STUDY. Outcomes of Primary Cutaneous Squamous Cell Carcinoma With Perineural Invasion

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1 STUDY Outcomes of Primary Cutaneous Squamous Cell Carcinoma With Perineural Invasion An 11-Year Cohort Study Joi B. Carter, MD; Matthew M. Johnson, MD; Tiffany L. Chua, MA, MPH; Pritesh S. Karia, MPH; Chrysalyne D. Schmults, MD, MSCE Objective: To identify factors associated with poor outcomes in perineurally invasive squamous cell carcinoma. Design: Retrospective cohort study. Setting: Two academic hospitals in Boston, Massachusetts. Patients: Adults with perineural SCC diagnosed from 1998 to Main Outcome Measures: Hazard ratios (HRs) for local recurrence, nodal metastasis, death from disease, and overall death, adjusted for known prognostic factors. Results: A total of 114 cases were included, all but 2 involving unnamed nerves. Only a single local recurrence occurred in cases with no risk factors other than nerve invasion. Tumors with large nerve ( 0.1 mm in caliber) invasion were significantly more likely to have other risk factors, including diameters of 2 cm or greater (P.001), invasion beyond the subcutaneous fat (P.003), multiple nerve involvement (P.001), infiltrative growth (P=.01), or lymphovascular invasion (P=.01). On univariate analysis, large nerve invasion was associated with increased risk of nodal metastasis (HR, 5.6 [95% CI, ]) and death from disease (HR, 4.5 [95% CI, ]). On multivariate analysis, tumor diameter of 2 cm or greater predicted local recurrence (HR, 4.8 [95% CI, ]), 1 risk factor predicted nodal metastasis (2 factors: HR, 4.1 [95% CI, ]), lymphovascular invasion predicted death from disease (HR, 15.3 [95% CI, ]), and overall death (HR, 1.1 [95% CI, ]). Invasion beyond subcutaneous fat also predicted overall death (HR, 2.1 [95% CI, ]). Conclusions: Squamous cell carcinoma involving unnamed small nerves ( 0.1 mm in caliber) may have a low risk of poor outcomes in the absence of other risk factors. Large-caliber nerve invasion is associated with an elevated risk of nodal metastasis and death, but this is due in part to multiple other risk factors associated with large-caliber nerve invasion. A larger study is needed to estimate the specific prognostic impact of nerve caliber. JAMA Dermatol. 2013;149(1):35-41 Author Affiliations: Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Carter); Miraca Life Sciences, Newton, Massachusetts (Dr Johnson); and Department of Dermatology, Brigham and Women s Hospital, Harvard Medical School, Boston (Ms Chua, Mr Karia, and Dr Schmults). SQUAMOUS CELL CARCINOMA (SCC) is the second most common type of skin cancer, with approximately new cases of SCC recorded in 2000 in the United States alone. 1 While most SCCs can be cured with excision or Mohs surgery, approximately 5% of all SCCs will metastasize, and the rate of metastasis increases up to 20% in SCCs with high-risk features. 2 Various guidelines delineating these high-risk features have been published based on available data. The American Joint Committee on Cancer (AJCC) published a modified staging system for cutaneous SCC in 2011, which included the following high-risk characteristics that have an impact on tumor stage: depth greater than 2 mm, Clark level IV or greater, perineural invasion, location on ear or vermillion lip, and poorly differentiated or undifferentiated growth pattern on histologic analysis. 2 Perineural invasion (PNI) is one of the new additions to the AJCC staging system and occurs in approximately 2.5% to 5% of primary SCCs. 3,4 Perineural invasion portends poor outcomes with reported risks of lymph node metastasis and distant metastasis of 35% and 15%, respectively, compared with SCC without See Practice Gaps at end of article PNI (in which risks were 15% and 3.3%, respectively in the same study). 5 Squamous cell carcinoma with PNI is also associated with increased mortality. One study reported a 64% 3-year diseasespecific survival for patients with SCC with PNI compared with 91% for SCC without PNI. 6 Previous studies have shown that the extent of nerve invasion has an impact on prognosis. Ross et al 7 found significantly Author Aff Departmen Massachuse Hospital, H School, Bos Miraca Life Massachuse and Depart Dermatolog Women s H Medical Sch (Ms Chua, Dr Schmult 35

