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Incidence of residual basal cell carcinoma in patients who appear tumor free after biopsy
DERMATOLOGIC SURGERY
I I n c i d e n c e o f residual basal cell c a r c i n o m a in patients w h o appear t u m o r free after b i o p s y Kristina A. Holmkvist, MD,a, b Gary S. Rogers, MD, a a n d Patrick R. Dahl, MD b
Boston, Massachusetts, and Fullerton, California Background: Basal cell carcinoma (BCC) biopsy sites often heal with no clinical evidence of residual tumor.
Objective: The purpose of our study is to determine whether such patients require further therapy. If biopsies can be curative, health care costs can be reduced by avoiding unnecessary surgery:.
Methods: We prospectively evaluated 41 consecutive subjects with 42 biopsy-confirmed BCCs who appeared disease free. Each biopsy site was excised and processed by the Mohs micrographic technique. The tissue block was sectioned horizontally at 30-1am intervals until exhausted. Sections were stained and examined microscopically for residual tumor.
Results: Tumor was identified in 28 (66%) of 42 cases. No statistically significant relationship was found between the presence or absence of residual tumor and the following variables: age, sex, tumor location, biopsy technique, histopathologic subtype, scar size, time from biopsy to surgery, and extent of inflammation in histologic sections.
Conclusion: Our data suggest that patients with small (< 1 cm) primary BCCs that appear to be completely removed after a biopsy procedure are at risk for recurrence without further treatment. (1 Am Acad Dermatol 1999;41:600-5.)
iopsy alone o f a small basal cell c a r c i n o m a (BCC) often appears curative from the clinical perspective. Patients frequently ask w h e t h e r surgery is necessary after a biopsy because clinical symptoms, such as bleeding, often clear. It is currently u n k n o w n what percentage of patients fitting this clinical description harbor residual tumor. Therefore o n e o f the goals o f o u r study was to determine the incidence of residual BCC in patients w h o a p p e a r to have b e e n "cured" by a biopsy. A n o t h e r goal o f the study was to d e t e r m i n e the m o s t appropriate m a n a g e m e n t for these patients. If clinical and histopathologic data could be used to predict the p r e s e n c e of residual t u m o r and n e e d for f u r t h e r treatment, s o m e patients could be spared unneces-
B
From the Department of Surgery, Boston University School of Medicine and Boston Medical Center, and Accredited Dermatology Medical Clinic Inc, Fuilerton. Supported bythe Department of Surgery, Boston University School of Medicine. Reprint requests:Kristina A. Holmkvist, MD, Accredited Dermatology Medical Clinic Inc, 301 W Bastanchury FId,Suite 24.5,Fullerton, CA 9283.5. Copyright 9 1999 by the American Academy of Dermatology, inc. 0190-9622/99/$8.00 + 0 16111100042
600
sary surgery. The resulting savings in health care resources could be significant. In o u r study we prospectively evaluated 41 consecutive subjects with 42 b i o p s y - c o n f i r m e d BCCs w h o lacked clinical e v i d e n c e o f residual disease. S p e c i m e n s containing the entire biopsy scar f r o m each patient were examined by means of the Mohs micrographic surgery (MMS) technique. We examined the relationship o f several clinical a n d histopathologic variables to the presence or absence of residual tumor.
MATERIAL AND METHODS All patients presenting to the MMS unit in the Department of Surgery at Boston Medical Center between July 1997 and February 1998 for treatment of biopsyproven BCC were examined clinically for evidence of residual tumor at the biopsy site. Bright lighting and a magnifying lens were used during the examination. The skin was stretched and palpated to detect subtle changes in surface contour or consistency. Patients with papular changes or prominent telangiectases consistent with residual tumor at the biopsy site were excluded from the study. Similarly, patients with markedly atrophic and firm scars, suggestive of the morpheaform variant of BCC, were excluded. Patients with a history of any treatment to the area other than biopsy were excluded. Finally, patients were excluded
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from the study if they had a history of radiation therapy or burn injury, to the area, a chronic inflammatory skin disease affecting the area, or a genodermatosis predisposed to cancel-. After a subject was entered into the study, the dimensions of the biopsy scar were recorded and the site was photographed. The entire biopsy site was then excised and processed by means of the MMS technique. No curettage was performed to the area before the excision. The frozen tissue block was sectioned at 30-~m intervals until exhausted. Sections were stained with toluidine blue and examined microscopically for residual tumor. Histopathologic evidence of scar was determined by the presence of increased dermal collagen density and vasculature. The extent of the inflammatory cell infiltrate in the sections was graded (0 = none, 1 = mild, 2 = moderate, and 3 = dense). The number of MMS stages required for tumor clearance and the dimensions of the final MMS defect were recorded. The date of the biopsy and the biopsy technique (punch vs shave) were obtained from the medical record. Biopsy slides were reviewed independently by a dermatopathologist (P. R. D.), who was blinded to the clinical data. The predominant histopathologic subtype of each BCC was determined. Average values or proportions were determined for each of the following variables: age, sex, tumor location, presence of clinically visible scar at the biopsy site, size of scar, histopathologic evidence of scar in the MMS section, extent of inflammation in the MMS section, presence of residual BCC in MMS sections, MMS stages required for tumor clearance, MMS defect size, time from biopsy to MMS, biopsy technique, and histopathologic subtype of BCC in the biopsy specimen. Analysis focused on determining differences between patients found to have residual tumor and patients who did not. Differences in continuous variables were tested for significance by means of the Student t test. Differences in categorical variables were tested by means of the chi-square test or Fisher's exact test, as appropriate. To adjust for confounding, patients with or without residual tumor were compared by means of multiple logistic regression. All analyses were performed by means of SAS software (Statistical Analysis Software) licensed to Boston University.
