Thanks to the readers who responded with the correct diagnosis to last week’s case! I’ve also presented this case at our weekly clinical pathology conference and I’ve found it extremely interesting and educational.
This was indeed a case of hepatosplenic T-cell lymphoma (HSTL), gamma-delta type. Characteristically, lymphadenopathy was absent and there was no peripheral involvement at presentation. Interestingly, however, the typical intrasinusoidal marrow involvement was a minor feature second to an interstitial process. Perhaps it was just caught at a progressed stage. The immunophenotype was fairly typical: CD2+, surface CD3+, CD4-, CD5-, CD7 partial dim, CD8 partial dim, CD16+, and CD56/CD57-. One reader pointed out that these lymphomas are usually CD4- and CD8-. This is true; but a solid subset will express partial CD8+ as this case did. Another interesting feature of this T-cell lymphoma is its predilection for expression of multiple KIR isoforms, for those of you keen on flow cytometry. Cytogenetic studies also showed the characteristic isochromosome 7q and associated trisomy 8. The spleen was also removed after diagnosis and representative images are shown below.
While it was more specifically named hepatosplenic gamma-delta T-cell lymphoma in the REAL classification, the WHO 2001 and 2008 classification calls this entity simply hepatosplenic T-cell lymphoma, as alpha-beta rearranged TCRs are found in a minority of cases. From my perspective, the main differential diagnoses here are:
1) gamma-delta T-large granular lymphocytic leukemia: often a very difficult distinction to make, though g-d T-LGLLs are quite rare (alpha-beta T-LGLs much more common). From my reading, T-LGLLs will often express some CD5 and/or CD57 (rather than CD56 in many HSTLs) and have the activated cytotoxic phenotype of TIA-1+, granzyme B+, and perforin+ by IHC. HSTLs would be TIA-1+ but granzyme M positive rather than granzyme B. Also, the isochromosome 7q/trisomy 8 associations are not classic for T-LGLLs. Probably most importantly, though, is the clinical picture: T-LGLLs will be relatively indolent and involve the peripheral blood.
2) peripheral T-cell lymphoma (NOS): if classical HSTL features are not present
3) aggressive NK cell leukemia/lymphoma: Asian females, EBV-associated, surface CD3 neg by flow cytometry
I suppose in some respects an adult T-cell leukemia/lymphoma might also be on the differential but one would need a different clinical and immunophenotypic picture (patient from Caribbean, Japan, or Africa; positive HTLV-1 status; more atypical lymphocytes [flower cells], CD4+, CD7-, CD8-, CD25(strong+), CD26+.
Another important aspect to point out with regard to hepatosplenic T-cell lymphomas is their association with chronic immune suppression and/or antigenic stimulation. The entity is also one type of post-transplant lymphoproliferative disorder (PTLD) – but of T cells. Patients with inflammatory bowel disease or following renal transplantation are especially at risk for this complication, especially those treated with the TNF-alpha blocking agents and immune suppressing drugs like infliximab and azathioprine, respectively.
In Dr Foucar’s 3rd edition of Bone Marrow Pathology – a must-read – it is also emphasized that HSTLs may also present with an exuberant myelomonocytic proliferation, sometimes mimicking a chronic or juvenile myelomonocytic leukemia (CMML or JMML, respectively).
While there is much more to be said of gamma-delta T cells, my space is limited! Suffice it to say, they are a minor subset of circulating and epithelial T cells involved in the innate immune response and the normal counterpart of primary cutaneous gamma-delta T-cell lymphomas, the other relatively well-described site for these cells to go mad.
Unfortunately for this patient, hepatosplenic T-cell lymphomas are very aggressive and median survival is <2 yrs. It is ultimately difficult to reach allogeneic stem cell transplant and none of the standard chemotherapeutic regimens work well for the disease. Early splenectomy, novel antifolates, cladribine, and monoclonal antibodies (including anti-CD52) have been employed with some effect but the optimal therapy is still years away at best. The post-solid organ transplant cases have a particularly dismal outlook and unlike other PTLDs immunosuppression these agents cannot simply be withdrawn. These patients are treated with HyperCVAD and other extremely intensive chemotherapeutic regimens for any hope of survival.
Hope this was helpful! Below are some helpful references…I highly recommend the Tripodo review from Nature Reviews Clinical Oncology. And just for completeness, I have no financial disclosures regarding this case.
Belhadj K et al. Hepatosplenic T-cell lymphoma is a rare clincopathologic entity with poor outcome: report on a series of 21 patients. Blood 2003;102(13):4261-9.
Jaeger et al. Hepatosplenic gammadelta T-cell lymphoma successfully treated with a combination of alemtuzumab and cladribine. Ann Onc 2008; 19(5):1025-6.
O’Conner OA et al. Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. BJH 2007;139:425-8.
Tey SK et al. Post-transplant hepatosplenic T-cell lymphoma successfully treated with HyperCVAD regimen. Am J Hemat 2008;83:330-3.
Tripodo C et al. Gamma-delta T-cell lymphomas. Nat Rev Clin Oncol 2009;6:707-717.
Vega F, LJ Medeiros, and P Gaulard. Hepatosplenic and Other ?? T-Cell Lymphomas. AJCP 2007;127:869-80.
Whole slide stereology is no longer something that scientists delivering quantitative pathology results can afford to ignore.