2 higher risks of recurrence, metastasis, and diseasespecific mortality in 24 SCCs with PNI of nerves 0.1 mm or greater in diameter compared with 24 SCCs with PNI less than 0.1 mm in diameter. Another study found no difference in 5-year recurrence for 34 SCCs with PNI that are 0.1 mm or smaller vs 28 SCCs with PNI larger than 0.1 mm. 8 However, this study was limited to patients treated with both surgery and radiation, most of whom had positive surgical margins prior to salvage radiation, portending a worse baseline prognosis. The study did find that focal nerve invasion carried a better prognosis than more extensive invasion. Similarly, patients with only microscopic PNI have been shown to have improved local disease control and 10-year survival compared with patients with clinically symptomatic or radiographic perineural invasion Thus, the degree of nerve invasion is likely prognostically important, although optimal classification of varying degrees of invasion remains uncertain. The lack of precise prognostic estimates for SCCs with different degrees of nerve invasion adjusted for other concomitant risk factors prevents clear guidance on the clinical approach to SCC with PNI. This is reflected in heterogeneity of management, as evidenced in a study of Mohs surgeons in which there was little consensus regarding when adjuvant radiation should be used. 12 Clarification of the prognostic significance of different degrees of PNI in combination with other risk factors would aid clinicians in selecting appropriate workup and treatment while minimizing unnecessary treatment and resulting morbidity. This study was undertaken to address the current knowledge gap by comparing outcomes of patients with SCC with large- ( 0.1mm) vs small- ( 0.1 mm) caliber PNI, adjusting for presence of other concomitant prognostic factors via multivariate analysis. METHODS IDENTIFICATION OF COHORT After approval from the Partners Healthcare institutional review board, all patients treated at Massachusetts General Hospital or Brigham and Women s Hospital from January 1, 1998, and December 31, 2008, with pathologically confirmed cutaneous SCC with PNI or neurotropism (NT) were identified via the dermatopathology and surgical pathology databases. The following words contained in the pathology reports were used to search the databases: squamous, nerve, nerves, neural, perineural, neurotropic, and neurotropism. Only patients with PNI in the primary tumor were included. Patients were excluded if the tumor did not have NT or PNI on review by the investigators, if the slides or medical records were not available, if the PNI was identified only in recurrent tumor, or if cutaneous origin of the primary tumor could not be confirmed. MEDICAL RECORD REVIEW Medical records were obtained, and the following information was extracted for each tumor: body location, date of procedure, tumor diameter, preceding scar, preceding radiation therapy, associated symptoms, duration of lesion prior to treatment, dates and methods of all treatments of the primary tumor, as well as any recurrence and/or metastasis, date and type of recurrence (local, in-transit, lymph node, distant organ), and whether a named nerve branch was involved. Patient-specific information was extracted including sex, race/ethnicity, skin cancer history, immunosuppression status, presence of noncutaneous malignant diseases, and, for deceased patients, cause of death as noted in medical records or death certificate. HISTOLOGIC EVALUATION Each case was assigned a study number, and slides were labeled with this unique study number to deidentify them. In a blinded fashion, slides of the tumors were reviewed (by M.M.J., J.B.C., and C.D.S.) for perineural invasion (defined as invasion of the nerve fiber or the presence of neoplastic cells within the perineural space, located between the perineurium and the nerve fiber) or neurotropism (defined as neoplastic cells adjacent to, but not within, the perineural space). Other histologic characteristics of the tumor were recorded, including maximum tumor depth in millimeters as well as by tissue level, involvement of margins on final excision of primary tumor, differentiation of tumor, and presence of lymphatic or vascular invasion. Recorded characteristics of the nerve(s) involved included diameter of the largest involved nerve, number of nerves involved, location of nerve invasion either within the tumor or discontiguous from the tumor, as well as tissue level of the perineural invasion. In cases in which any of this information was ambiguous, a consensus opinion was reached (by J.B.C. and C.D.S.). Both biopsy and excision specimens were evaluated for each primary tumor. Tumors were classified for study analysis according to the greatest degree of nerve involvement seen. STATISTICAL ANALYSIS Cases were