PATHOLOGY

Utility of ALK-1 Protein Expression and ALK Rearrangements in Distinguishing Inflammatory Myofibroblastic Tumor from Malignant Spindle Cell Lesions of the Urinary Bladder
Sukov WR, Cheville JC, Carlson AW, Shearer BM, Piatigorsky EJ, Grogg KL, Sebo TJ, Sinnwell JP, Ketterling RP
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Mod Pathol. 2007; 20: 592-603

• Inflammatory myofibroblastic tumor of the urinary bladder is an unusual spindle cell neoplasm that displays cytologic atypia, infiltrative growth and mitotic activity mimicking malignant tumors, such as leiomyosarcoma, rhabdomyosarcoma and sarcomatoid carcinoma. The objective of this study was to determine if anaplastic lymphoma kinase (ALK-1) protein expression detected by immunohistochemistry and ALK rearrangements detected by fluorescence in situ hybridization (FISH) were useful in distinguishing inflammatory myofibroblastic tumor from malignant spindle cell tumors of the urinary bladder. In inflammatory myofibroblastic tumor, ALK-1 expression was identified in 13 of 21 cases (62%) and ALK rearrangements in 14 of 21 cases (67%). All cases of inflammatory myofibroblastic tumor demonstrating ALK-1 expression, carried ALK rearrangements. One case negative for ALK-1 expression exhibited ALK rearrangement. ALK rearrangements were more common in women (P=0.0032). Leiomyosarcoma, sarcomatoid carcinoma, embryonal rhabdomyosarcoma and reactive myofibroblastic proliferations were negative for ALK-1 protein and ALK rearrangements. Immunohistochemistry using markers of muscle, epithelial, neural, and follicular dendritic cell differentiation showed overlap between inflammatory myofibroblastic tumor with and without ALK gene rearrangements, and between inflammatory myofibroblastic tumor and spindle cell malignancies. However, coexpression of cytokeratin and muscle-specific antigens was unique to inflammatory myofibroblastic tumor, observed in approximately half the tumors. This study indicates that detection of ALK protein and ALK gene rearrangements are useful in distinguishing inflammatory myofibroblastic tumor from spindle cell malignancies in the urinary bladder. Additionally, our findings suggest that ALK rearrangement is the primary mechanism for ALK activation and that inflammatory myofibroblastic tumor likely represents a heterogeneous group of spindle cell proliferations with the majority associated with ALK translocations, and the remaining associated with other etiologies.
  
  
• Editorial Comment
  Inflammatory myofibroblastic tumor is a rare lesion occurring at a number of anatomic sites, including the urinary bladder. The vast majority of these tumors behave in a benign fashion, although occasionally tumors can recur following surgical excision. Due to the fact that displays cytologic atypia, infiltrative growth and mitotic activity, the tumor mimics aggressive malignant tumors, such as leiomyosarcoma and sarcomatoid carcinoma.
  The differential diagnosis is of utmost importance and particularly difficult for the pathologist. The sarcomatoid variant of urothelial carcinoma is a very aggressive tumor. In a study by Lopez-Beltran et al., 70% of patients died of cancer at 1 to 48 months (mean 17 months) (1). Leiomyosarcoma is a rare malignant mesenchymal tumor that arises from urinary bladder smooth muscle and is the most common sarcoma of the urinary bladder. Although previous reports suggest that 5-year survival after partial or radical cystectomy approaches 70%, the largest recent study indicates that 70% of patients with leiomyosarcoma developed recurrent or metastatic disease, resulting in death in nearly half (2).
  The study by Sukov et al. emphasizes the importance of immunohistochemistry as a help for the pathologist in the differential diagnosis of spindle cell lesions of the urinary bladder. In inflammatory myofibroblastic tumor there is a clonal aberration typically involving chromosome 2p (3). This results in rearrangement of the ALK gene which codifies a receptor of tyrosine-kinase and hence over-expression of ALK-1 protein which is disclosed by immunohistochemistry in up of 62% of the cases.

References

1. Lopez-Beltran A, Pacelli A, Tothenberg HJ, Wollan PC, Zincke H, Blute ML, Bostwick DG: Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. J Urol. 1998; 159: 1497-1503.
2. Martin SA, Sears DL, Sebo TJ, Lohse CM, Cheville JC: Smooth muscle neoplasms of the urinary bladder: a clinicopathologic comparison of leiomyoma and leiomyosarcoma. Am J Surg Pathol. 2002; 26: 292-300.
3. Tsuzuki T, Magi-Galluzzi C, Epstein JI: ALK-1 expression in inflammatory myofibroblastic tumor of the urinary bladder. Am J Surg Pathol. 2004; 28: 1609-14.

Dr. Athanase Billis
Full-Professor of Pathology
State University of Campinas, Unicamp
Campinas, São Paulo, Brazil
E-mail: athanase@fcm.unicamp.br