ORIGINAL ARTICLES Diameter of Involved Nerves Predicts Outcomes in Cutaneous Squamous Cell Carcinoma with Perineural Invasion: An Investigator-Blinded Retrospective Cohort Study AMY S. ROSS, MD, Ã FAITH MILLER WHALEN, MD, y ROSALIE ELENITSAS, MD, z XIAOWEI XU, MD, PHD, y ANDREA B. TROXEL,SCD, z AND CHRYSALYNE D. SCHMULTS, MD J BACKGROUND Perineural invasion (PNI) has been associated with poor prognosis in cutaneous squamous cell carcinoma (CSCC), but it is unclear how different degrees of nerve involvement affect prognosis. OBJECTIVE To determine whether the diameter of nerves invaded by CSCC affects outcomes of recur- rence, metastasis, and disease-specific and overall survival. METHODS A retrospective cohort study was conducted of patients with CSCC with PNI. Dermatopa- thologists blinded to subject outcomes determined the diameter of the largest involved nerve. RESULTS Data were obtainable for 48 patients. Small-caliber nerve invasion (SCNI) of nerves less than 0.1 mm in diameter was associated with significantly lower risks of all outcomes of interest. Disease- specific death was 0% in subjects with SCNI, versus 32% in those with large-caliber nerve invasion (LCNI) (p = .003). Other factors associated with significantly worse survival were recurrent or poorly differen- tiated tumors or tumor diameter of 2 cm or greater or depth of 1 cm or greater. On multivariate analysis, only tumor diameter and age predicted survival. CONCLUSIONS The individual prognostic significance of factors associated with poor survival remains uncertain. Small-caliber nerve invasion may not adversely affect outcomes. Defining PNI as tumor cells within the nerve sheath and routine recording of diameter of involved nerves, tumor depth, and histo- logic differentiation on pathology reports will facilitate further study. The authors have indicated no significant interest with commercial supporters. T he incidence of cutaneous squamous cell carci- noma (CSCC) continues to rise in the United States, accounting for approximately 200,000 new cases annually. Although the prognosis is generally excellent, nodal and distant metastasis can occur, and an estimated 2,500 people in the United States die each year from CSCC. 1 Factors reported to increase the risk of local recur- rence, metastasis, and death include tumor diameter of 2cm or greater, depth beyond the dermis, immune compromise of the host, and histologic features including poorly differentiated tumor cells and perineural invasion (PNI). 2 PNI has been estimated to occur in 2% to 14% of CSCCs. It has been as- sociated with a markedly poor prognosis, with rates of metastasis as high as 47% and survival rates less than 30% reported in the literature. 3–5 A recent re- view of CSCC outcomes showed CSCC with PNI to have significantly higher risks of local recurrence, distant metastasis, and disease-specific death than nonperineural CSCC with other high-risk factors. In & 2009 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc.  ISSN: 1076-0512  Dermatol Surg 2009;35:1859–1866  DOI: 10.1111/j.1524-4725.2009.01354.x 1859 Ã Division of Dermatology, Department of Medicine, Vanderbilt School of Medicine, Nashville, Tennessee; y College of Medicine, Temple University, Philadelphia, Pennsylvania; z Division of Dermatopathology, Department of Dermatology, y Department of Pathology, and z Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; and J Mohs Micrographic Surgery Center Harvard Medical School, Dana Farber/Brigham and Women’s Hospital, Boston, Massachusetts.