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A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma
A prospective evaluation of the clinical, histologic, and therapeutic variables associated with incidental perineural invasion in cutaneous squamous cell carcinoma Michael Campoli, MD, PhD,a David G. Brodland, MD,b and John Zitelli, MDb Minneapolis, Minnesota, and Pittsburgh, Pennsylvania Background: The prognosis and management of incidental perineural invasion (PNI) in patients with cutaneous squamous cell carcinoma (CSCC) has not been well defined. Objective: We sought to investigate the clinical, histologic, and treatment characteristics associated with incidental PNI, histologic PNI extending beyond the tumor bulk, in patients with CSCC. Methods: We conducted a multicenter prospective analysis of patients with CSCC undergoing Mohs micrographic surgery. Results: The incidence of PNI was 4.6% in 753 CSCC cases. PNI was significantly associated with tumors of the head and neck (P = .039), larger tumor diameter (P \ .001), presence of clinically palpable lymphadenopathy (P = .012), and recurrent (P \ .001) and painful (P \ .001) tumors. Further, PNI was significantly associated with poor tumor differentiation (P \ .001), greater tumor thickness (P \ .001), a greater number of Mohs stages (P \.001), and larger estimated maximum Mohs margin (P \.001) required to clear the tumor. Limitations: The low numbers of patients demonstrating incidental PNI limits this study. Conclusions: The association of incidental PNI with clinicopathological indicators of poor prognosis suggests that incidental PNI may serve as a marker to improve the precision in the prognostic assessment of patients with CSCC. ( J Am Acad Dermatol 2014;70:630-6.) Key words: Mohs micrographic surgery; perineural invasion; prognostic factors; squamous cell carcinoma.
lthough no definitive, comprehensive clinicopathological system for cutaneous squamous cell carcinomas (CSCC) has yet been adopted, the presence of tumor cell invasion into and/or approximating a nerve (perineural invasion [PNI]) has been suggested to be an indicator of poor prognosis.1-14 The incidence of PNI in CSCC has been reported to range from 2.4% to 14%.1,2,12,15-28 The presence of PNI is frequently associated with those tumors demonstrating extensive soft-tissue spread,
A
frequent recurrences, and a decreased overall survival.1,2,19,20,28-30 Given its potential role in the clinical course of CSCC, some recommend that patients with PNI be treated with wider surgical margins, undergo sentinel lymph node dissection, and/or be treated with postoperative radiation therapy.25,31-36 Although PNI has been suggested to be a marker for more aggressive disease, it must be stressed that, with the exception of 1 study,24 most of the available
From the Fairview Medical Group, Minneapolisa; and Zitelli and Brodland PC, Pittsburgh.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication November 22, 2013. Reprint requests: Michael Campoli, MD, PhD, Dermatologic Surgery, 5200 Fairview Blvd, Wyoming, MN 55092. E-mail: [email protected].
Members of the study group who contributed to the data collection for this work are listed at the end of the article. Published online January 16, 2014. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.11.034
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information regarding PNI in CSCC has been obThe criterion for inclusion was all cases of histotained from a small number of heterogeneous logically confirmed CSCC treated with Mohs microretrospective studies.1,2,15-31 Many of these studies graphic surgery. Table I summarizes the clinical, have failed to present a unified definition of PNI, pathologic, and treatment parameters that were have used conventional techniques to evaluate hisassessed. The clinical variables immune suppression, topathology, and have not taken into account hetradiation exposure, and scarring skin conditions erogeneity of the patient populations investigated or were defined as: (1) organ transplant recipients, histopathological characterpatients with chronic lymistics of the lesions analyzed. phocytic leukemia, patients CAPSULE SUMMARY Moreover, none of the availwith AIDS and/or patients on able studies have presented a immunosuppressive medicaThe prognosis of patients with clear distinction between tions; (2) patients with a hiscutaneous squamous cell carcinoma PNI that is an incidental tory of ionizing radiation or showing incidental perineural invasion is finding on histology and psoralen plus ultraviolet A not well defined. PNI that is associated with exposure; and (3) patients This study demonstrates the clinical, gross neurologic deficits. with a history of burn injury, histologic, and treatment characteristics The latter, often referred to chronic nonhealing wound, associated with incidental perineural as clinical PNI, has clearly or immunobullous or coninvasion. been shown to be associated nective tissue disease. All with poor prognosis.1,2 On patients demonstrating craThis information strengthens our ability nial nerve deficits were the other hand, there is a to identify and stratify those patients excluded from the study. paucity of information availwith cutaneous squamous cell The degree of anaplasia was able regarding PNI that is not carcinoma at risk of perineural invasion. based on subjective assessdiscovered on normal pathment of differentiation. The ologic specimens but discovcategories were well, moderately, and poorly differered incidentally separate from the tumor bulk entiated, when the percentage of anaplastic cells in through histologic evaluation during surgical resecthe lesions were less than 25%, between 25% and tion in asymptomatic patients with CSCC, ie, inci50%, and greater than 50%, respectively. dental PNI. All surgeons used the previously described stanThe limited information available regarding incidard frozen section Mohs micrographic surgery dental PNI in CSCC has led to uncertainty in its technique.38 The treating Mohs micrographic surtreatment in patients. This uncertainty is evidenced by both the nonevidence-based consensus recomgeons carried out all excisions, mapping, and tissue mendations, developed by multidisciplinary examination. panels,13,14 and the variation in concordance rates Tumor thickness was established by comments made in the original biopsy report. In those cases between surgeons on how to treat these patients.37 where no depth was available on the original biopsy The goal of this work is to perform a multicenter report, measurements of tumor depth were made on prospective evaluation of the clinical, histologic, and the debulked tumor by the treating Mohs microtreatment characteristics associated with incidental graphic surgeons. PNI in patients with CSCC. The results