assigned to 1 of 2 groups: small-caliber nerve group (PNI of nerves 0.1mm) and large-caliber nerve group (PNI of nerves 0.1 mm). Tests for differences in patient characteristics by nerve caliber group were performed using 2 test for nominal variables and t tests for continuous variables. In analyses with low case numbers of nominal variables, Fisher exact test was used. Large and small nerve caliber groups were compared regarding 4 outcomes of interest (local recurrence [LR], nodal metastasis [NM], death from SCC/disease-specific death [DSD], and all-cause death [ACD]) adjusted for other potential risk factors via multivariate Cox proportional hazard models developed through forward stepwise selection using a stay criterion of.05 or less. Other risk factors included age, sex, immunosuppression, tumor diameter, tumor depth, differentiation, number of nerves involved, lymphovascular invasion, and number of independent prognostic factors present ( Jambusaria-Pahlajani et al 13 ). Each tumor was analyzed as an independent case. Data analysis was performed using SAS statistical software (version 9.2; SAS Institute Inc). All hypothesis tests used a 2-sided significance level of.05. RESULTS PATIENT AND TUMOR CHARACTERISTICS The initial pathology database query identified 164 cases as primary cutaneous SCCs with PNI or NT. Twentythree cases were excluded after histologic review because they had only NT (n=13) or did not have any identifiable PNI or NT (n=10). Of the 141 remaining cases, 15 cases were excluded owing to incomplete slide sets, and 12 cases were excluded owing to insufficient follow-up information in the medical record. The final co- 36

3 Table 1. Tumor Characteristics by Nerve Caliber Group a Tumor Characteristic Large-Caliber (n = 46) Type of PNI, No. (%) Treatment of primary tumor Standard excision 35 (76) 55 (80) Radiation monotherapy 0 1 (1.5) Mohs 6 (9) 11 (16) Other combination therapy 5 (11) 1 (12) Tumor diameter 2 cm 29 (63) 63 (93) 2 cm 17 (37) 5 (7) Tumor differentiation Well 10 (22) 22 (32) Moderate 27 (59) 36 (53) Poor 9 (20) 10 (15) Depth of invasion Dermis 8 (17) 35 (52) Subcutaneous fat 19 (41) 26 (38) Beyond subcutaneous fat 19 (41) 7 (10) Nerves involved, No. 1 9 (20) 45 (66) (52) 19 (28) 5 13 (28) 4 (6) None 39 (85) 67 (99) Location of PNI Intratumor 20 (44) 46 (68) Extratumor 13 (28) 18 (27) Both 13 (28) 4 (6) Infiltrative pattern Yes 32 (70) 31 (46) No 14 (30) 37 (54) Maximal tumor depth 4 mm 5 (11) 24 (35) 4 mm 35 (76) 42 (62) Named nerve involved Yes 2 (4) 0 (0) No 44 (96) 68 (100) Vascular invasion Yes 8 (17) 2 (3) No 38 (83) 66 (97) Lymphatic invasion Yes 7 (15) 1 (2) No 39 (85) 67 (99) Small-Caliber (n = 68) P Value b Abbreviation: PNI, perineural invasion. a Large-caliber PNI: largest nerve invaded by tumor 0.1 mm or greater in diameter; small-caliber PNI: largest involved nerve less than 0.1 mm in diameter. b 2 or Fisher exact test Table 2. Number of Outcome Events by Nerve Caliber Group Outcome of Interest Type of PNI, No. (%) Large-Caliber (n = 46) hort contained 114 cases of primary SCC, with PNI occurring in 96 patients, 46 cases with large-caliber nerve invasion, and 68 with small-caliber nerve invasion. The large-caliber and small-caliber groups were similar in many regards: there was a male predominance (71% male) and mean (SD) age at time of diagnosis was 71 (12) years. All cases occurred in patients identified as white with the exception of a single case in an African American and 5 cases in persons of unknown race. Two cases were in Latinos. Eight patients had more than 1 SCC with PNI. Six of these patients had 2 SCCs with PNI, 1 patient had 3, and a single heart transplant patient had 11 SCCs with PNI. Since the event rate was low in this subgroup (2 LRs and 1 NM occurring in 2 persons, both of whom had 2 SCCs with PNI), each case of SCC with PNI was analyzed independently. Immunostaining (cytokeratin) had been performed in only 4 cases. Two cases involved named nerves, all others involved unnamed nerves. Of 21 cases in which radiologic imaging of the primary tumor was obtained, no case had radiologic evidence of nerve invasion. One patient noted a sharp pain at the site of the tumor. There was no other clinical evidence of nerve invasion. Additional characteristics, including all variables that significantly differed between large- and smallcaliber nerve groups, are summarized in Table 1. Tumors with large-caliber nerve invasion were statistically more likely to have other risk factors than smallcaliber nerve invasion cases, specifically tumor diameter greater than 