RESULTS D u r i n g a 7 - m o n t h p e r i o d from July 1997 to F e b r u a r y 1998, 218 p a t i e n t s w e r e r e f e r r e d to o u r MMS unit for t r e a t m e n t o f 264 s e p a r a t e BCCs. O f t h e s e p a t i e n t s , 44 (20%) m e t t h e criteria for o u r study. O n e patient p r e s e n t e d with 2 s e p a r a t e lesions that m e t the criteria for o u r study. Thirty-seven of t h e p a t i e n t s w e r e r e f e r r e d to o u r p r a c t i c e after t h e i r biopsies w e r e p e r f o r m e d elsewhere. T h e r e m a i n i n g 7 patients w e r e referred from o u r o w n g r o u p practice. Three patients were eventually rejected from the s t u d y g r o u p after w e o b t a i n e d a n d r e v i e w e d t h e i r
original b i o p s y slides. O u r d i a g n o s e s in t h e s e cases w e r e fibrous papule, intravascular papillary e n d o t h e lial hyperplasia, a n d s e b o r r h e i c keratosis with focal basaloid proliferation. Patients' ages r a n g e d from 31 to 77 years (average, 56 years). Twenty-seven (66%) w e r e female a n d 14 (34%) w e r e male. T h e m o s t c o m m o n l o c a t i o n for t u m o r s was t h e n o s e (18 cases), f o l l o w e d by t h e paranasal a r e a (9 cases), f o r e h e a d (7 cases), c h e e k (5 cases), eyelid (2 cases), a n d n e c k (1 case). We w e r e able to l o c a t e each b i o p s y site by clinical e x a m i n a t i o n o n t h e d a y o f MMS. T h e g r e a t e s t d i a m e t e r o f t h e b i o p s y scars r a n g e d from 0.3 to 1.5 c m (average, 0.6 cm). H i s t o p a t h o l o g i c e v i d e n c e o f scar was d e t e c t e d in t h e M o h s s e c t i o n s f r o m e a c h case. T h e e x t e n t o f t h e i n f l a m m a t o r y cell infiltrate in t h e M o b s s e c t i o n s r a n g e d from mild to heavy. In 22 cases (54%) it was j u d g e d to b e m o d e r a t e , in 19 cases (45%) mild, a n d in 1 case (2%) d e n s e . Residual BCC was f o u n d in 28 (66%) o f 42 cases. T h e n u m b e r o f MMS s t a g e s r e q u i r e d for t u m o r c l e a r a n c e r a n g e d f r o m 1 to 4 (average, 2). T h r e e cases w i t h r e s i d u a l t u m o r r e q u i r e d o n l y o n e stage of MMS for t u m o r clearance b e c a u s e t h e r e s i d u a l t u m o r was l o c a t e d d e e p within t h e specim e n a n d far from t h e surgical margins. T h e g r e a t e s t d i a m e t e r of t h e post-MMS defects r a n g e d from 0.4 to 2.9 c m (average, 1.1 cm.) A typical case is s h o w n in Fig 1. Time from b i o p s y to MMS r a n g e d from 27 to 168 days (average, 87 days.) Shave b i o p s y was u s e d for t h e diagnosis o f 36 lesions (86%.) Punch b i o p s y was u s e d in 5 c a s e s (12%). In o n e case, t h e b i o p s y n q e t h o d c o u l d n o t b e d e t e r m i n e d from e i t h e r t h e m e d i c a l r e c o r d o r e x a m i n a t i o n o f t h e b i o p s y slides that contained multiple tissue fragments. Biopsy slides w e r e available for review in e a c h case. T h e pred o m i n a n t h i s t o p a t h o l o g i c s u b t y p e o f BCC was n o d u lar in 17 cases (40%), m i c r o n o d u l a r in 15 c a s e s (36%), infiltrative in 8 cases (19%) a n d superficial in 2 cases (5%). No statistically significant r e l a t i o n s h i p was f o u n d b e t w e e n the p r e s e n c e o r a b s e n c e of residual t u m o r a n d t h e following variables: age, sex, t u m o r location, b i o p s y technique, h i s t o p a t h o l o g i c subtype, scar size, t i m e from b i o p s y to MMS, a n d e x t e n t of t h e inflamm a t o r y cell infiltrate in t h e MMS sections.
DISCUSSION O u r s t u d y f o c u s e d o n t h e evaluation a n d m a n a g e m e n t o f p a t i e n t s w h o a p p e a r to b e " c u r e d " a f t e r b i o p s y to a BCC, Accurate i n f o r m a t i o n r e g a r d i n g t h e p r o b a b i l i t y of residual t u m o r has n o t b e e n available in p r e v i o u s l y p u b l i s h e d m e d i c a l l i t e r a t u r e . Two thirds o f t h e clinically disease-free b i o p s y sites in o u r
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Fig 1. Photographs of typical patient. This 47-year-old woman presented for Mohs micrographic surgery 55 days after biopsy. A, No clinical evidence of tumor in area of well-healed biopsy scar. B, Micronodular basal cell carcinoma extends to deep and lateral margins of shave biopsy specimen. (Hematoxylin-eosin stain; original magnification xlO.) No residual tumor was identified in initial Mohs micrographic surgery layer. C, Resulting postoperative defect was relatively small, allowing for primary wound closure.
study were shown to contain microscopic foci of BCC. This statistic is helpful for determining appropriate management and counseling patients. A patient may be reluctant to undergo further treatment for a BCC when symptoms such as bleeding and crusting have cleared after biopsy. The patient may be pleased with the cosmetic outcome at this point and fear additional and unnecessary scarring. With the knowledge gained in our study, the physician and the patient can make more informed management decisions. The procedure we describe for examining a biopsy site for residual tumor should serve as a standard. MMS is a highly sensitive m e t h o d for determining the adequacy of surgical margins because it allows for examination of 100% of the true surgical margin using horizontal sections. In contrast, routine (vertical) pathology sections allow for examination of only a small portion of the true surgical margin. In our study, however, we were interested in examining the entire specimen, not just the surgical margin.