reported The diagnosis of PNI was defined as the presence herein are the preliminary findings published in of tumor cell invasion into and/or the partial or anticipation of a 5-year follow-up study. complete encasement of a nerve resulting in histologically discernible tumor encircling or partially encircling a nerve either described in the biopsy METHODS report or as identified in the debulking specimen or A prospective, multicenter analysis of the clinical, Mohs sections. Cases that did not demonstrate PNI in histologic, and treatment characteristics of patients the original biopsy specimen or in any Mohs stage undergoing Mohs micrographic surgery for CSCC were classified as negative. within 4 academic and 11 private practice Mohs micrographic surgery sites was conducted over 25 Statistical analysis working days. Institutional review board approval All data were included in the original analysis. was obtained from the Western Institutional Review Patients were separated by PNI status and variables Board (protocol No. 20100110). Fellowship-trained were compared between categories using indepenMohs micrographic surgeons treated all patients and dent t tests or x2 tests, as appropriate, using software recorded all data. d
d
d
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Table I. Documented parameters of patients with cutaneous squamous cell carcinoma Clinical
Histologic
Therapeutic
Age Gender Reason for referral Presence of cranial nerve deficits
Presence of PNI Nerve diameter \ or [ 0.1 mm Degree of differentiation Clark level [V
Treating Mohs micrographic surgeon Postoperative diameter No. of Mohs stages Maximum width of excision required to clear tumor
Preoperative tumor diameter Anatomic location History of treatments Clinically palpable regional lymphadenopathy Pain associated with tumor Immune suppression Scarring skin condition Arsenic exposure Radiation exposure
Invasion beyond fat
PNI, Perineural invasion.
Table II. Clinical characteristics of study participants Clinical variables
No. of patients Mean age, y Male/female Anatomic location Head and neck Trunk Extremities Referred Primary vs recurrent Lymphadenopathy Pain associated with tumor Clinical risk factors* Treatment setting academic/ private practice
PNI (n = 35)
No PNI (n = 718)
P
33 78 24 (72.7%)/9 (27.3%)
620 75 442 (71.3%)/178 (28.7%)
.056 .769
32 2 1 26 21 2 25 11 21
513 175 30 519 514 6 305 100 345
(91.4%) (5.7%) (2.9%) (78.8%) (60%)/14 (40%) (5.7%) (71.4%) (31.5%) (60%)/14 (40%)
(71.4%) (24.4%) (4.2%) (83.4%) (71.6%)/204 (28.4%) (0.8%) (42.4%) (13.9%) (48%)/373 (52%)
.039
.810 <.001 .012 <.001 .004 .0167
Bold values indicate statistical significance. PNI, Perineural invasion. *Includes presence of immune suppression, scarring skin condition, arsenic exposure, or radiation exposure.
(STATA, Version 10, StataCorp LP, College Station, TX). All continuous variables were checked for normality and type I error rate was set at a = 0.05.
RESULTS A total of 653 patients were recruited into the study resulting in the analysis of 753 CSCC (Table II). PNI was diagnosed in 35 CSCC (4.6%) from 33 patients (5%). There were 21 cases of incidental PNI of 629 cases of primary CSCC (3.3%) and 14 cases of incidental PNI of 124 cases with recurrent CSCC (11.3%) comprising 57.6% and 42.4% of all incidental PNI cases, respectively. Previous treatments for recurrent CSCC with and without PNI included excision (78.5% and 33.6%), cryotherapy (14.2% and 60.0%), electrodesiccation and curettage
(21.5% and 20%), imiquimod (7.1% and 0%), 5fluorouracil (0% and 6.4%), Mohs micrographic surgery (0% and 3.6%), photodynamic therapy (0% and 0.9%), and radiation (0% and 1.8%), respectively. PNI was significantly associated with recurrent CSCC (P \.001) and treatment in an academic setting (P = .0167). CSCC with PNI was most common on the head and neck (31 cases, 88.5%), with 7 on the scalp (20%), 7 on the temple (20%), 5 on the forehead (14.2%), 5 on the cheek (14.2%), 3 on the ear (8.6%), 2 on the nose (5.7%), 1 on the eyelid (2.9%), and 1 on the neck (2.9%). The remaining PNI cases were located on the trunk (2 cases [5.7%]) and extremities (2 cases [5.7%]). PNI was significantly associated with tumors located on the head and
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neck (P = .039) and those on the scalp and temple (P = .018). The presence of regionally palpable lymphadenopathy and pain associated with the tumor was identified in 2 (5.7%) and 25 (71.4%) of the CSCC cases demonstrating PNI, compared with 6 (0.8%) and 305 (42.4%) of those cases without PNI. Given the relatively low number of CSCC demonstrating PNI, the clinical variables including immune suppression, radiation exposure, and scarring skin conditions were grouped together. In this regard, in 11 (31.5%) of the PNI cases and 100 (13.9%) of the non-PNI cases 1 or more of these clinical variables were identified. PNI was significantly associated with the presence of regionally palpable lymphadenopathy (P = .012), pain associated with the tumor (P \ .001), and the presence of 1 or more of aforementioned clinical variables (P = .004). The most common histologic subtypes for patients with PNI were well/moderately differentiated (22 cases, 62.8%) and poorly differentiated (13 cases, 37.2%), whereas for patients without PNI there were 690 (96.1%) well/moderately differentiated tumors and 28 (3.9%) poorly differentiated tumors. PNI was significantly associated with poorly differentiated histology (P \.001) (Table III). The mean tumor thickness and number of lesions Clark level V or greater in the CSCC cases demonstrating PNI was 6.4 6 3 mm (median 6 mm, range 120 mm) and 23 (65.7%) lesions, respectively (Table III). In contrast, in those cases without incidental PNI mean tumor thickness and number of lesions Clark level V or greater was 2.5 6 1 mm (median 1 mm, range 1-12 mm) and 43 (5.9%) lesions, respectively. PNI was found to be significantly associated with greater mean tumor thickness and Clark level V or greater (P \.001). In CSCC demonstrating PNI, 17 (48.6%) cases were found in nerves greater than 0.1 mm in diameter. Of these cases, 7 (41.1%) were recurrent tumors, 14 (82.4%) demonstrated painful tumors, 12 (70.6%) were greater than 2.0 cm in size, and 100% of the cases required 3 or more stages to clear the tumor. In contrast, of the CSCC with PNI in nerves smaller than 0.1 mm in diameter, 7 (38.9%) were recurrent tumors, 10 (55.6%) were painful tumors, 4 (22.2%) were greater than 2.0 cm in size, and 4 (22.2%) required 3 or more stages to clear the tumor. Notably, CSCC demonstrating PNI in nerves greater than 0.1 mm in diameter were significantly associated with larger tumor preoperative size, tumor thickness, tumor postoperative size, and greater number of stages required to clear the tumor (P \.001).
