Haematologica 2002; 87:(03)ECR11
[Medline] [prev] [index] [next]Hepatosplenic gd T-cell lymphoma with a novel cytogenetic alteration and cerebrospinal fluid infiltration: biological and clinical features
Daris Ferrari,* Gianpaolo Girmenia,* Luca Migliorini,° Annamaria Nosari,@ Enrica Morra@
*Unità di Ematologia, Ospedale "C. Cantù", Abbiategrasso. °Servizio di Anatomia Patologica Ospedale "G. Fornaroli", Magenta. @ Divisione di Ematologia, Ospedale Niguarda "Cà Granda", Milan, Italy
Post-thymic T and NK cell lymphomas are neoplasms recently included in the WHO and REAL classifications.1-3 These lymphomas are distinguishable by immunophenotype and molecular genetic studies but share some common features to antigen expression, function and pattern of disease.
These extranodal malignancies comprise an aggressive subgroup: extranodal NK/T cell lymphoma, nasal and nasal-type, blastic NK cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and hepatosplenic T-cell lymphoma.
Hepatosplenic gd T-cell lymphoma is a rare entity with distinct morphological and clinical picture4 characterized by a progressive and fatal course and resistance to chemotherapy. The main clinical features are fever, hepatosplenomegaly, no lymph node involvement and leukemic spread in the terminal phase. A similar aggressive hepatosplenic lymphoma arising from ab T-cell receptor, characterized by female preponderance and sometimes by presence of isochromosome 7q has been recently described.5,6
Malignant lymphocytes of hepatosplenic gd T-cell lymphoma are generally medium-sized lymphocytes with pale blue abundant cytoplasm, irregular nucleus and prominent nucleoli. Disease distribution is mainly in the spleen, liver and bone marrow. The diagnosis is often made after splenectomy. In the terminal phase malignant cells are found in the bloodstream and can infiltrate the cerebrospiral fluid space causing severe neurologic alterations. Hepatosplenic gd T-cell lymphoma expresses gd T-cell receptor (TCR), Vd1, T lineage receptor CD2, CD3, CD7 and cytotoxic granule associated protein (TIA-1) while the NK-cell associated antigen CD56 is expressed in 60-70% of cases. CD4, CD8, perforin and granzyme B are generally not expressed.7 There is not a unique cytogenetic alteration characteristic of the disease, but it is very frequent to find an isochromosome 7q, often in combination with trisomy 8.8
A 23-year old woman was admitted to our hospital with massive splenomegaly and a two-month history of fever (38°C). The physical examination revealed pallor, splenomegaly (16 cm under the costal margin), mild hepatomegaly and no lymphadenomegaly. Extensive analysis did not reveal infection by EBV, HCV, HIV, cytomegalovirus, toxoplasma, mycobacteri, a brucella, plasmodium or leishmania. Splenectomy was performed. The spleen weighed 1700 g, was red-brown in colour, consistently harder than normal, without focal lesions. There was a prominent sinusoidal infiltrate of medium-size T-lymphocytes, characterized by a pale basophil cytoplasm, irregular nucleus and evident nucleoli. The neoplastic population was positive for LCA and T-lineage markers. CD3 and CD43 antigens were strongly positive, while CD4 CD5, CD8, CD20, CD79a, CD23, CD30 and CD68 were not expressed. The NK marker CD56 was present on the cellular surface. PCR and molecular analysis of gd TCR showed a rearranged monoclonal pattern. Liver biopsy revealed the presence of the same cellular type found in the spleen, occupying the sinusoidal vessels and leaving an intact lobular structure. The bone marrow biopsy was infiltrated by medium-size T-cells expressing CD3, CD43 and CD56. Cytogenetic study on marrow aspirate, according to a standard method, was normal. The hematologic parameters during the course of the illness are reported in Table 1.The patient was treated according to the VACOP-B protocol for 12 weeks without evidence of response. Soon after treatment neoplastic T lymphocytes appeared in peripheral blood. The karyotype demonstrated the presence of a unique alteration, 46X,-X,del(4)(q31),i(7)(q10),+8/46,XX, not evident in the first sample. Although the disease did not respond to chemotherapy, the patient was fit and well for 12 months, until B symptoms reappeared. We treated the patient according to the DHAP protocol, but leukemic progression prompted us to start an aggressive LAL protocol. The result was quite frustrating. In a few days she developed headache, dyplopia, and leg paresthesias. A lumbar puncture revealed massive infiltration with T lymphocytes. The patient was treated with intrathecal methotrexate (MTX) and cytarabine (ARA-C), associated with high dose MTX (continuous infusion) and high dose ARA-C. The response was good and the symptoms subsided while the CSF became negative. Less than a month later there was a blood relapse which was treated with cladribine. We did not achieve any result and the patient died in a few days from disseminated intravascular coagulopathy (DIC), 18 months from diagnosis.
gd and ab hepatosplenic T-cell lymphomas share the same aggressive and invasive growth pattern. Their clinical behavior is almost always fatal and no chemotherapy treatment is available at the moment to achieve a stable and lasting remission. This case presented a normal cytogenetic analysis in the first sample while a complex karyotype, and particularly deletion in chromosome 4, was observed during the course of the disease. This may result from the acquisition of secondary abnormalities in addition to isochromosome 7. The CSF infiltration was treated successfully but progression of disease was not changed.References