Additional sections were produced for microscopic examination by step sectioning through the entire specimen until it was exhausted. Another measure we took to ensure detection of residual tumor was to avoid curetting the biopsy site before excising the scar. Curettage is often used at the time of MMS to delineate the clinical margins of the BCC and debulk visible tumor. This p r o c e d u r e can remove all evidence of residual tumor. 1 Routine data collected from a MMS practice regarding the incidence of residual tumor may be highly misleading unless all of the procedures above are followed precisely. In several of our study cases, residual tumor was detected only in the inner-most portion of the tissue block, far from the surgical margin. During our usual practice, this t u m o r would have been removed by curettage or discarded without examination along with the remainder of the frozen tissue block. If certain clinical or histologic factors were related to residual tumor, more accurate projections could be made regarding outcomes. In our study, we found
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no association between the following factors and residual tumor: age, sex, t u m o r location, biopsy technique, histopathologic subtype, scar size, time from biopsy to MMS, and extent of the inflammatory cell infiltrate in the MMS sections. Therefore we were unable to develop a model for predicting the likelihood of residual tumor in an individual patient. Anatomic location is thought to be an important risk factor for recurrence of BCC. We found no relationship between anatomic site and the risk of residual tumor after biopsy. If any relationship exists, a larger study group would be needed to identify highrisk areas. Many of the lesions in our study were located on the nose, which is considered a high-risk site for recurrent t u m o r s . 2-4 In our analysis, this site was no more likely to contain residual tumor than other anatomic locations. Although there was no statistically significant relationship between biopsy technique and residual tumor at the time of MMS, our study included only 5 lesions diagnosed by the punch method. A larger n u m b e r of lesions diagnosed by the punch technique would clarify any relationship. The histopathologic subtype of BCC in the biopsy specimen was unrelated to the likelihood of residual tumor in our study. There are several potential explanations for this finding. First, some of the shave biopsy specimens we examined were extremely small and superficial. It is difficult to classify a tumor when little pathologic material is available for examination. Second, more than one histologic subtype of BCC may be present within the same tumor. A recent study of MMS patients undergoing treatment for primary BCC showed correlation between the histologic subtype in the initial specimen and the final MMS stage in only 43% of cases.5 It is well known that certain histologic subtypes (ie, morpheaform, infiltrative, and micronodular) are more likely to be associated with positive margins after excision. 6,7 Their more aggressive behavior may be because of lengthier subclinical extensions that have been d e m o n strated by others. 8 It is unclear why this scenario does not hold true for patients who appear tumorfree after biopsy. The extent of inflammation in the MMS sections was unrelated to residual tumor, it is interesting to note that we found inflammation, as evidenced by a mononuclear cell infiltrate, in each specimen. The average length of time from biopsy to MMS was almost 3 months. Histologic evidence of scar was identified in each specimen and confirmed that MMS was performed in the correct anatomic location in cases where the biopsy site was difficult to see clinically. Numerous investigators have theorized that inflammation is responsible for clearing residual
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tumor after incomplete excEsion and curettage and electrodesiccation procedures. 9-12 Although our study was not designed to directly investigate the function of inflammation in tumor eradication, we found no evidence to s u p p o r t this hypothesis. Spencer et a113 studied the influence of inflammation on microscopic residual BCC after curettage and electrodesiccation procedures, a situation similar to ours. They found no evidence that inflammation contributed to destruction of BCC. Other factors related to wound healing, yet to be determined, may be responsible. We can only speculate as to the outcomes our patients may have experienced without further surgical treatment. Patients with incompletely excised BCC do not necessarily experience further clinical disease. According to various studies, the risk for clinical recurrence ranges from 19% t o 6 7 % . 2,3,10,12,14-21 Some authors r e c o m m e n d management by observation alone for patients with a positive surgical margin based on these figures.l~ 2~ Calculated recurrence rates may be artificially low for several reasons. Subjects were followed up for less than 5 years in some of these studies. Silverman et a122 showed that 27% of recurrences occurred 5 or more years after treatment to a primary lesion. Furthermore, most studies were retrospective in design and relied on a review of medical records to determine whether a patient had a recurrence. Patients with recurrences may have gone undetected or been lost to follow-up. The incidence of residual tumor after incomplete excision of a primary lesion has been reported by at least 2 groups of investigators. This clinical situation is similar but not identical to that in our study. These patients had an attempt at treatment, whereas ours had undergone a smaller diagnostic procedure with no therapeutic intention. Tumors that result in a positive margin after excision may have different biologic behavior than those that persist after a shave biopsy. Bieley et al 9 retrospectively reviewed records from patients treated with MMS after incomplete excision of primary BCC. Residual tumor was identified in 55% of cases. Only cases requiring a second stage of MMS were classified as having residual tumor. No additional measures, such as step sectioning, were taken to identify residual tumor. In another study, Sarma, Griffing, and Weilbaecher 23 found residual tumor in 7% of reexcision specimens from patients with a history of incompletely excised BCC. The reexcision specimens were processed by means of step sectioning. It is unclear why the results from the 2 studies are so different. The second surgical procedure was performed within 1 month in both studies. Differences in surgical technique and pathologic evaluation may be responsible for the discrepancy.