Table III. Histologic characteristics of cutaneous squamous cell carcinoma lesions Histologic variable
Differentiation Well/moderately differentiated Poorly differentiated Keratoacanthoma type Acantholytic Adenosquamous Thickness, mm \2 2-2.9 3-3.9 4-4.9 5-5.9 $6 ND Clark level $ V, mm
PNI (n = 35)
No PNI (n = 718)
P
\.001 22 (62.8%)
690 (96.1%)
13 (37.2%) 0
28 (3.9%) 6 (0.8%)
0 0 3 (8.5%) 0 2 (5.7%) 7 (20%) 5 (14.3%) 18 (51.5%) 23 (65.7%)
1 (0.1%) 2 (0.2%) \.001 321 (44.8%) 149 (20.7%) 99 (13.8%) 55 (7.6%) 29 (4.0%) 60 (8.4%) 5 (0.7%) 43 (5.9%) \.001
ND, No data; PNI, perineural invasion.
Tumor diameters before and after Mohs micrographic surgery were significantly larger in cases with PNI when compared with those without PNI (P \.001) (Table IV). Analysis of preoperative tumor diameter showed that 23 (65.7%) tumors with PNI were 2 cm or larger compared with only 115 (16.0%) of those with no PNI. In addition, defect sizes were 3 cm or larger in 22 (62.9%) cases with PNI compared with only 94 (13.1%) cases without PNI. In cases of CSCC with PNI, the mean number of Mohs stages and estimated maximum Mohs margin required to clear the tumor was 2.7 6 1.4 (median 2, range 1-10) and 8.0 6 6.0 mm (median 5 mm, range 1-25 mm), respectively (Table IV). In contrast, in non-PNI cases, the mean number of Mohs stages and estimated maximum width was 1.3 6 0.6 (median 1, range 1-5) and 2.9 6 2.1 mm (median 2 mm, range 1-12 mm). PNI was significantly correlated with a greater number of Mohs stages and a larger estimated maximum Mohs margin required to clear the tumor (P \ .001) (Table IV). Table V summarizes the clinical, histologic, and therapeutic variables statistically associated with incidental PNI in CSCC.
DISCUSSION We have identified 35 cases of incidental PNI in 753 cases of CSCC (4.6%). A majority of the CSCC exhibiting PNI (88.5%) were located on the head and neck and these findings are consistent with previous reports in the literature.1,2,12,15-28 The incidence of
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Table IV. Therapeutic characteristics of cutaneous squamous cell carcinoma lesions Therapeutic variable
PNI (n = 35)
No PNI (n = 718)
\1 1-1.9 2-2.9 3-3.9 $4 No. of Mohs layers 1 2 3 4 5 $6 Total Mohs margin, mm \2 2-2.9 3-3.9 4-4.9 5-5.9 $6
P
\.001
Tumor size, cm Preoperative 5 (14.3%) 7 (20%) 9 (25.7%) 5 (14.3%) 9 (25.7%)
Postoperative 0 (0%) 8 (22.9%) 5 (14.3%) 2 (5.7%) 20 (57.1%)
Preoperative 311 (43.3%) 291 (40.6%) 82 (11.4%) 19 (2.6%) 14 (2.1%)
Postoperative 89 (12.5%) 371 (51.8%) 162 (22.6%) 56 (7.8%) 38 (5.3%) \.001
5 15 6 5 1 3
(14.3%) (42.9%) (17.1%) (14.3%) (2.9%) (8.5%)
503 163 42 7 2 1
(70.0%) (22.8%) (5.9%) (0.9%) (0.3%) (0.1%)
2 4 2 7 3 17
(5.7%) (11.4%) (5.7%) (20.0%) (8.6%) (48.6%)
72 365 123 68 31 59
(10.0%) (50.9%) (17.1%) (9.5%) (4.3%) (8.2%)
\.001
PNI, Perineural invasion.
