Anaplastic large-cell lymphoma with aberrant expression of multiple cytokeratins masquerading as metastatic carcinoma of unknown primary.

Case Report A 52-year-old woman without a significant past medical history presented to her primary care physician in July 2011 for evaluation of a large, nontender, firm, fixed left inguinal mass. A computed tomography (CT) scan of the abdomen and pelvis confirmed bulky left inguinal adenopathy measuring up to 5.6 cm and numerous left iliac nodes measuring up to 4.7 cm, but was otherwise negative. An excisional left inguinal lymph node biopsy showed a neoplasm with anaplastic morphology. The tumor cells formed cohesive clusters that were centered in the subcapsular spaces and near sinuses with extension into the paracortex (Fig 1A). On high-power examination, the tumor cells were pleomorphic, with vesicular chromatin and prominent to inconspicuous nucleoli (Fig 1B). Immunohistochemistry showed that the tumor cells were positive for CD30 and the cytokeratins epithelial membrane antigen (EMA), intercellular adhesion molecule 5 (CAM5.2), and OSCAR (Figs 1C through 1E). Focal positive staining for cytokeratins AE1/AE3 was also noted. CD45, CD15, S100, CD2, CD3, CD5, CD7, CD10, CD19, CD20, anaplastic lymphoma kinase (ALK1), cytokeratin 7 (CK7), CK20, thyroid transcription factor 1, granzyme B, T-cell intracellular antigen, synaptophysin, and chromogranin were negative. Tand B-cell receptor gene rearrangement studies were negative. A pathologic diagnosis: “consistent with metastatic poorly differentiated carcinoma,” was rendered by the initial institution after review and concurrence by pathologists at a National Cancer Institute–designated cancer center. Evaluation for a primary site of carcinoma included a negative upper endoscopy, colonoscopy, mammogram, and gynecologic exam. CA-125 and carcinoembryonic antigen were normal. The patient developed low-grade fevers, abdominal discomfort, and a diffuse, dry, flaky maculopapular pruritic rash. She received one cycle of carboplatin and Taxol (Bristol-Myers Squibb, Princeton, NJ) on October 14, 2011, for presumed carcinoma of unknown primary (CUP). A repeat CT scan on November 2, 2011, showed progression of her abdominal and pelvic adenopathy when compared with a CT scan from October 13, 2011. She was empirically treated with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, completing six cycles in February 2012, with a marked decrease in the bulky adenopathy. In January 2012, a sample from her initial biopsy was sent for a CancerType ID gene test (bioTheranostics, San Diego, CA) for molecular classification; this test measures and integrates the expression of 92 genes to distinguish 28 tumor types and 50 subtypes. On the basis of the gene expression profiling, there was a 96% chance that the primary malignancy was lymphoma. The patient’s bulky pelvic adenopathy recurred less than a month after completion of cyclophosphamide, doxorubicin, vincristine, and prednisone treatment. Positron emission tomography CT scanning showed additional new lesions involving the mediastinum, midesophagus, and bones. She developed daily fevers, drenching sweats, and increasing weakness, and her weight decreased by 30 pounds. A new right inguinal lymph node biopsy in April 2012 showed similar morphologic and immunohistochemical findings as her previous biopsy, although more numerous tumor cells were seen in this subsequent biopsy. The differential diagnosis on the repeat biopsy included classical Hodgkin lymphoma (cHL), anaplastic large-cell lymphoma (ALCL), and metastatic, poorly differentiated carcinoma. Numerous atypical mitoses and apoptotic figures were seen along with necrosis. Additional immunostains showed that the tumor cells also expressed CD4, CD33, CAM5.2, and Wilms’ tumor 1, but were negative for a large panel of antibodies including ALK1, paired box gene-5, and other T-cell antigens (CD1, CD2, CD3, CD5, CD7, and CD8). T-cell receptor (TCR) gamma rearrangement studies showed a biclonal TCR rearrangement (Fig 1F). The molecular results, the morphology, and the immunophenotype were most consistent with an anaplastic lymphoma kinase(ALK) –negative ALCL with aberrant cytokeratin expression. The patient began treatment with the CD30-targeted antibody-drug conjugate brentuximab vedotin; however, she died less than 1 week after treatment initiation.