2 cm (37% vs 7%; P.001), maximum depth of tumor greater than 4 mm (76% vs 62%; P =.003), invasion beyond subcutaneous fat (41% vs 10%; P.001), vascular invasion (17% vs 3%; P =.01) and lymphatic invasion (15% vs 2%; P =.02). They were also more likely to have multiple nerves involved (P.001) and to have nerve involvement both within as well as discontiguous from the tumor (P =.002) (Table 1). Tumors with largercaliber nerve invasion had significantly shorter follow-up time than those with small-caliber invasion (2.7 vs 4.0 years; P =.02), which would tend to underestimate occurrence of poor outcomes in the large-caliber group. However, this difference was adjusted for in Cox models. Thirty-seven SCCs (24% of cases) occurred in immunocompromised patients (27 with organ transplants, 6 with chronic lymphocytic leukemia, 3 with lymphoma, and 1 with human immunodeficiency virus). Immunosuppression was equally common in large- and smallcaliber nerve groups and was not significantly associated with any outcomes of interest on univariate or multivariate modeling. TREATMENT Small-Caliber (n = 68) P Value a Local recurrence 10 (22) 8 (12).15 Nodal metastases 8 (17) 3 (4).03 Death from SCC 6 (13) 2 (3).06 All-cause death 22 (48) 30 (44).70 Abbreviations: PNI, perineural invasion; SCC, squamous cell carcinoma. a Fisher exact test. Treatment of the primary tumor included standard excision (n = 72 cases), standard excision plus radiation (n = 15 cases), standard excision plus lymph node dissection (n = 3 cases), Mohs surgery (n = 15 cases), Mohs surgery plus radiation (n = 2 cases), radiation monotherapy (n = 1 case), electrodessication and curettage (n = 1 case), or other combination therapy (n = 5 cases). Adjuvant radiation was performed in a total of 20 cases (18%) (n = 5 in the smallcaliber nerve invasion group, n = 15 in the large-caliber nerve invasion group). Treatment type was not associated 37

4 Table 3. Number of Outcome Events by Number of Non Perineural Invasion Risk Factors Present a Risk Factors, No. (%) Caliber of PNI, Events (No.) Large (n = 46) Risk factors 8 (17) 12 (26) 18 (39) 8 (17) Local recurrence (n = 10) 0 2 (20) 4 (40) 4 (40) Nodal metastases (n = 8) 0 2 (25) 3 (38) 3 (38) Death from SCC (n = 6) (50) 3 (50) All-cause death (n = 22) 3 (14) 6 (27) 8 (36) 5 (23) Small (n = 68) Risk factors 21 (31) 36 (53) 11 (16) 0 Local recurrence (n = 8) 1 (13) 4 (50) 3 (38) 0 Nodal metastases (n = 3) 0 2 (67) 1 (33) 0 Death from SCC (n = 2) (100) 0 All-cause death (n = 30) 11 (37) 11 (37) 8 (27) 0 Abbreviations: PNI, perineural invasion; RF, risk factor; SCC, squamous cell carcinoma. a Risk factors (not including PNI): moderate or poor tumor differentiation, tumor diameter of at least 2 cm, or depth of invasion beyond subcutaneous fat. Table 4. Unadjusted Hazard Ratios (HRs) Predicting Outcomes of Interest in Univariate Analysis a Local Recurrence Nodal Metastases Death From SCC All-Cause Death Characteristic HR (95% CI) P Value HR (95% CI) P Value HR (95% CI) P Value HR (95% CI) P Value Age, y 1.0 ( ) ( ) ( ) ( ).001 Sex Female 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] Male 7.8 ( ).046 HR inestimable all... HR inestimable all ( ).21 events in males events in males Nerve caliber involved Small-caliber 1 [Reference] 1 [Reference] 1 [Reference] 1.0 [Reference] Large-caliber 1.9 ( ) ( ) ( ) ( ).18 Tumor diameter 2 cm 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] 2 cm 4.8 ( ) ( ) ( ) ( ).005 Tumor differentiation Well 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] Moderate or poor 3.2 ( ).13 HR inestimable all... HR inestimable all ( ).81 events in this group events in this group Named nerve involved No 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] Yes 3.1 ( ) (1-64.1) ( ) ( ).63 Depth of invasion Dermis/subcutaneous 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] fat Beyond subcutaneous 3.1 ( ) ( ) ( ) ( ).09 fat Nerves involved, No. 1 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ).31 Risk factors, No [Reference] 1 [Reference] 1 [Reference] 1 [Reference] ( ) a 4.1 ( ) ( ) ( ) ( ) ( ) ( ).02 Vascular or lymphatic invasion No 1 [Reference] 1 [Reference] 1 [Reference] 1 [Reference] Yes 2.1 ( ) ( ) ( ) ( ).004 a Risk factors included: moderate or poor tumor differentiation, tumor diameter of at least 2 cm, or depth of invasion beyond subcutaneous fat. b Reference group of 0 to 2 risk factors was used for nodal metastasis outcome only. with differences in outcomes of interest. Of the 17 cases treated with Mohs surgery, 2 had PNI identified during Mohs surgery that had not been identified on initial biopsy. In 1 of these cases, clear margins could not be obtained, and the patient underwent adjuvant radiation. Clear margins were obtained in the other 16 Mohs cases. 38