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Several investigators have detected foci of residual BCC within curettage and electrodesiccation sites at a rate higher than expected given the overall cure rate of 95% or more for the technique.2, 24 The rate of residual tumor after 1 month was 21% in one study. 13 In another study, 30% of patients had residual t u m o r immediately after curettage and electrodesiccation. 11 Again, it is u n k n o w n why the majority of these patients do not experience clinical recurrences. These findings suggest that some of our patients with residual tumor at the biopsy site may have had favorable clinical outcomes without MMS. In addition, we may have found a higher incidence of residual tumor with a shorter tinqe interval between biopsy and MMS. The time interval in our study averaged almost 3 months. A prospective, long-term study of patients managed by observation alone would be helpful in elucidating the natural course of disease. Unfortunately, a second biopsy procedure is not reliable for determining residual tumor in patients such as ours. Torres et al 1 found that 63% or more of subsequent shave biopsies yield false-negative results, as determined by MMS. Once a surgical procedure has been p e r f o r m e d and a w o u n d has healed, multiple foci of tumor may be present at the site of a previous solitary, contiguously spreading skin cancer. Furthermore, foci of residual tumor may not be located immediately beneath the clinically visualized surgical scar. Dzubow 25 theorizes that iatrogenic "skip" areas may be created by immunemediated partial regression at the periphery of the wound. He recommends a second Mohs layer when tumor cannot be identified in the first. Eliezri and Cohen 26 emphasize the importance of excising all scar tissue from previous procedures before evaluating the adequacy of surgical margins. They describe a mechanism of tumor persistence after MMS involving scar formation in the central area of a wound and retraction of tumor nests toward the periphery:. Even if only some patients with residual tumor after biopsy experience a recurrence without treatment, an argument can be made for surgical intervention. The patients in our study tended to have small wounds after MMS, and reconstruction was usually simple. Few patients required grafts or flaps for wound closure. Delaying treatment until clinical recurrence would undoubtedly result in a number of larger wounds requiring m o r e extensive surgery. Recurrent tumors are more difficult to cure than primary t u m o r s . 27 The cost of treating these patients would most likely outweigh any savings achieved by avoiding or delaying surgery in others. In sum, two thirds of patients who appear tumorfree after biopsy have residual BCC. Clinical and
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histopathologic characteristics are not helpful in predicting which lesions require further therapy. We therefore r e c o m m e n d treatment for all patients in this situation to decrease morbidity and p r o m o t e the efficient use of health care resources. REFERENCES
1. Torres A, Seeburger J, Robinson D, Glogau R.The reliability of a second biopsy for determining residual tumor. J Am Acad Dermato11992;27:70-3. 2. Shanoff L8, Spira M, Hardy SB. Basal cell carcinoma: a statistical approach to rational management. Plast Reconstr Surg 1967; 39:619-24. 3. Roenigk RK, Ratz JL, Bailin PL, Wheeland RG.Trends in the presentation and treatment of basal cell carcinoma. Dermatol Surg Oncol 1986;12:860-5. 4. Koplin L, Zarem HA. Recurrent basal cell carcinoma: a review concerning the incidence, behavior, and management of recurrent basal cell carcinoma, with emphasis on the incompletely excised lesion. Plast Reconstr Surg 1980;65:656-64. 5. Orengo IF, Salasche SJ, Fewkes J, Khan J, Thornby J, Rubin F. Correlation of histologic subtypes of primary basal cell carcinoma and number of Mohs stages required to achieve a tumorfree plane.J Am Acad Dermato11997;37:395-7. 6. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma and treatment implications. J Am Acad Dermato11990;23:1118-26. 7. Johnson TM,Tromovitch TA, Swanson NA. Combined curettage and excision: a treatment method for primary basal cell carcinoma.J Am Acad Dermato11991;24:613-7. 8. Salasche SJ, Amonette PA. Morpheaform basal cell epitheliomas, a study of subclinical extensions in a series of 51 cases. J Dermatol Surg Onco11981;7:387-94. 9. Bieley HC, Krisner RS, Reyes BA, Garland LD.The use of Mohs micrographic surgery for determination of residual tumor in incompletely excised basal cell carcinoma.J Am Acad Dermatol 1992;26:754-6. I0. Hauben DJ, Zirkin H, Mahler D, Sacks M.The biologic behavior of basal cell carcinoma: analysis of recurrence in excised basal cell carcinoma: part II. Plast Reconstr Surg 1982;69:110-6. 1 I. Edens BL, Bartlow GA, Haghighi P, Astarita RW, Davidson TM. Effectiveness of curettage and electrodesiccation in the removal of basal cell carcinoma. J Am Acad Dermatol 1983;9: 383-8. 12. Dellon AL, DeSilva S, Connolly M, Ross A. Prediction of recurrence in incompletely excised basal cell carcinoma. Plast Reconstr Surg 1985;75:860-71. 13. Spencer JM, Tannenbaum A, Sloan L, Amonette PA. Does inflammation contribute to the eradication of basal cell carcinoma following curettage and electrodesiccation? Dermatol Surg 1997;23:625-31. 14. Richmond JM, Davie RM. The significance of incomplete excision in patients with basal cell carcinoma. Br J Plast Surg 1987; 40:63-7. 15. Sussman LAE, Liggins DR Incompletely excised basal cell carcinoma:A management dilemma? Aust NZ J Surg 1996;66:276-8. 16. Park AJ, Strick M,Watson JD. Basal cell carcinomas: Do they need to be followed up? J R Coll Surg Edinb 1994;39:109-I I. 17. Liu FF, Maki E, Warde P, Payne D, Fitzpatrick P. A management approach to incompletely excised basal cell carcinomas of skin. Int J Radiat Oncol Biol Phys 1991;20:423-8. 18. De Silva SP,Dellon AL. Recurrence rate of positive margin basal cell carcinoma: results of a five-year prospective study. J Surg Oncol 1985;28:72-4.
