A Poorly Differentiated Malignant Neoplasm Lacking Lung Markers Harbors an EML4-ALK Rearrangement and Responds to Crizotinib

Abstract

Suspected metastatic site lesions that are poorly differentiated present a diagnostic challenge when morphologic and immunohistochemical profiling cannot establish the primary tumor site. Here we present a patient diagnosed with both a malignant neoplasm in the lung and a right upper extremity (RUE) neoplasm of unclear histogenetic origin. Immunohistochemical staining performed on the latter specimen was inconclusive in determining the site of origin. Although the lung biopsy sample was insufficient for molecular testing, hybrid capture-based comprehensive genomic profiling (FoundationOne) identified an EML4-ALK rearrangement in the RUE lesion. Crizotinib treatment resulted in a major response in both the RUE and the lung lesions. This report illustrates the utility of comprehensive genomic profiling employed at the initial presentation of an unknown primary malignant neoplasm, which resulted in the front-line use of targeted therapy and a significant and sustained antitumor response.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site

“…This patient with CUP also achieved a major response to targeted therapy when comprehensive profiling was performed up front and revealed an ALK fusion that responded dramatically to crizotinib therapy. 18 …”

ALKFusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy

“…Multiple examples have been published of clinical responses to selected anti‐ALK targeted therapy for patients whose non‐NSCLC tumors harbor f ALK . In this cohort of patients, novel examples of responses to ALK‐targeted therapy include case Non‐NSCLC 092, a non‐Langerhans cell histiocytosis with a robust response to crizotinib (Figure ), and Non‐NSCLC 037, a renal cell carcinoma with a significant response to alectinib (Figure ).…”

“…The case Non‐NSCLC 166 was submitted as a CUP with massive secondary pulmonary involvement and showed no expression of epithelial markers (cytokeratin, TTF1, etc.). Based on subsequent analysis, this tumor is likely a sarcoma and possibly a high‐grade variant of inflammatory myofibroblastic tumor metastatic to the lung from a soft tissue origin . Thus, for this CUP case, reclassification as a form of sarcoma appears warranted.…”

“…As seen in supplementary online Table 4, these smooth muscle sarcomas may be derived from soft tissues, including both superficial sites and deep sites such as the retroperitoneum, walls of the intestine, and the uterus. Evidence has also emerged that these ALK fusion driven sarcomas are responsive to both first‐generation therapies, such as crizotinib, as well as second‐ and third‐generation inhibitors .…”

“…The impressive efficacy of targeting f ALK in NSCLC and ALCL raised interest in ALK alterations in other cancer types. Several studies have shown the efficacy of anti‐ALK therapies in a wide variety of malignancies , but these studies are small‐scale and generally limited to individual case reports or case studies. In addition, many of these publications targeted ALK alterations that were not classic gene fusions, and included both ALK gene amplifications and ALK ‐activating base substitutions .…”