5 RISK FACTORS FOR OUTCOMES OF INTEREST The overall risks of outcomes of interest were as follows: LR, 16%; NM, 10%; DSD, 7%; and ACD, 46%. Table 2 and Table 3 tabulate the number of events for each outcome by nerve caliber group and by number of non-pni risk factors present (moderate or poor differentiation, diameter 2 cm, or invasion beyond subcutaneous fat). Outcomes were excellent in cases in which PNI was the only risk factor (regardless of nerve caliber) with only a single local recurrence in these 29 cases. On univariate analysis (Table 4), large-caliber nerve invasion was associated with significantly increased risks of NM and DSD (hazard ratio [HR], 5.6 [95% CI, , and HR, 4.5 [95% CI, ], respectively).on multivariate analysis, nerve caliber did not predict any outcome of interest. However, tumor diameter of 2 cm or greater predicted LR (HR, 4.8 [95% CI, ), presence of multiple risk factors predicted NM (2 factors: HR, 4.1 [95% CI, ], and 3 factors: HR, 14.1 [95% CI, ]), and lymphovascular invasion predicted DSD (HR, 15.3 [95% CI, ]) and ACD (HR, 1.1 [95% CI, ]). Invasion beyond subcutaneous fat and older age also predicted ACD (HR, 2.1 [95% CI, ], and HR, 1.1 [95% CI, ], respectively). The results of the multivariate models are summarized in Table 5. COMMENT Perineural invasion of unnamed nerves without other risk factors may have a better prognosis than previously thought. There was only a single local recurrence in this 29-patient subset. Conversely, in cases with other risk factors, a 4- and 14-fold increased risk of nodal metastasis was found in patients with 2 and 3 other risk factors, respectively. Cases with large-caliber nerve invasion were significantly more likely to have other concomitant risk factors, including nerve diameter of 2 cm or greater, invasion beyond the subcutaneous fat or a 4-mm depth, multiple nerve involvement, infiltrative growth, or lymphovascular invasion. Large-caliber nerve invasion was associated with an increased risk of nodal metastasis and death from SCC on univariate analysis. However, on multivariate analysis, other risk factors predominated in predicting poor outcomes, including tumor diameter of 2 cm or greater, presence of more than 1 non-pni risk factor, lymphovascular invasion, and invasion beyond subcutaneous fat. Perineural invasion was recently added to the AJCC SCC staging criteria as a high-risk characteristic. However, there are data to suggest that limited nerve involvement may not have an impact on prognosis as adversely as advanced nerve invasion (Table 6) The findings of this study are consistent with those data, because largecaliber PNI was associated with a 4- to 5-fold increased risk of nodal metastasis and death due to SCC on univariate analysis, indicating that it may be associated with a worse prognosis than small-caliber PNI. Thus, SCC with large-caliber nerve invasion may be considered highrisk, and adjuvant therapy may be considered in such cases. The results further indicate that regardless of nerve Table 5. Adjusted Hazard Ratios (HRs) Predicting Outcomes of Interest in Multivariate Analysis a Outcome HR (95% CI) P Value Local Recurrence Tumor diameter 2 cm 1 [Reference] 2 cm 4.8 ( ).001 Nodal Metastasis Risk factors a [Reference] ( ) ( ).001 Death From SCC Vascular or lymphatic invasion No 1 [Reference] Yes 15.3 ( ).001 All-Cause Death Age 1.1 ( ).001 Vascular or lymphatic invasion No 1 [Reference] Yes 1.1 ( ).004 Depth of invasion Dermis/subcutaneous fat 1 [Reference] Invasion beyond subcutaneous fat 2.1 ( ).04 Abbreviation: SCC, squamous cell carcinoma. a Risk factors included moderate or poor tumor differentiation, tumor diameter of at least 2 cm, or depth of invasion beyond subcutaneous fat. caliber, patients without other risk factors (moderate or poor differentiation, diameter of 2 cm or greater, or tumor penetration beyond subcutaneous fat) have a good prognosis. This is an important finding because it suggests that there are factors other than PNI that may be more robust prognostic indicators. Because largecaliber PNI occurs together with the strong prognostic predictors described herein more often than smallcaliber nerve invasion, it may be a marker for tumors with a particularly poor prognosis owing to the presence of numerous high-risk features. This study was limited to patients diagnosed as having SCC with PNI at 2 