Anaplastic Large Cell Lymphoma, Common Type, ALK1+ with Variant Translocation Leticia Quintanilla-Martinez Ingolstaedter Landstraße 1 Oberschleissheim, Germany

Case History: Cervical lymph node in a 30-year-old male patient. The bone marrow at diagnosis was free of disease. The lymph node architecture was completely effaced by a diffuse proliferation of large lymphoid cells with abundant pale eosinophilic cytoplasm and large nuclei with prominent nucleoli. Many cells revealed an eccentric, horseshoe or kidney-shaped nuclei with enhancement of the Golgi area. The neoplastic cells were CD4+ and ALK1+ in the cytoplasm. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Anaplastic large cell lymphoma, common type, ALK1+ with variant translocation. Discussion. ALCL accounts for approximately 3% of adult non-Hodgkin lymphomas and up to 30% of childhood lymphomas. ALCL involves both nodal and extranodal sites including skin, bone marrow, soft tissues, lung and liver. There are at least three forms of ALCL based on the presence or absence of the characteristic t(2;5) translocation. Primary systemic ALK+ ALCL (most frequent in the first three decades of life and shows a male predominance with a ration of 6.5) CD30+, ALK+, EMA+, CD3-, CD4+ Primary systemic ALK- ALCL (prevalent in older individuals with a M:F ratio of 0.9) CD30+, ALK-, EMA+, CD3+ Primary cutaneous ALCL CD30+, CD3+, ALK-, EMA- ALCL can present with different morphologies, which sometimes causes difficulties in the diagnosis. Of note is that despite the different morphologies, in most of the cases "hallmark cells" can be identified. "Hallmark cells" are characterized by eccentric, horseshoe or kidney-shaped nuclei often with an eosinophilic region near the nucleus. Three morphologic variants are accepted in the WHO classification: ALCL, common or classic type (70% of the cases, 60-90% ALK+) ALCL, lymphohistiocytic variant (10% of the cases, 80-100% ALK+) ALCL, small cell variant (5-10% of the cases, 100% ALK+) Other rare histological patterns giant cell-rich sarcomatoid signet-ring like In some cases like in the lymphohistiocytic variant, the neoplastic cells might be overwhelmed by the reactive infiltrate making necessary the immunohistochemical analysis for the recognition of the neoplastic cells. In the small cell variant, the cells tend to accumulate around the blood vessels, where the large cell morphology is better appreciated. In the lymph node in early stages of infiltration, the changes can be very subtle with preferential paracortical and subcapsular involvement and with intrasinusoidal dissemination, which can be misinterpreted as metastatic carcinoma. In advanced stages the infiltrate is diffuse. The tumors cells are CD30+ in 100% of the cases. ALK expression is detectable in 60-85% of the cases. The ALK staining may be cytoplasmic and nuclear or only nuclear depending of the translocation. The t(2;5) translocation gives a nuclear and cytoplasmic positivity, whereas all other translocation partners result in a cytoplasmic staining. ALK is virtually diagnostic of ALCL, since no normal cell expresses ALK, except for rare neurons in the brain. Nevertheless, its expression has been reported in rare cases of rhabdomyosarcomas and in inflammatory myofibroblastic tumors. Concerning T-cell expression, most of the ALK+ALCL are CD3- (>75%), CD5 and CD7 negative, whereas CD4 and CD2 are positive. Most of the cases express the cytotoxic granule-associated proteins TIA-1, granzyme B and/or perforin. The main differential diagnosis is Hodgkin lymphoma, mainly the syncytial variant of nodular sclerosis, which may contain confluent sheets of RS cell variants and mimic ALCL. In these cases immunophenotype helps to make the differential diagnosis since RS cells are B-cells that can be identified with PAX5 and lack the expression of ALK protein. References: Falini B, et al. ALK+ Lymphoma: Clinico-Pathological findings and outcome. Blood 1999, 93:2697 Stein H, et al. CD30+ anaplastic large cell lymphoma: a review of its histopathologic,genetic, and clinical features. Blood 2000, 96:3681-3695 Bonzheim I, et al. ALCL lack the expression of T-cell receptor molecules or molecules of proximal T-cell receptor signaling. Blood 2004, 104:3358-3360