PNI we have reported is also consistent with the incidence of 5.95% reported by Leibovitch et al24 and is within the range of reported incidences (2.4%-14%).1,2,12,15-28 Nevertheless, it is difficult to compare most of these studies, because many of the previous reports have failed to present a unified definition of PNI, have used conventional histopathological techniques to evaluate histology, and have not strictly limited their analysis to incidental PNI. The number of CSCC cases with incidental PNI we have reported makes our series the largest prospective report in the literature. It is likely that the use of Mohs tissue sections may more accurately identify the true incidence of incidental PNI in CSCC, because the use of en face sections allows for better detection of tumors cells within the perineural space through a more thorough evaluation of the tissue section.38 From a clinical standpoint, incidental PNI was associated with tumors located on the head and neck, clinically palpable regional lymphadenopathy, painful tumors, recurrent tumors, and clinical variables such as immune suppression, radiation exposure, and scarring skin conditions. We were unable to independently assess the association between incidental PNI and separate clinical variables given the relatively low number of incidental PNI cases. Despite this, the association of incidental PNI with these clinical risk variables is in agreement with those in the literature.15-28 Five-year follow-up studies on this cohort of patients are in progress
and will help to strengthen these findings to identify and stratify those patients with CSCC at risk of PNI. Two reported risk factors for aggressive CSCC include tumor thickness and degree of tumor differentiation.14 In the current study, incidental PNI was significantly associated with both greater tumor thickness and more poorly differentiated histology (P \ .001). Our findings support previous studies15-21,24 indicating that PNI is more often seen in thicker and less differentiated histology subtypes of CSCC. Although we acknowledge that the data regarding tumor thickness must be interpreted with caution, the association between PNI and tumor thickness is likely to be significant, because tumor thickness greater than 6 mm has been the only standalone prognostic variable for high-risk CSCC.6 Whether tumors greater than 6 mm are more likely to demonstrate PNI or PNI leads to thicker and more aggressive tumor remains to be determined. More recently, 2 studies have suggested that higher risks of recurrence, metastasis, and diseasespecific mortality have been associated with PNI when it is found in nerves greater than 0.1 mm in diameter.28-30,39 We have found that CSCC demonstrating PNI in nerves greater than 0.1 mm in diameter were significantly associated with preoperative and postoperative tumor diameters, tumor thickness, and number of stages required to clear the tumor (P \ .001). The association of PNI in nerves
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Table V. Summary of clinical, histologic, and therapeutic variables associated with perineural invasion in cutaneous squamous cell carcinoma lesions Variables
Anatomic location on the head and neck Recurrent tumors Clinically palpable regional lymphadenopathy Pain associated with tumor Immune suppression/radiation/scarring skin condition Treatment setting in academic center Poorly differentiated Greater tumor thickness Greater preoperative tumor size Greater No. of Mohs layers Total Mohs margin
P
.039 \.001 .012 \.001 .004 .0167 \.001 \.001 \.001 \.001 \.001
greater than 0.1 mm with the latter clinicopathological indicators of high-risk CSCC argue in favor of the notion that nerve diameter represents a significant prognostic factor in CSCC. Whether these findings will carry through in the survival analysis of this cohort of patients remains to be determined. Tumor diameter has also been shown to be associated with more aggressive CSCC.15-28 We found that CSCC exhibiting PNI demonstrated preoperative tumor diameters that were significantly larger with more than 65% being greater than 2 cm compared with 16.1% CSCC without PNI (P \.001). Moreover, the postoperative defect sizes in CSCC with PNI were on average about 7 times larger than those tumors without PNI (P \ .001). Lastly, the mean number of Mohs stages required for complete tumor extirpation and estimated Mohs margin required to clear the tumor in cases of incidental PNI was on average 2 and 2.8 times larger, respectively, than those cases of CSCC without PNI (P \ .05). The latter findings, in conjunction with the association between PNI and incomplete removal of primary tumor, demonstrate the more invasive nature of CSCC with PNI and emphasize the need for margin control in the treatment of these tumors. In conclusion, this is the largest prospective multicenter study to our knowledge investigating the clinical, histologic, and treatment characteristics associated with incidental PNI in patients with CSCC. Although incidental PNI is an uncommon feature of CSCC, it was found to be associated with previously established markers of poor prognosis including tumor size, tumor depth, clinical risk factors, and significant subclinical extension. To this end, the association of incidental PNI with markers of poor
prognosis suggests that it may be a covariable in the clinical course of CSCC. Our findings suggest that documenting incidental PNI in histologic specimens may serve as a marker to improve the prognostic assessment of patients for future studies and provide vital information regarding clinical settings one may expect to see PNI, thereby alerting the treating clinician to the possibility. Moreover, given that comprehensive evaluation of tissue sections may more accurately identify PNI and the association between incidental PNI and previously established markers of poor prognosis, treatment of CSCC with Mohs micrographic surgery may offer significant benefit in identification and stratification of patients at risk and complete extirpation of high-risk CSCC. Five-year follow-up studies are in progress this cohort of patients to determine whether incidental PNI is associated with the clinical course of disease in patients with CSCC. The following are members of the study group who contributed to the data collection for this work: John Boyer, MD, Mohs Micrographic Surgery and Skin Care Clinic, Honolulu, HI; Gregory Bricca, MD, California Skin Surgery Center, Roseville, CA; Joel Cook, MD, Department of Dermatology, Medical University of South Carolina, Charleston, SC; James R. Debloom II, MD, South Carolina Skin Cancer Center, Greenville, SC; Cary Dunn, MD, West Coast Dermatology, Sarasota, FL; Mike Fazio, MD, INC, Sacramento, CA; Scott Freeman, MD, Sunrise Dermatology, Mobile, AL; Bob Griego, MD, Skin Cancer Specialist, Mesa, AZ; Ali Hendi, MD, Skin Cancer Specialist, Chevy Chase, MD; Michael Huether, MD, Arizona Skin Cancer Surgery Center, Tucson, AZ; Karen Johnson, MD, Denver, CO; Joy Kunishige, MD, Zitelli and Brodland PC, Pittsburgh, PA; Brad Merritt, MD, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC; Timothy Parker, MD, Advanced Dermatologic Surgery, Overland Park, KS; Larisa Ravitsky, MD, Ohio Skin Care Institute, Gahanna, OH. REFERENCES 1. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification, part one. J Cutan Pathol 2006;33:191-206. 2. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification, part two. J Cutan Pathol 2006;33:261-79. 3. Broders AC. Practical points on the microscopic grading of carcinoma. N Y State J Med 1932;32:667-71. 4. Graham JH, Helwig EB. Premalignant cutaneous and mucocutaneous diseases. In: Graham JH, Johnson WC, Helwig EB, editors. Dermal pathology. Hagerstown (MD): Harper and Row; 1972. p. 561. 5. Mehregan AH, Hashimoto K. Pinkus’ guide to dermatohistopathology. Norwalk (CT): Appleton and Lange; 1991. 6. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990;94:624-7. 7. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell
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lthough no definitive, comprehensive clinicopathological system for cutaneous squamous cell carcinomas (CSCC) has yet been adopted, the presence of tumor cell invasion into and/or approximating a nerve (perineural invasion [PNI]) has been suggested to be an indicator of poor prognosis.1-14 The incidence of PNI in CSCC has been reported to range from 2.4% to 14%.1,2,12,15-28 The presence of PNI is frequently associated with those tumors demonstrating extensive soft-tissue spread,
A
frequent recurrences, and a decreased overall survival.1,2,19,20,28-30 Given its potential role in the clinical course of CSCC, some recommend that patients with PNI be treated with wider surgical margins, undergo sentinel lymph node dissection, and/or be treated with postoperative radiation therapy.25,31-36 Although PNI has been suggested to be a marker for more aggressive disease, it must be stressed that, with the exception of 1 study,24 most of the available
From the Fairview Medical Group, Minneapolisa; and Zitelli and Brodland PC, Pittsburgh.b Funding sources: None. Conflicts of interest: None declared. Accepted for publication November 22, 2013. Reprint requests: Michael Campoli, MD, PhD, Dermatologic Surgery, 5200 Fairview Blvd, Wyoming, MN 55092. E-mail: [email protected].
Members of the study group who contributed to the data collection for this work are listed at the end of the article. Published online January 16, 2014. 0190-9622/$36.00 Ó 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.11.034
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information regarding PNI in CSCC has been obThe criterion for inclusion was all cases of histotained from a small number of heterogeneous logically confirmed CSCC treated with Mohs microretrospective studies.1,2,15-31 Many of these studies graphic surgery. Table I summarizes the clinical, have failed to present a unified definition of PNI, pathologic, and treatment parameters that were have used conventional techniques to evaluate hisassessed. The clinical variables immune suppression, topathology, and have not taken into account hetradiation exposure, and scarring skin conditions erogeneity of the patient populations investigated or were defined as: (1) organ transplant recipients, histopathological characterpatients with chronic lymistics of the lesions analyzed. phocytic leukemia, patients CAPSULE SUMMARY Moreover, none of the availwith AIDS and/or patients on able studies have presented a immunosuppressive medicaThe prognosis of patients with clear distinction between tions; (2) patients with a hiscutaneous squamous cell carcinoma PNI that is an incidental tory of ionizing radiation or showing incidental perineural invasion is finding on histology and psoralen plus ultraviolet A not well defined. PNI that is associated with exposure; and (3) patients This study demonstrates the clinical, gross neurologic deficits. with a history of burn injury, histologic, and treatment characteristics The latter, often referred to chronic nonhealing wound, associated with incidental perineural as clinical PNI, has clearly or immunobullous or coninvasion. been shown to be associated nective tissue disease. All with poor prognosis.1,2 On patients demonstrating craThis information strengthens our ability nial nerve deficits were the other hand, there is a to identify and stratify those patients excluded from the study. paucity of information availwith cutaneous squamous cell The degree of anaplasia was able regarding PNI that is not carcinoma at risk of perineural invasion. based on subjective assessdiscovered on normal pathment of differentiation. The ologic specimens but discovcategories were well, moderately, and poorly differered incidentally separate from the tumor bulk entiated, when the percentage of anaplastic cells in through histologic evaluation during surgical resecthe lesions were less than 25%, between 25% and tion in asymptomatic patients with CSCC, ie, inci50%, and greater than 50%, respectively. dental PNI. All surgeons used the previously described stanThe limited information available regarding incidard frozen section Mohs micrographic surgery dental PNI in CSCC has led to uncertainty in its technique.38 The treating Mohs micrographic surtreatment in patients. This uncertainty is evidenced by both the nonevidence-based consensus recomgeons carried out all excisions, mapping, and tissue mendations, developed by multidisciplinary examination. panels,13,14 and the variation in concordance rates Tumor thickness was established by comments made in the original biopsy report. In those cases between surgeons on how to treat these patients.37 where no depth was available on the original biopsy The goal of this work is to perform a multicenter report, measurements of tumor depth were made on prospective evaluation of the clinical, histologic, and the debulked tumor by the treating Mohs microtreatment characteristics associated with incidental graphic surgeons. PNI in patients with CSCC. The results reported The diagnosis of PNI was defined as the presence herein are the preliminary findings published in of tumor cell invasion into and/or the partial or anticipation of a 5-year follow-up study. complete encasement of a nerve resulting in histologically discernible tumor encircling or partially encircling a nerve either described in the biopsy METHODS report or as identified in the debulking specimen or A prospective, multicenter analysis of the clinical, Mohs sections. Cases that did not demonstrate PNI in histologic, and treatment characteristics of patients the original biopsy specimen or in any Mohs stage undergoing Mohs micrographic surgery for CSCC were classified as negative. within 4 academic and 11 private practice Mohs micrographic surgery sites was conducted over 25 Statistical analysis working days. Institutional review board approval All data were included in the original analysis. was obtained from the Western Institutional Review Patients were separated by PNI status and variables Board (protocol No. 20100110). Fellowship-trained were compared between categories using indepenMohs micrographic surgeons treated all patients and dent t tests or x2 tests, as appropriate, using software recorded all data. d
d
d
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Table I. Documented parameters of patients with cutaneous squamous cell carcinoma Clinical
Histologic
Therapeutic
Age Gender Reason for referral Presence of cranial nerve deficits
Presence of PNI Nerve diameter \ or [ 0.1 mm Degree of differentiation Clark level [V
Treating Mohs micrographic surgeon Postoperative diameter No. of Mohs stages Maximum width of excision required to clear tumor
Preoperative tumor diameter Anatomic location History of treatments Clinically palpable regional lymphadenopathy Pain associated with tumor Immune suppression Scarring skin condition Arsenic exposure Radiation exposure
Invasion beyond fat
PNI, Perineural invasion.
