-2 staining, and in situ assessment of EBV.  In the appropriate clinical setting, NHL containing EBV is almost certainly representative of an “immunodeficiency-related” NHL, either from HIV, iatrogenic immunosuppression, or idiopathic causes.  Hodgkin’s disease is somewhat different, as up to 30-40% of HD is EBV positive in several series, without clear relationship to otherwise immunosuppressed state.

            In addition to EBV staining, certain histological features are highly suggestive of immunodeficiency related lymphomas: these include otherwise unusual immunoblastic reactions, and extensive plasmacytic differentiation of malignant cells.  Immunophenotypically, these cells can “lose” standard B-cell antigens, and are often CD19/CD20 negative.

Quantitative EBV PCR is an emerging technology that may allow early, more reliable diagnosis, however additional study is required before routine clinical use.

With longer follow-up, increasing numbers of patients with immunodeficiency related lymphomas not associated with EBV have been reported. These EBV negative lymphomas demonstrate a histological and clinical presentation similar to immunocompetent subjects, however, clinical outcome was poor, with a median survival of only 7 months.  T-cell NHL, unrelated to EBV or HHV-8, also appears to be increased late after solid organ transplantation. A single case of EBV-negative primary effusion lymphoma related to HHV-8 has been reported in a cardiac transplant recipient with a history of Kaposi’s sarcoma.

 

            Despite these principles, in many cases a clinico-pathological correlation is necessary to implicate immnunosuppression as an etiology of NHL.  Clinical features including “effusion lymphomas”, extensive extranodal disease, CNS involvement, in the setting of immunosuppression may be suggestive. 

 

PATHOLOGICAL EVALUATION OF immunodeficiency related lymphomas.

 

Routine histology: polymorphic or monomorphic population.

 

EBV status: LMP-1 and EBER.

 

Clonality of T cells, B cells and EBV.

 

Therapeutic markers, including CD20

 

NHL as a consequence of immunosuppression has several unique features, which differentiates it from NHL in the immunocompetent host.  Most patients present with lymphadenopathy or a mass, however extranodal involvement, a poor prognostic indicator in large cell lymphoma, is often present.  In many series, isolated extranodal disease is the most common presentation of PTLPD, and similar to HIV related lymphoma a minority of patients have disease confined to the lymphatic system. CNS involvement occurred in 22% of PTLPDs in a registry experience of over 1000 patients. Other common extranodal sites include the lung and gastrointestinal tract, which may be associated with a better prognosis.  Again, despite these “rules”, I’ve seen lymphoma in the immunocompromised setting occur as stage I disease. 

 

 

 

Case 1:

 

Overall comment:

More information is required to determine whether this lymphoma may be related to Elidel cream. 

 

 

Additional information requested: 

Formal pathology report would be critical.  “Histiocytic lymphoma” is outdated terminology, and it is impossible at present to determine whether or not this pathologic description suggests a lymphoma as a result of systemic immunosuppression or not. Additionally, the treatment interval seems short to result in the “remission” described.

 

Concomitant medications, and any past steroid use for eczema would be other helpful information.

 

Causal relationship to Elidel cream:

Unable to comment.

 

 

 

Case 2:

 

Overall comment:

This case is unlikely to be related to Elidel cream.

 

Additional information requested:

None.

 

Causal relationship to Elidel cream:

Unlikely related. 

 

Why not related:

The histology (lymphoblastic NHL; T cell type) is not commonly associated with immunosuppression, and is not atypical for a child of that age.

 

 

Case 3:

 

Overall comment:

More information is required to determine whether this lymphoma may be related to Elidel cream. 

 

Causal relationship to Elidel cream:

Unable to comment.

 

 

 

 

Case 4:

 

Overall comment:

As the histology reflects a very rare T cell lymphoma that is notoriously difficult to diagnose, I would suggest it is possible that he had an underlying evolving NHL that resulted in Elidel therapy, rather than Elidel contributing to his lymphoma. 

 

 

Additional information requested: 

Details regarding therapy (particularly any systemic therapies) for his longstanding eczema.

 

Causal relationship to Elidel cream:

Unlikely related.

 

Why not related:

Histology is very rare, and not associated to date with immunosuppression.  As this disease is notoriously difficult to diagnose, he may have had lymphoma prior to beginning Elidel. 

 

 

 

 

 

 

 


 

 

 

OVERALL ASSESSMENT (cases 1-4)

 

In my estimation, there is no “signal” emerging that topical therapy with Elidel contributed to these cases of lymphoma.  Specifically, (with the caveat of limited information), the histologies reported, and clinical presentation, are not those usually associated with post transplant lymphoproliferative disorder, or of lymphoma occurring in the immunocompromised setting.