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19. Gooding CA, White G, Yatsuhashi M. Significance of marginal extension in excised basal-cell carcinoma. N Engl J Med 1965; 273:923-4. 20. Pascal RR, Hobby LW, Lattes R, Crikelair GF. Prognosis of"incompletely excised" versus "completely excised" basal cell carcinoma. Plast Reconstr Surg 1968;41:328-32. 21. Taylor GA, Barisoni B.Ten years experience in the surgical treatment of basal cell carcinoma. Br J Surg 1973;60:522-5. 22. Silverman MK, Kopf AW, Grin CM, Bart RS, Levenstein MJ. Recurrence rates of treated basal cell carcinomas part 1: overview. J Dermatol Surg Oncol 1991 ;17:713-8. 23. Sarma DR Griffing CC, Weilbaecher TG. Observations on the inadequately excised basal cell carcinomas.J Surg Onco11984; 25:79-80.
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24. Knox JM, Lyles TW, Shapiro EM, Martin RD. Curettage and electrodesiccation in the treatment of skin cancer. Arch Dermatol 1960;82:197-204. 25. Dzubow LM. False-negative tumor-free margins following Mohs surgery. J Dermatol Surg Oncol 1988;14:600-2. 26. Eliezri YD, Cohen PR. Cancer recurrence following Mohs micrographic surgery: a mechanism of tumor persistence. Plast Reconstr Surg 1992;90:121-5. 27. Menn H, Robins P, Kopf A, et aI.The recurrent basal cell epithelioma: a study of 100 cases of recurrent, re-treated basal cell epitheliomas. Arch Dermatol 1971;103:628-31.
I I n c i d e n c e o f residual basal cell c a r c i n o m a in patients w h o appear t u m o r free after b i o p s y Kristina A. Holmkvist, MD,a, b Gary S. Rogers, MD, a a n d Patrick R. Dahl, MD b
Boston, Massachusetts, and Fullerton, California Background: Basal cell carcinoma (BCC) biopsy sites often heal with no clinical evidence of residual tumor.
Objective: The purpose of our study is to determine whether such patients require further therapy. If biopsies can be curative, health care costs can be reduced by avoiding unnecessary surgery:.
Methods: We prospectively evaluated 41 consecutive subjects with 42 biopsy-confirmed BCCs who appeared disease free. Each biopsy site was excised and processed by the Mohs micrographic technique. The tissue block was sectioned horizontally at 30-1am intervals until exhausted. Sections were stained and examined microscopically for residual tumor.
Results: Tumor was identified in 28 (66%) of 42 cases. No statistically significant relationship was found between the presence or absence of residual tumor and the following variables: age, sex, tumor location, biopsy technique, histopathologic subtype, scar size, time from biopsy to surgery, and extent of inflammation in histologic sections.
Conclusion: Our data suggest that patients with small (< 1 cm) primary BCCs that appear to be completely removed after a biopsy procedure are at risk for recurrence without further treatment. (1 Am Acad Dermatol 1999;41:600-5.)
iopsy alone o f a small basal cell c a r c i n o m a (BCC) often appears curative from the clinical perspective. Patients frequently ask w h e t h e r surgery is necessary after a biopsy because clinical symptoms, such as bleeding, often clear. It is currently u n k n o w n what percentage of patients fitting this clinical description harbor residual tumor. Therefore o n e o f the goals o f o u r study was to determine the incidence of residual BCC in patients w h o a p p e a r to have b e e n "cured" by a biopsy. A n o t h e r goal o f the study was to d e t e r m i n e the m o s t appropriate m a n a g e m e n t for these patients. If clinical and histopathologic data could be used to predict the p r e s e n c e of residual t u m o r and n e e d for f u r t h e r treatment, s o m e patients could be spared unneces-
B
From the Department of Surgery, Boston University School of Medicine and Boston Medical Center, and Accredited Dermatology Medical Clinic Inc, Fuilerton. Supported bythe Department of Surgery, Boston University School of Medicine. Reprint requests:Kristina A. Holmkvist, MD, Accredited Dermatology Medical Clinic Inc, 301 W Bastanchury FId,Suite 24.5,Fullerton, CA 9283.5. Copyright 9 1999 by the American Academy of Dermatology, inc. 0190-9622/99/$8.00 + 0 16111100042
600
sary surgery. The resulting savings in health care resources could be significant. In o u r study we prospectively evaluated 41 consecutive subjects with 42 b i o p s y - c o n f i r m e d BCCs w h o lacked clinical e v i d e n c e o f residual disease. S p e c i m e n s containing the entire biopsy scar f r o m each patient were examined by means of the Mohs micrographic surgery (MMS) technique. We examined the relationship o f several clinical a n d histopathologic variables to the presence or absence of residual tumor.