academic medical centers. It is possible that there are differences between patients seen at academic centers and those seen elsewhere. However, the study population was confined to those with primary tumors. Thus, the tendency for overestimation of poor outcomes at academic hospitals owing to tertiary care of recurrent tumors was minimized. Although to our knowledge this is the largest cohort study of primary SCC with PNI to date, it was powered only to define the strongest prognostic predictors. A larger study might show that additional risk factors significant on univariate analyses, such as caliber of involved nerves and number of nerves involved, are also independent predictors of outcomes in SCC with PNI. Because only 2 cases in this cohort had invasion of named nerves, the prognosis of this type of extensive PNI could not be fully evaluated. Since prognosis has previously been reported to be poor in patients with involvement of named nerves, named nerve invasion should continue to be regarded as having a high risk of poor outcomes, regardless of presence or absence of other risk factors. 39

6 Table 6. Previous Outcome Studies of Cutaneous Squamous Cell Carcinoma (SCC) With Perineural Invasion (PNI) Source Current study Goepfert et al, Lin et al, Ballantyne et al, Leibovitch et al, Ross et al, McCord et al, and McCord et al, Garcia-Serra et al, Study Description 11-y retrospective cohort of all SCC with PNI at 2 academic hospitals 10-y retrospective cohort of SCC of the head and neck at a single academic hospital 14-y retrospective cohort of SCC with PNI treated with radiation at a single hospital without clinical features Several -year retrospective cohort of head and neck SCC at a single academic hospital 10-y multicenter prospective cohort of SCC treated with Mohs surgery 10-y retrospective cohort of all SCC with PNI at a single academic hospital 30-y retrospective cohort of head and neck BCC and SCC with PNI treated with radiation at a single hospital (IPNI: 31 SCC. Clinical PNI: 46 SCC) 34-y retrospective cohort of head and neck BCC and SCC at a single academic hospital (MPNI: 48 SCCs; clinical PNI: 57 SCCs) Sample Size Primary Recurrent Treatment Excision, Mohs, ± RT Local Recurrence Nodal Metastasis No. (%) Distant Metastasis Disease-Specific Death 18 (16) 11 (10) 1 (2) 8 (7) NR 34 (47) 25 (35) 11 (15) NR Surgery RT, RT alone 5-y RFS PNI 0.1 mm (n = 34); RFS = 77%; 0.1 mm (n = 28); RFS = 86%; unspecific diameter (n = 71); RFS = 75% 6 28 Surgery, RT NR NR NR 53% Mohs, ± RT 2 (8) at 5 y follow-up SCNI a 22 1 LCNI b IPNI CPNI MPNI CPNI Mohs, WLE, ±RT Surgery RT, RT only Surgery RT, RT only SCNI: 2 (9) LCNI: 12 (50) IPNI: 8 (23) CPNI: 29 (47) MPNI: 14% CPNI: 38% None None None SCNI: No events LCNI: 9 (38) IPNI: 1 (3) CPNI: 6 (10) MPNI:14% CPNI: 5% SCNI: No events LCNI: 8 (32) IPNI: 2 (6) CPNI: 1 (2) MPNI: 3% CPNI: 0% SCNI: No events LCNI: 8 (32) IPNI: 26 CPNI: 54 NR Abbreviations: BCC, basal cell carcinoma; CPNI, clinical PNI; IPNI, incidental PNI; MPNI, microscopic PNI; NR, not recorded; RFS, relapse-free survival; RT, radiation therapy; SCC, squamous cell carcinoma; WLE, wide local excision. a Small-caliber nerve invasion ( 0.1 mm in diameter). b Large-caliber nerve invasion ( 0.1 mm in diameter). Because all patients in this study had PNI, the prognostic importance of PNI as a whole, relative to other risk factors, could not be evaluated. In a larger cohort study of SCC outcomes that contains SCC with and without PNI (Schmults et al 15 ), PNI invasion is an independent prognostic factor in multivariate analysis ( Jambusaria- Pahlajani et al 13 ). However, a still-larger, populationbased study of SCC outcomes will likely be necessary to establish the prognostic impact of different gradations of PNI (eg, nerve caliber) in multivariate analysis. Based on the univariate data herein showing good outcomes with small nerve invasion and worse outcomes with large nerve invasion, and other studies that have shown a poor prognosis for patients with SCC with large named nerve or otherwise extensive nerve invasion, it is likely that larger studies will bear out in multivariate modeling that extensive nerve invasion is independently associated with worse outcomes, while lesser nerve invasion is not. Since small-caliber nerve invasion without other risk factors had an excellent prognosis in this study, adjuvant therapy in such cases may not be necessary. In conclusion, SCC invading unnamed nerves of caliber smalller than 0.1 mm without other risk factors may have a good prognosis. However, perineurally invasive SCCs with other risk factors (moderate or poor differentiation, diameter of 2 cm, or deep invasion beyond subcutaneous fat) have a high risk of poor outcomes and may be considered for adjuvant therapy. Large-caliber nerve invasion commonly occurs concomitantly with other risk factors and may therefore be a marker of poor prognosis. Larger studies are needed to estimate the specific prognostic impact of large-caliber nerve invasion on SCC outcomes. Accepted for Publication: June 20, Correspondence: Chrysalyne D. Schmults, MD, MSCE, Mohs and Dermatologic Surgery Center, Department of Dermatology, Brigham and Women s Hospital, 1153 Cen- 40