Table II. Clinical characteristics of study participants Clinical variables
No. of patients Mean age, y Male/female Anatomic location Head and neck Trunk Extremities Referred Primary vs recurrent Lymphadenopathy Pain associated with tumor Clinical risk factors* Treatment setting academic/ private practice
PNI (n = 35)
No PNI (n = 718)
P
33 78 24 (72.7%)/9 (27.3%)
620 75 442 (71.3%)/178 (28.7%)
.056 .769
32 2 1 26 21 2 25 11 21
513 175 30 519 514 6 305 100 345
(91.4%) (5.7%) (2.9%) (78.8%) (60%)/14 (40%) (5.7%) (71.4%) (31.5%) (60%)/14 (40%)
(71.4%) (24.4%) (4.2%) (83.4%) (71.6%)/204 (28.4%) (0.8%) (42.4%) (13.9%) (48%)/373 (52%)
.039
.810 <.001 .012 <.001 .004 .0167
Bold values indicate statistical significance. PNI, Perineural invasion. *Includes presence of immune suppression, scarring skin condition, arsenic exposure, or radiation exposure.
(STATA, Version 10, StataCorp LP, College Station, TX). All continuous variables were checked for normality and type I error rate was set at a = 0.05.
RESULTS A total of 653 patients were recruited into the study resulting in the analysis of 753 CSCC (Table II). PNI was diagnosed in 35 CSCC (4.6%) from 33 patients (5%). There were 21 cases of incidental PNI of 629 cases of primary CSCC (3.3%) and 14 cases of incidental PNI of 124 cases with recurrent CSCC (11.3%) comprising 57.6% and 42.4% of all incidental PNI cases, respectively. Previous treatments for recurrent CSCC with and without PNI included excision (78.5% and 33.6%), cryotherapy (14.2% and 60.0%), electrodesiccation and curettage
(21.5% and 20%), imiquimod (7.1% and 0%), 5fluorouracil (0% and 6.4%), Mohs micrographic surgery (0% and 3.6%), photodynamic therapy (0% and 0.9%), and radiation (0% and 1.8%), respectively. PNI was significantly associated with recurrent CSCC (P \.001) and treatment in an academic setting (P = .0167). CSCC with PNI was most common on the head and neck (31 cases, 88.5%), with 7 on the scalp (20%), 7 on the temple (20%), 5 on the forehead (14.2%), 5 on the cheek (14.2%), 3 on the ear (8.6%), 2 on the nose (5.7%), 1 on the eyelid (2.9%), and 1 on the neck (2.9%). The remaining PNI cases were located on the trunk (2 cases [5.7%]) and extremities (2 cases [5.7%]). PNI was significantly associated with tumors located on the head and
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neck (P = .039) and those on the scalp and temple (P = .018). The presence of regionally palpable lymphadenopathy and pain associated with the tumor was identified in 2 (5.7%) and 25 (71.4%) of the CSCC cases demonstrating PNI, compared with 6 (0.8%) and 305 (42.4%) of those cases without PNI. Given the relatively low number of CSCC demonstrating PNI, the clinical variables including immune suppression, radiation exposure, and scarring skin conditions were grouped together. In this regard, in 11 (31.5%) of the PNI cases and 100 (13.9%) of the non-PNI cases 1 or more of these clinical variables were identified. PNI was significantly associated with the presence of regionally palpable lymphadenopathy (P = .012), pain associated with the tumor (P \ .001), and the presence of 1 or more of aforementioned clinical variables (P = .004). The most common histologic subtypes for patients with PNI were well/moderately differentiated (22 cases, 62.8%) and poorly differentiated (13 cases, 37.2%), whereas for patients without PNI there were 690 (96.1%) well/moderately differentiated tumors and 28 (3.9%) poorly differentiated tumors. PNI was significantly associated with poorly differentiated histology (P \.001) (Table III). The mean tumor thickness and number of lesions Clark level V or greater in the CSCC cases demonstrating PNI was 6.4 6 3 mm (median 6 mm, range 120 mm) and 23 (65.7%) lesions, respectively (Table III). In contrast, in those cases without incidental PNI mean tumor thickness and number of lesions Clark level V or greater was 2.5 6 1 mm (median 1 mm, range 1-12 mm) and 43 (5.9%) lesions, respectively. PNI was found to be significantly associated with greater mean tumor thickness and Clark level V or greater (P \.001). In CSCC demonstrating PNI, 17 (48.6%) cases were found in nerves greater than 0.1 mm in diameter. Of these cases, 7 (41.1%) were recurrent tumors, 14 (82.4%) demonstrated painful tumors, 12 (70.6%) were greater than 2.0 cm in size, and 100% of the cases required 3 or more stages to clear the tumor. In contrast, of the CSCC with PNI in nerves smaller than 0.1 mm in diameter, 7 (38.9%) were recurrent tumors, 10 (55.6%) were painful tumors, 4 (22.2%) were greater than 2.0 cm in size, and 4 (22.2%) required 3 or more stages to clear the tumor. Notably, CSCC demonstrating PNI in nerves greater than 0.1 mm in diameter were significantly associated with larger tumor preoperative size, tumor thickness, tumor postoperative size, and greater number of stages required to clear the tumor (P \.001).