MATERIAL AND METHODS All patients presenting to the MMS unit in the Department of Surgery at Boston Medical Center between July 1997 and February 1998 for treatment of biopsyproven BCC were examined clinically for evidence of residual tumor at the biopsy site. Bright lighting and a magnifying lens were used during the examination. The skin was stretched and palpated to detect subtle changes in surface contour or consistency. Patients with papular changes or prominent telangiectases consistent with residual tumor at the biopsy site were excluded from the study. Similarly, patients with markedly atrophic and firm scars, suggestive of the morpheaform variant of BCC, were excluded. Patients with a history of any treatment to the area other than biopsy were excluded. Finally, patients were excluded
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from the study if they had a history of radiation therapy or burn injury, to the area, a chronic inflammatory skin disease affecting the area, or a genodermatosis predisposed to cancel-. After a subject was entered into the study, the dimensions of the biopsy scar were recorded and the site was photographed. The entire biopsy site was then excised and processed by means of the MMS technique. No curettage was performed to the area before the excision. The frozen tissue block was sectioned at 30-~m intervals until exhausted. Sections were stained with toluidine blue and examined microscopically for residual tumor. Histopathologic evidence of scar was determined by the presence of increased dermal collagen density and vasculature. The extent of the inflammatory cell infiltrate in the sections was graded (0 = none, 1 = mild, 2 = moderate, and 3 = dense). The number of MMS stages required for tumor clearance and the dimensions of the final MMS defect were recorded. The date of the biopsy and the biopsy technique (punch vs shave) were obtained from the medical record. Biopsy slides were reviewed independently by a dermatopathologist (P. R. D.), who was blinded to the clinical data. The predominant histopathologic subtype of each BCC was determined. Average values or proportions were determined for each of the following variables: age, sex, tumor location, presence of clinically visible scar at the biopsy site, size of scar, histopathologic evidence of scar in the MMS section, extent of inflammation in the MMS section, presence of residual BCC in MMS sections, MMS stages required for tumor clearance, MMS defect size, time from biopsy to MMS, biopsy technique, and histopathologic subtype of BCC in the biopsy specimen. Analysis focused on determining differences between patients found to have residual tumor and patients who did not. Differences in continuous variables were tested for significance by means of the Student t test. Differences in categorical variables were tested by means of the chi-square test or Fisher's exact test, as appropriate. To adjust for confounding, patients with or without residual tumor were compared by means of multiple logistic regression. All analyses were performed by means of SAS software (Statistical Analysis Software) licensed to Boston University.
RESULTS D u r i n g a 7 - m o n t h p e r i o d from July 1997 to F e b r u a r y 1998, 218 p a t i e n t s w e r e r e f e r r e d to o u r MMS unit for t r e a t m e n t o f 264 s e p a r a t e BCCs. O f t h e s e p a t i e n t s , 44 (20%) m e t t h e criteria for o u r study. O n e patient p r e s e n t e d with 2 s e p a r a t e lesions that m e t the criteria for o u r study. Thirty-seven of t h e p a t i e n t s w e r e r e f e r r e d to o u r p r a c t i c e after t h e i r biopsies w e r e p e r f o r m e d elsewhere. T h e r e m a i n i n g 7 patients w e r e referred from o u r o w n g r o u p practice. Three patients were eventually rejected from the s t u d y g r o u p after w e o b t a i n e d a n d r e v i e w e d t h e i r
original b i o p s y slides. O u r d i a g n o s e s in t h e s e cases w e r e fibrous papule, intravascular papillary e n d o t h e lial hyperplasia, a n d s e b o r r h e i c keratosis with focal basaloid proliferation. Patients' ages r a n g e d from 31 to 77 years (average, 56 years). Twenty-seven (66%) w e r e female a n d 14 (34%) w e r e male. T h e m o s t c o m m o n l o c a t i o n for t u m o r s was t h e n o s e (18 cases), f o l l o w e d by t h e paranasal a r e a (9 cases), f o r e h e a d (7 cases), c h e e k (5 cases), eyelid (2 cases), a n d n e c k (1 case). We w e r e able to l o c a t e each b i o p s y site by clinical e x a m i n a t i o n o n t h e d a y o f MMS. T h e g r e a t e s t d i a m e t e r o f t h e b i o p s y scars r a n g e d from 0.3 to 1.5 c m (average, 0.6 cm). H i s t o p a t h o l o g i c e v i d e n c e o f scar was d e t e c t e d in t h e M o h s s e c t i o n s f r o m e a c h case. T h e e x t e n t o f t h e i n f l a m m a t o r y cell infiltrate in t h e M o b s s e c t i o n s r a n g e d from mild to heavy. In 22 cases (54%) it was j u d g e d to b e m o d e r a t e , in 19 cases (45%) mild, a n d in 1 case (2%) d e n s e . Residual BCC was f o u n d in 28 (66%) o f 42 cases. T h e n u m b e r o f MMS s t a g e s r e q u i r e d for t u m o r c l e a r a n c e r a n g e d f r o m 1 to 4 (average, 2). T h r e e cases w i t h r e s i d u a l t u m o r r e q u i r e d o n l y o n e stage of MMS for t u m o r clearance b e c a u s e t h e r e s i d u a l t u m o r was l o c a t e d d e e p within t h e specim e n a n d far from t h e surgical margins. T h e g r e a t e s t d i a m e t e r of t h e post-MMS defects r a n g e d from 0.4 to 2.9 c m (average, 1.1 cm.) A typical case is s h o w n in Fig 1. Time from b i o p s y to MMS r a n g e d from 27 to 168 days (average, 87 days.) Shave b i o p s y was u s e d for t h e diagnosis o f 36 lesions (86%.) Punch b i o p s y was u s e d in 5 c a s e s (12%). In o n e case, t h e b i o p s y n q e t h o d c o u l d n o t b e d e t e r m i n e d from e i t h e r t h e m e d i c a l r e c o r d o r e x a m i n a t i o n o f t h e b i o p s y slides that contained multiple tissue fragments. Biopsy slides w e r e available for review in e a c h case. T h e pred o m i n a n t h i s t o p a t h o l o g i c s u b t y p e o f BCC was n o d u lar in 17 cases (40%), m i c r o n o d u l a r in 15 c a s e s (36%), infiltrative in 8 cases (19%) a n d superficial in 2 cases (5%). No statistically significant r e l a t i o n s h i p was f o u n d b e t w e e n the p r e s e n c e o r a b s e n c e of residual t u m o r a n d t h e following variables: age, sex, t u m o r location, b i o p s y technique, h i s t o p a t h o l o g i c subtype, scar size, t i m e from b i o p s y to MMS, a n d e x t e n t of t h e inflamm a t o r y cell infiltrate in t h e MMS sections.