7 tre St, Ste 4349, Jamaica Plain, MA Author Contributions: Drs Carter and Schmults had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the analysis. Study concept and design: Carter and Schmults. Acquisition of data: Carter, Johnson, Chua, and Karia. Analysis and interpretation of data: Carter, Karia, and Schmults. Drafting of the manuscript: Carter and Karia. Critical revision of the manuscript for important intellectual content: Carter, Johnson, Chua, Karia, and Schmults. Statistical analysis: Karia and Schmults. Administrative, technical, and material support: Carter and Karia. Study supervision: Carter and Schmults. Conflict of Interest Disclosures: None reported. Additional Contributions: We thank Travis Hollmann, MD, PhD, and Victor Neel, MD, PhD. REFERENCES 1. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005; 294(6): Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol. 2011;64(6): Leibovitch I, Huilgol SC, Selva D, Hill D, Richards S, Paver R. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia, II: perineural invasion. J Am Acad Dermatol. 2005;53(2): Mohs FE, Lathrop TG. Modes of spread of cancer of skin. AMA Arch Derm Syphilol. 1952;66(4): Goepfert H, Dichtel WJ, Medina JE, Lindberg RD, Luna MD. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg. 1984;148 (4): Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005;23(4): Ross AS, Whalen FM, Elenitsas R, Xu X, Troxel AB, Schmults CD. Diameter of involved nerves predicts outcomes in cutaneous squamous cell carcinoma with perineural invasion: an investigator-blinded retrospective cohort study. Dermatol Surg. 2009;35(12): Lin C, Tripcony L, Keller J, et al. Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features. Int J Radiat Oncol Biol Phys. 2012;82(1): McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys. 2000;47 (1): McCord MW, Mendenhall WM, Parsons JT, Flowers FP. Skin cancer of the head and neck with incidental microscopic perineural invasion. Int J Radiat Oncol Biol Phys. 1999;43(3): Garcia-Serra A, Hinerman RW, Mendenhall WM, et al. Carcinoma of the skin with perineural invasion. Head Neck. 2003;25(12): Jambusaria-Pahlajani A, Hess SD, Katz KA, Berg D, Schmults CD. Uncertainty in the perioperative management of high-risk cutaneous squamous cell carcinoma among Mohs surgeons. Arch Dermatol. 2010;146(11): Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC Tumor (T) Staging for Cutaneous Squamous Cell Carcinoma and a Proposed Alternative Tumor Staging System. JAMA Derm. In Press. 14. Ballantyne AJ. Perineural invasion by SCC. J Dermatol Surg Oncol. 1984;10(7): Schmults CD, Karia PS, Carter JB, Han J, Qureshi AA. Factors predictive of recurrence and death in cutaneous squamous cell carcinoma: a 10-year single institution study. JAMA Derm. In Press. PRACTICE GAPS Data Needed for Management of Cutaneous Squamous Cell Carcinoma A common task for dermatologists is treatment of primary and/or recurrent cutaneous squamous cell carcinoma (SCC). A biopsy specimen is taken to confirm the diagnosis, and the pathology report is reviewed for prognostic parameters of the tumor, which typically include degree of differentiation and margin involvement but may or may not comment on perineural invasion. Perineural invasion has long been considered to be an adverse prognostic parameter and is found in many other cutaneous malignant tumors, notably basal cell carcinoma, microcystic adnexal carcinoma, and melanoma. In SCC, involvement of large, named nerves documented by clinical signs, symptoms, or radiographic evidence is generally accepted as a significant adverse finding and is usually treated by adjuvant therapy following surgical removal. But what about microscopic nerve involvement seen on the diagnostic biopsy material or subsequent tissue obtained during surgical removal? Carter et al 1 evaluated their experience in 114 cases of SCC with histologically documented perineural invasion managed