A 38 year old man with abdominal pain, diarrhea, and lymphadenopathy
Majed M. Pharaon, M.D., Jeffrey A. Vos, M.D., Sharon L. Wenger, Ph.D.
A 38 year old man with a past medical history of chronic back pain, emphysema, anxiety, recurrent pancreatitis, alcohol abuse, and nicotine abuse presents with complaint of abdominal pain, diarrhea, and generalized lymphadenopathy. He also reported a 1 week history of fever, a 30 lb weight loss over 3 months, and generalized weakness for the past 2-3 months. Physical examination was remarkable for bilateral cervical and inguinal lymphadenopathy. A bone marrow biopsy was performed and revealed no abnormalities. A biopsy from a periaortic lymph node was performed (see figures 1 - 11).
The specimen is labeled as “periaortic lymph node” and consists of a 1.0 x 0.5 x 0.5 cm aggregate of red-tan tissue.
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Anaplastic large cell lymphoma (ALCL) is a systemic (nodal) T-cell lymphoma characterized by pleomorphic CD30+ large T cells that often involve nodal sinuses. ALCL, ALK-positive is uncommon and accounts for approximately 3% of adult non-Hodgkin lymphomas and 10-20% of childhood lymphomas. There is a male predominance in younger patients and slight female predominance in older patients. Majority of patients (70%) present with advanced disease (stage III-IV) with peripheral and/or abdominal lymphadenopathy. B symptoms such as high fever, weight loss, and fatigue are often present. It frequently involves both lymph nodes and extranodal sites such as skin, bone, soft tissues, lung, and liver. Involvement of the mediastinum is less frequent than in classical Hodgkin lymphoma. Involvement of the bone marrow is uncommon; however, the presence of tumor may be subtle. On H&E analysis, 10% of cases show bone marrow involvement, although detection is increased to 30% when utilizing immunohistochemistry.
Histologic types that have been described include the common type (70% of ALCLs) with pleomorphic or monomorphic large tumor cells, the lymphohistiocytic variant (10%), small cell variant (5% to 10%), and Hodgkin-like variant (3%). Microscopically, the involved lymph node shows partial to complete effacement of the architecture or may be confined to the nodal sinuses. The characteristic tumor cells are pleomorphic, large, have circular or horseshoe-shaped nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. These “hallmark cells” are present in all morphologic variants and are a key diagnostic feature of ALCL. In the small-cell variant, the hallmark cells are often concentrated around blood vessels and are less conspicuous, which can result in misdiagnosis as peripheral T-cell lymphoma, NOS.
The lymphoma cells are always positive for CD30 in a membranous and Golgi staining pattern (figure 8). The strongest staining is seen in the hallmark cells. The majority of cases are positive for EMA (figure 9) as well. In conjunction with lack of CD45 immunoreactivity (figure 5), which occurs in a significant number of cases, this staining pattern may lead to an incorrect diagnosis of metastatic carcinoma. Most cases of the ALCL, ALK-positive, express one or more of the T-cell markers. CD3, however, is negative in more than 75% of cases often resulting in a diagnostic dilemma (figure 3). CD2, CD5, and CD4 (figure 5) are more useful and are positive in about 70% of cases. CD43 (figure 7) as well as expression of one or more of the cytotoxic associated antigens, such as TIA1, granzyme B, and/or perforin, are also frequently positive. ALCL, ALK-positive, is negative for CD20 (figure 4), CD15, BCL2, and EBER.
Molecular and genetic features
About 90% of ALCL, ALK-positive cases show clonal rearrangement of the T-cell receptor gene (TCR). In 70% to 80% of the cases, the translocation (2;5)(p23;q35) is present which encodes a nuclear phosphoprotein (NPM)/ALK fusion protein (figure 11) resulting in a nuclear and diffuse cytoplasmic ALK staining pattern. A less common genetic abnormality (10% to 20% of cases) is the translocation (1;2)(q25;p23), encoding a tropomyosin3 (TPM3)/ALK fusion protein, resulting in an ALK staining pattern characterized by diffuse cytoplasmic reactivity with peripheral intensification.
ALCLs, ALK-positive and ALCL, ALK-negative have the same morphology and CD30 staining pattern. However ALCL, ALK-negative is negative for ALK expression by immunohistochemistry and no underlying translocation involving the ALK gene (chromosome 2) is present. In addition, PTCL-NOS with high CD30 expression is in the differential diagnosis but is also negative for ALK staining and the characteristic translocation, similar to ALCL, ALK-negative. It is important to differentiate between these entities due to their difference in prognosis (see below). Poorly differentiated metastatic carcinoma should be considered in the differential diagnosis as well since it can resemble ALCL morphologically and due to the EMA positive, CD45 negative staining profile, frequently encountered in ALCL. A negative cytokeratin stain would exclude the diagnosis of a carcinoma in this situation.
Treatment and prognosis
The most common treatment regimen used for ALCL is CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). ALCL, ALK-positive patients have a favorable prognosis compared to ALCLs, ALK-negative and PTCL-NOS with high CD30 expression. The 5-year overall survival rate is 80% for ALCL, ALK-positive versus 40% for ALCL, ALK-negative. Furthermore, in cases of PTCL-NOS with high CD30 expression, the overall 5-year survival is only 20%, emphasizing the importance of accurate distinction between these T-cell lymphomas.
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