DISCUSSION O u r s t u d y f o c u s e d o n t h e evaluation a n d m a n a g e m e n t o f p a t i e n t s w h o a p p e a r to b e " c u r e d " a f t e r b i o p s y to a BCC, Accurate i n f o r m a t i o n r e g a r d i n g t h e p r o b a b i l i t y of residual t u m o r has n o t b e e n available in p r e v i o u s l y p u b l i s h e d m e d i c a l l i t e r a t u r e . Two thirds o f t h e clinically disease-free b i o p s y sites in o u r
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Fig 1. Photographs of typical patient. This 47-year-old woman presented for Mohs micrographic surgery 55 days after biopsy. A, No clinical evidence of tumor in area of well-healed biopsy scar. B, Micronodular basal cell carcinoma extends to deep and lateral margins of shave biopsy specimen. (Hematoxylin-eosin stain; original magnification xlO.) No residual tumor was identified in initial Mohs micrographic surgery layer. C, Resulting postoperative defect was relatively small, allowing for primary wound closure.
study were shown to contain microscopic foci of BCC. This statistic is helpful for determining appropriate management and counseling patients. A patient may be reluctant to undergo further treatment for a BCC when symptoms such as bleeding and crusting have cleared after biopsy. The patient may be pleased with the cosmetic outcome at this point and fear additional and unnecessary scarring. With the knowledge gained in our study, the physician and the patient can make more informed management decisions. The procedure we describe for examining a biopsy site for residual tumor should serve as a standard. MMS is a highly sensitive m e t h o d for determining the adequacy of surgical margins because it allows for examination of 100% of the true surgical margin using horizontal sections. In contrast, routine (vertical) pathology sections allow for examination of only a small portion of the true surgical margin. In our study, however, we were interested in examining the entire specimen, not just the surgical margin.
Additional sections were produced for microscopic examination by step sectioning through the entire specimen until it was exhausted. Another measure we took to ensure detection of residual tumor was to avoid curetting the biopsy site before excising the scar. Curettage is often used at the time of MMS to delineate the clinical margins of the BCC and debulk visible tumor. This p r o c e d u r e can remove all evidence of residual tumor. 1 Routine data collected from a MMS practice regarding the incidence of residual tumor may be highly misleading unless all of the procedures above are followed precisely. In several of our study cases, residual tumor was detected only in the inner-most portion of the tissue block, far from the surgical margin. During our usual practice, this t u m o r would have been removed by curettage or discarded without examination along with the remainder of the frozen tissue block. If certain clinical or histologic factors were related to residual tumor, more accurate projections could be made regarding outcomes. In our study, we found
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no association between the following factors and residual tumor: age, sex, t u m o r location, biopsy technique, histopathologic subtype, scar size, time from biopsy to MMS, and extent of the inflammatory cell infiltrate in the MMS sections. Therefore we were unable to develop a model for predicting the likelihood of residual tumor in an individual patient. Anatomic location is thought to be an important risk factor for recurrence of BCC. We found no relationship between anatomic site and the risk of residual tumor after biopsy. If any relationship exists, a larger study group would be needed to identify highrisk areas. Many of the lesions in our study were located on the nose, which is considered a high-risk site for recurrent t u m o r s . 2-4 In our analysis, this site was no more likely to contain residual tumor than other anatomic locations. Although there was no statistically significant relationship between biopsy technique and residual tumor at the time of MMS, our study included only 5 lesions diagnosed by the punch method. A larger n u m b e r of lesions diagnosed by the punch technique would clarify any relationship. The histopathologic subtype of BCC in the biopsy specimen was unrelated to the likelihood of residual tumor in our study. There are several potential explanations for this finding. First, some of the shave biopsy specimens we examined were extremely small and superficial. It is difficult to classify a tumor when little pathologic material is available for examination. Second, more than one histologic subtype of BCC may be present within the same tumor. A recent study of MMS patients undergoing treatment for primary BCC showed correlation between the histologic subtype in the initial specimen and the final MMS stage in only 43% of cases.5 It is well known that certain histologic subtypes (ie, morpheaform, infiltrative, and micronodular) are more likely to be associated with positive margins after excision. 6,7 Their more aggressive behavior may be because of lengthier subclinical extensions that have been d e m o n strated by others. 8 It is unclear why this scenario does not hold true for patients who appear tumorfree after biopsy. The extent of inflammation in the MMS sections was unrelated to residual tumor, it is interesting to note that we found inflammation, as evidenced by a mononuclear cell infiltrate, in each specimen. The average length of time from biopsy to MMS was almost 3 months. Histologic evidence of scar was identified in each specimen and confirmed that MMS was performed in the correct anatomic location in cases where the biopsy site was difficult to see clinically. Numerous investigators have theorized that inflammation is responsible for clearing residual