in 2 academic centers over an 11-year period. They focused on the outcomes of patients with large vs small microscopic nerve involvement (diameter, 0.1 mm vs 0.1 mm) and adjusted for other concomitant prognostic factors. Large-caliber nerve involvement ( 0.1 mm) was found to have an elevated risk of nodal metastasis and death, but these cases were associated with multiple other risk factors. Small-caliber nerve involvement had a much lower adverse risk. The authors advocate for the need of a larger study to fully evaluate the impact of nerve involvement based on size of nerves and number of involved nerves as independent prognostic variables. If we return to our patient with cutaneous SCC, what information do we need to better plan treatment? The list below of adverse prognostic factors in cutaneous SCC shows important adverse prognostic factors 2 and includes documenting the number of nerves involved and caliber of the largest nerve. Anatomic location on ear or nonglabrous lip Tumor size greater than 2 cm 41

8 Tumor thickness greater than 2 mm Clark level of at least 4 Cytologic differentiation classified as poor Perineural involvement classified as more largercaliber nerves than small-caliber nerves It may also be helpful to also document the type of procedure: Mohs vs surgical excision, as en face sectioning allows a much larger examination of the deep margin of the tumor. Standardization of evaluation for nerve involvement would make data more comparable, and there could be documentation of the number of fields examined or the use of double staining for cytokeratin and S100 protein. This is important to ensure that negative nerve involvement is a true finding. Collecting this information in a prospective fashion across multiple sites, both primary and referral, will help provide answers to multiple questions. Should adjuvant therapy be used if perineural invasion is present? Is there a cutoff of nerve caliber? Should a larger excision or an additional Mohs layer be performed if there is nerve involvement? Capturing specific information about tumors in a pathology report in a standardized format will provide the data on which to base recommendations and guidelines for care. Antoinette F. Hood, MD Evan R. Farmer, MD Author Affiliations: Department of Dermatology, Eastern Virginia Medical School, Norfolk (Dr Hood); and Miraca Life Sciences Research Foundation, Irving, Texas (Dr Farmer). Correspondence: Dr Hood, Department of Dermatology, Eastern Virginia Medical School, 721 Fairfax Ave, Norfolk, VA (Hoodaf_194110@evms.edu). Conflict of Interest Disclosures: None reported. 1. Carter JB, Johnson MM, Chua TL, et al. Outcomes of primary cutaneous squamous cell carcinoma with perineural invasion: an 11-year cohort study. JAMA Dermatol. 2013;149(1): Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol. 2011; 64(6): The Best of the Best Top-Accessed Article: Primary Generalized and Localized Hypertrichosis in Children Vashi RA, Mancini AJ, Paller AS. Primary generalized and localized hypertrichosis in children. Arch Dermatol. 2001;137(7): Primary Generalized and Localized Hypertrichosis in Children remains an essential reference for physicians caring for children with primary hypertrichosis. In this article, Vashi and colleagues present a framework for recognizing and classifying primary hypertrichosis and defining patterns and associations. They highlight the limited treatment options and the significance of the psychosocial burden of these disfiguring conditions. As the authors noted, and to this day, the management of hypertrichosis in the pediatric population remains a challenge. Most of the currently available removal options are temporary, uncomfortable, and/or costly. Moreover, there are few data regarding their use in pediatric patients. Over the last decade, there have been significant discoveries relating to the identification of genes expressed in the hair follicle, and knowledge has been gained from families with rare hair disorders. 1 Understanding the potential genetic causes of primary hypertrichosis may provide insight into hair follicle development and normal hair growth, which could lead to improved treatments for this rare disorder. From October 2010 to August 2011, this article was accessed 1997 times on the Archives of Dermatology website. Maria C. Garzon, MD Contact Dr Garzon at the Department of Dermatology, Columbia University, 161 Fort Washington Ave, New York, NY (mcg2@columbia.edu). 1. Shimomura Y, Christiano AM. Biology and genetics of hair. Annu Rev Genomics Hum Genet. 2010;11: