AITL is a biologically and clinically heterogeneous entity whose true nature remains to be clarified1
. Histology of lymph node is often diagnostic, showing partial effacement of normal architecture by polymorphic inflammatory infiltrates of large immunoblasts, small lymphocytes, plasma cells, eosinophils, histiocytes and marked vascular proliferation2-4
Skin involvement of AITL is frequent, as seen in our series, but underestimated due to lack of suspicion. Jaffe et al4
included AITL in T-cell and NK-cell lymphomas with frequent or constant cutaneous involvement. Although the diagnosis in LN is characteristic and the skin is frequently involved, the skin lesions are not well characterized in the dermatologic literature. In addition, the skin lesions in AITL have been regarded as nonspecific in most cases. A cutaneous eruption was observed in up to 50% of patients with AITL7
. Skin lesions can precede, occur simultaneously, or develop after the diagnosis of the disease7,8
. In our study, skin lesions were nonspecific, generalized, maculopapular eruptions mimicking a viral exanthem or a drug eruption. However, a wide range of skin lesions has been described including papules, plaques, nodules, erosions, urticarial or purpuric eruptions or diffuse erythema5-8
Our study showed that the cells in the skin biopsy were not atypical. In comparison to superficial perivascular lymphocytic infiltration in drug or viral exanthem, cutaneous AITL showed superficial and deep lymphohistiocytic infiltrate with proliferation of vessels. In cases of non-diagnostic skin pathology, clonal TCR gene rearrangement was helpful for diagnosis. Since skin involvement of lymphomas is a poorer sign, accurate and prompt diagnosis of cutaneous involvement of AITL showing equivocal clinicopathologic findings should be made by clinical, immunohistochemical and molecular analysis.
Infectious diseases and agents have been reported to be associated with AITL, especially lymphotrophic viruses such as EBV. However, Brown et al7
reported remarkably heterogeneous EBV expression in cutaneous lesions of AITL. HHV-6 and -8 were isolated from the peripheral blood of AITL patients, and a possible role for these viruses in AITL has emerged from serologic and molecular studies. In a case report of AITL with disseminated HHV-6 infection in a patient with acute myeloblastic leukemia, the authors insisted that immunosuppression associated with AML and the additional iatrogenic immunosuppression predisposed the patient to reactivated HHV-6 infection10
. However, Luppi et al9,11
revealed an association with HHV-6 and HHV-8 in only some cases. Another study also concluded that there was no significant association between T-cell clonality and HHV-6 or EBV infection, although lymph node biopsies revealed 22% of lymphotropic viral genome of HHV-6, 40% of EBV, but none of HHV-8. In this background of uncertain association with HHVs and because skin lesions in AITL cases can mimic viral exanthem and HHVs are known to be associated with viral exanthem, pityriasis or skin lymphomas, the association of HHV-6, -7, and -8 with AITL should be investigated by the more accurate method of hetero-duplex PCR. HHV-7, a beta-herpesvirus genetically close to HHV-6, utilizes CD4 as a receptor on the lymphocyte surface11
. In our study, no association of HHVs with AITL was seen compared to other lymphomas. One case of HHV-8 (+) may be coincidental or related to the coexistence of Kaposi's sarcoma. The heterogeneity and variability of these viruses in previous studies and in our study suggest that these viral infections are not primary events in the pathogenesis of AITL.
Dermatologists should be aware of AITL and include skin lesions of AITL among the differential diagnoses of fever of unknown origin with generalized skin rash13-15
. As the skin lesions closely mimic a benign condition and the skin biopsies of skin lesions of AITL are not malignant, clonality testing with clinical suspicion is crucial for early and accurate diagnosis and can prevent mistreatment or confusion of treatment policy.
In conclusion, AITL is not associated with HHVs. Skin eruptions accompanied by AITL are frequent and are not nonspecific, but rather are a cardinal component of AITL. Symmetric maculopapular, nonspecific-looking skin manifestation may indicate diagnosis of this unique T cell lymphoma.