Table III. Histologic characteristics of cutaneous squamous cell carcinoma lesions Histologic variable
Differentiation Well/moderately differentiated Poorly differentiated Keratoacanthoma type Acantholytic Adenosquamous Thickness, mm \2 2-2.9 3-3.9 4-4.9 5-5.9 $6 ND Clark level $ V, mm
PNI (n = 35)
No PNI (n = 718)
P
\.001 22 (62.8%)
690 (96.1%)
13 (37.2%) 0
28 (3.9%) 6 (0.8%)
0 0 3 (8.5%) 0 2 (5.7%) 7 (20%) 5 (14.3%) 18 (51.5%) 23 (65.7%)
1 (0.1%) 2 (0.2%) \.001 321 (44.8%) 149 (20.7%) 99 (13.8%) 55 (7.6%) 29 (4.0%) 60 (8.4%) 5 (0.7%) 43 (5.9%) \.001
ND, No data; PNI, perineural invasion.
Tumor diameters before and after Mohs micrographic surgery were significantly larger in cases with PNI when compared with those without PNI (P \.001) (Table IV). Analysis of preoperative tumor diameter showed that 23 (65.7%) tumors with PNI were 2 cm or larger compared with only 115 (16.0%) of those with no PNI. In addition, defect sizes were 3 cm or larger in 22 (62.9%) cases with PNI compared with only 94 (13.1%) cases without PNI. In cases of CSCC with PNI, the mean number of Mohs stages and estimated maximum Mohs margin required to clear the tumor was 2.7 6 1.4 (median 2, range 1-10) and 8.0 6 6.0 mm (median 5 mm, range 1-25 mm), respectively (Table IV). In contrast, in non-PNI cases, the mean number of Mohs stages and estimated maximum width was 1.3 6 0.6 (median 1, range 1-5) and 2.9 6 2.1 mm (median 2 mm, range 1-12 mm). PNI was significantly correlated with a greater number of Mohs stages and a larger estimated maximum Mohs margin required to clear the tumor (P \ .001) (Table IV). Table V summarizes the clinical, histologic, and therapeutic variables statistically associated with incidental PNI in CSCC.
DISCUSSION We have identified 35 cases of incidental PNI in 753 cases of CSCC (4.6%). A majority of the CSCC exhibiting PNI (88.5%) were located on the head and neck and these findings are consistent with previous reports in the literature.1,2,12,15-28 The incidence of
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Table IV. Therapeutic characteristics of cutaneous squamous cell carcinoma lesions Therapeutic variable
PNI (n = 35)
No PNI (n = 718)
\1 1-1.9 2-2.9 3-3.9 $4 No. of Mohs layers 1 2 3 4 5 $6 Total Mohs margin, mm \2 2-2.9 3-3.9 4-4.9 5-5.9 $6
P
\.001
Tumor size, cm Preoperative 5 (14.3%) 7 (20%) 9 (25.7%) 5 (14.3%) 9 (25.7%)
Postoperative 0 (0%) 8 (22.9%) 5 (14.3%) 2 (5.7%) 20 (57.1%)
Preoperative 311 (43.3%) 291 (40.6%) 82 (11.4%) 19 (2.6%) 14 (2.1%)
Postoperative 89 (12.5%) 371 (51.8%) 162 (22.6%) 56 (7.8%) 38 (5.3%) \.001
5 15 6 5 1 3
(14.3%) (42.9%) (17.1%) (14.3%) (2.9%) (8.5%)
503 163 42 7 2 1
(70.0%) (22.8%) (5.9%) (0.9%) (0.3%) (0.1%)
2 4 2 7 3 17
(5.7%) (11.4%) (5.7%) (20.0%) (8.6%) (48.6%)
72 365 123 68 31 59
(10.0%) (50.9%) (17.1%) (9.5%) (4.3%) (8.2%)
\.001
PNI, Perineural invasion.
PNI we have reported is also consistent with the incidence of 5.95% reported by Leibovitch et al24 and is within the range of reported incidences (2.4%-14%).1,2,12,15-28 Nevertheless, it is difficult to compare most of these studies, because many of the previous reports have failed to present a unified definition of PNI, have used conventional histopathological techniques to evaluate histology, and have not strictly limited their analysis to incidental PNI. The number of CSCC cases with incidental PNI we have reported makes our series the largest prospective report in the literature. It is likely that the use of Mohs tissue sections may more accurately identify the true incidence of incidental PNI in CSCC, because the use of en face sections allows for better detection of tumors cells within the perineural space through a more thorough evaluation of the tissue section.38 From a clinical standpoint, incidental PNI was associated with tumors located on the head and neck, clinically palpable regional lymphadenopathy, painful tumors, recurrent tumors, and clinical variables such as immune suppression, radiation exposure, and scarring skin conditions. We were unable to independently assess the association between incidental PNI and separate clinical variables given the relatively low number of incidental PNI cases. Despite this, the association of incidental PNI with these clinical risk variables is in agreement with those in the literature.15-28 Five-year follow-up studies on this cohort of patients are in progress
and will help to strengthen these findings to identify and stratify those patients with CSCC at risk of PNI. Two reported risk factors for aggressive CSCC include tumor thickness and degree of tumor differentiation.14 In the current study, incidental PNI was significantly associated with both greater tumor thickness and more poorly differentiated histology (P \ .001). Our findings support previous studies15-21,24 indicating that PNI is more often seen in thicker and less differentiated histology subtypes of CSCC. Although we acknowledge that the data regarding tumor thickness must be interpreted with caution, the association between PNI and tumor thickness is likely to be significant, because tumor thickness greater than 6 mm has been the only standalone prognostic variable for high-risk CSCC.6 Whether tumors greater than 6 mm are more likely to demonstrate PNI or PNI leads to thicker and more aggressive tumor remains to be determined. More recently, 2 studies have suggested that higher risks of recurrence, metastasis, and diseasespecific mortality have been associated with PNI when it is found in nerves greater than 0.1 mm in diameter.28-30,39 We have found that CSCC demonstrating PNI in nerves greater than 0.1 mm in diameter were significantly associated with preoperative and postoperative tumor diameters, tumor thickness, and number of stages required to clear the tumor (P \ .001). The association of PNI in nerves
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Table V. Summary of clinical, histologic, and therapeutic variables associated with perineural invasion in cutaneous squamous cell carcinoma lesions Variables
Anatomic location on the head and neck Recurrent tumors Clinically palpable regional lymphadenopathy Pain associated with tumor Immune suppression/radiation/scarring skin condition Treatment setting in academic center Poorly differentiated Greater tumor thickness Greater preoperative tumor size Greater No. of Mohs layers Total Mohs margin
P
.039 \.001 .012 \.001 .004 .0167 \.001 \.001 \.001 \.001 \.001
greater than 0.1 mm with the latter clinicopathological indicators of high-risk CSCC argue in favor of the notion that nerve diameter represents a significant prognostic factor in CSCC. Whether these findings will carry through in the survival analysis of this cohort of patients remains to be determined. Tumor diameter has also been shown to be associated with more aggressive CSCC.15-28 We found that CSCC exhibiting PNI demonstrated preoperative tumor diameters that were significantly larger with more than 65% being greater than 2 cm compared with 16.1% CSCC without PNI (P \.001). Moreover, the postoperative defect sizes in CSCC with PNI were on average about 7 times larger than those tumors without PNI (P \ .001). Lastly, the mean number of Mohs stages required for complete tumor extirpation and estimated Mohs margin required to clear the tumor in cases of incidental PNI was on average 2 and 2.8 times larger, respectively, than those cases of CSCC without PNI (P \ .05). The latter findings, in conjunction with the association between PNI and incomplete removal of primary tumor, demonstrate the more invasive nature of CSCC with PNI and emphasize the need for margin control in the treatment of these tumors. In conclusion, this is the largest prospective multicenter study to our knowledge investigating the clinical, histologic, and treatment characteristics associated with incidental PNI in patients with CSCC. Although incidental PNI is an uncommon feature of CSCC, it was found to be associated with previously established markers of poor prognosis including tumor size, tumor depth, clinical risk factors, and significant subclinical extension. To this end, the association of incidental PNI with markers of poor
prognosis suggests that it may be a covariable in the clinical course of CSCC. Our findings suggest that documenting incidental PNI in histologic specimens may serve as a marker to improve the prognostic assessment of patients for future studies and provide vital information regarding clinical settings one may expect to see PNI, thereby alerting the treating clinician to the possibility. Moreover, given that comprehensive evaluation of tissue sections may more accurately identify PNI and the association between incidental PNI and previously established markers of poor prognosis, treatment of CSCC with Mohs micrographic surgery may offer significant benefit in identification and stratification of patients at risk and complete extirpation of high-risk CSCC. Five-year follow-up studies are in progress this cohort of patients to determine whether incidental PNI is associated with the clinical course of disease in patients with CSCC. The following are members of the study group who contributed to the data collection for this work: John Boyer, MD, Mohs Micrographic Surgery and Skin Care Clinic, Honolulu, HI; Gregory Bricca, MD, California Skin Surgery Center, Roseville, CA; Joel Cook, MD, Department of Dermatology, Medical University of South Carolina, Charleston, SC; James R. Debloom II, MD, South Carolina Skin Cancer Center, Greenville, SC; Cary Dunn, MD, West Coast Dermatology, Sarasota, FL; Mike Fazio, MD, INC, Sacramento, CA; Scott Freeman, MD, Sunrise Dermatology, Mobile, AL; Bob Griego, MD, Skin Cancer Specialist, Mesa, AZ; Ali Hendi, MD, Skin Cancer Specialist, Chevy Chase, MD; Michael Huether, MD, Arizona Skin Cancer Surgery Center, Tucson, AZ; Karen Johnson, MD, Denver, CO; Joy Kunishige, MD, Zitelli and Brodland PC, Pittsburgh, PA; Brad Merritt, MD, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC; Timothy Parker, MD, Advanced Dermatologic Surgery, Overland Park, KS; Larisa Ravitsky, MD, Ohio Skin Care Institute, Gahanna, OH. REFERENCES 1. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification, part one. J Cutan Pathol 2006;33:191-206. 2. Cassarino DS, Derienzo DP, Barr RJ. Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classification, part two. J Cutan Pathol 2006;33:261-79. 3. Broders AC. Practical points on the microscopic grading of carcinoma. N Y State J Med 1932;32:667-71. 4. Graham JH, Helwig EB. Premalignant cutaneous and mucocutaneous diseases. In: Graham JH, Johnson WC, Helwig EB, editors. Dermal pathology. Hagerstown (MD): Harper and Row; 1972. p. 561. 5. Mehregan AH, Hashimoto K. Pinkus’ guide to dermatohistopathology. Norwalk (CT): Appleton and Lange; 1991. 6. Breuninger H, Black B, Rassner G. Microstaging of squamous cell carcinomas. Am J Clin Pathol 1990;94:624-7. 7. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell
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