A 27-year-old woman presented with shortness of breath, tachycardia, fever of unknown origin, widespread lymphadenopathy, general malaise, and weight loss. A fine needle aspiration and core biopsy of an enlarged cervical lymph node is performed. Representative photomicrograph including H&E and immunohistochemistry are shown below. Molecular analysis was positive for a T-cell gene rearrangement.
The correct answer is ...
ALK-positive anaplastic large cell lymphoma (ALCL).
The histologic sections show an atypical lymphohistiocytic infiltrate with a significant population of large, atypical cells. Many of these cells have ample eosinophilic cytoplasm and round to horseshoe-shaped nuclei with prominent nucleoli (so-called “hallmark” cells). The provided immunohistochemistry images demonstrate that these cells are positive for CD30 (strong uniform), ALK, CD2 (weak), PAX5 (weak, granular staining), and are negative for CD3 and CD20. This phenotype is not sufficient to establish T-cell lineage on its own and could be seen in either B-cell or T-cell lineage neoplasms. In combination with the molecular results, which were positive for a T-cell gene rearrangement indicating T-lineage, the findings are diagnostic for ALK-positive ALCL.
In this case, the tumor cells were also positive for CD4, CD7 (partial/weak), CD45, and granzyme B, and negative for CD8, CD15, TCR beta F1, TCR delta, and cytokeratin AE1/AE3 (not shown). Loss of T-cell antigens such as CD3, as seen in this case, is very common in ALCL and can pose a significant diagnostic challenge. There was also aberrant expression of a B-cell lineage-associated marker PAX5. Aberrant PAX5 in ALCL is uncommon and often adds even more challenge for the pathologist, when Hodgkin's lymphoma or ALK(+) large B-cell lymphoma can enter the differential. Cases of ALCL with aberrant PAX5 expression often require molecular confirmation of lineage, as performed in this case.
In contrast to ALK-negative ALCL, ALK-positive ALCL tends to occur in children and young adults, and often presents with widespread lymphadenopathy and extranodal disease. ALK-positive ALCL also tends to have a better prognosis than its ALK-negative counterpart. This disease generally responds favorably to treatment with systemic chemotherapy and has a 5-year overall survival rate of 85%.
The large cell size and cohesiveness of this neoplasm is reminiscent of a metastatic carcinoma. While carcinoma is certainly on the differential diagnosis of ALK-positive anaplastic large cell lymphoma, and some carcinomas can display ALK positivity, CD30 and other hematopoietic markers would be negative. Metastatic carcinoma is excluded by establishing T-cell lineage in this case.
Another diagnostic consideration is classic Hodgkin's lymphoma, as ALCL hallmark cells may resemble Reed-Sternberg/Hodgkin cells, and both are positive for CD30, and this case also showed partial positivity for PAX5. The strong uniform expression of ALK by immunohistochemistry reveals the underling genetic aberrancy and excludes Hodgkin's lymphoma in this case.
ALK-positive large B-cell lymphoma may also be considered in the differential diagnosis of ALK-positive anaplastic large cell lymphoma. The neoplastic cells in this entity are large and have abundant cytoplasm and may resemble either plasmablasts (with eccentric nuclei) or immunoblasts (with central nuclei and prominent nucleoli). They typically have a phenotype more akin to plasma cells, with positivity for CD138, MUM1, and other plasma-cell associated markers; CD30 is only rarely focally or partially expressed. In this case, this diagnosis is excluded by strong uniform expression of CD30 and the presence of a T-cell gene rearrangement.
Clarissa Jordan, M.D.
Resident, Anatomic & Clinical Pathology
Daniel (Dan) Larson, M.D.
Senior Associate Consultant, Hematopathology
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science