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tumor after incomplete excEsion and curettage and electrodesiccation procedures. 9-12 Although our study was not designed to directly investigate the function of inflammation in tumor eradication, we found no evidence to s u p p o r t this hypothesis. Spencer et a113 studied the influence of inflammation on microscopic residual BCC after curettage and electrodesiccation procedures, a situation similar to ours. They found no evidence that inflammation contributed to destruction of BCC. Other factors related to wound healing, yet to be determined, may be responsible. We can only speculate as to the outcomes our patients may have experienced without further surgical treatment. Patients with incompletely excised BCC do not necessarily experience further clinical disease. According to various studies, the risk for clinical recurrence ranges from 19% t o 6 7 % . 2,3,10,12,14-21 Some authors r e c o m m e n d management by observation alone for patients with a positive surgical margin based on these figures.l~ 2~ Calculated recurrence rates may be artificially low for several reasons. Subjects were followed up for less than 5 years in some of these studies. Silverman et a122 showed that 27% of recurrences occurred 5 or more years after treatment to a primary lesion. Furthermore, most studies were retrospective in design and relied on a review of medical records to determine whether a patient had a recurrence. Patients with recurrences may have gone undetected or been lost to follow-up. The incidence of residual tumor after incomplete excision of a primary lesion has been reported by at least 2 groups of investigators. This clinical situation is similar but not identical to that in our study. These patients had an attempt at treatment, whereas ours had undergone a smaller diagnostic procedure with no therapeutic intention. Tumors that result in a positive margin after excision may have different biologic behavior than those that persist after a shave biopsy. Bieley et al 9 retrospectively reviewed records from patients treated with MMS after incomplete excision of primary BCC. Residual tumor was identified in 55% of cases. Only cases requiring a second stage of MMS were classified as having residual tumor. No additional measures, such as step sectioning, were taken to identify residual tumor. In another study, Sarma, Griffing, and Weilbaecher 23 found residual tumor in 7% of reexcision specimens from patients with a history of incompletely excised BCC. The reexcision specimens were processed by means of step sectioning. It is unclear why the results from the 2 studies are so different. The second surgical procedure was performed within 1 month in both studies. Differences in surgical technique and pathologic evaluation may be responsible for the discrepancy.
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Several investigators have detected foci of residual BCC within curettage and electrodesiccation sites at a rate higher than expected given the overall cure rate of 95% or more for the technique.2, 24 The rate of residual tumor after 1 month was 21% in one study. 13 In another study, 30% of patients had residual t u m o r immediately after curettage and electrodesiccation. 11 Again, it is u n k n o w n why the majority of these patients do not experience clinical recurrences. These findings suggest that some of our patients with residual tumor at the biopsy site may have had favorable clinical outcomes without MMS. In addition, we may have found a higher incidence of residual tumor with a shorter tinqe interval between biopsy and MMS. The time interval in our study averaged almost 3 months. A prospective, long-term study of patients managed by observation alone would be helpful in elucidating the natural course of disease. Unfortunately, a second biopsy procedure is not reliable for determining residual tumor in patients such as ours. Torres et al 1 found that 63% or more of subsequent shave biopsies yield false-negative results, as determined by MMS. Once a surgical procedure has been p e r f o r m e d and a w o u n d has healed, multiple foci of tumor may be present at the site of a previous solitary, contiguously spreading skin cancer. Furthermore, foci of residual tumor may not be located immediately beneath the clinically visualized surgical scar. Dzubow 25 theorizes that iatrogenic "skip" areas may be created by immunemediated partial regression at the periphery of the wound. He recommends a second Mohs layer when tumor cannot be identified in the first. Eliezri and Cohen 26 emphasize the importance of excising all scar tissue from previous procedures before evaluating the adequacy of surgical margins. They describe a mechanism of tumor persistence after MMS involving scar formation in the central area of a wound and retraction of tumor nests toward the periphery:. Even if only some patients with residual tumor after biopsy experience a recurrence without treatment, an argument can be made for surgical intervention. The patients in our study tended to have small wounds after MMS, and reconstruction was usually simple. Few patients required grafts or flaps for wound closure. Delaying treatment until clinical recurrence would undoubtedly result in a number of larger wounds requiring m o r e extensive surgery. Recurrent tumors are more difficult to cure than primary t u m o r s . 27 The cost of treating these patients would most likely outweigh any savings achieved by avoiding or delaying surgery in others. In sum, two thirds of patients who appear tumorfree after biopsy have residual BCC. Clinical and
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histopathologic characteristics are not helpful in predicting which lesions require further therapy. We therefore r e c o m m e n d treatment for all patients in this situation to decrease morbidity and p r o m o t e the efficient use of health care resources. REFERENCES
1. Torres A, Seeburger J, Robinson D, Glogau R.The reliability of a second biopsy for determining residual tumor. J Am Acad Dermato11992;27:70-3. 2. Shanoff L8, Spira M, Hardy SB. Basal cell carcinoma: a statistical approach to rational management. Plast Reconstr Surg 1967; 39:619-24. 3. Roenigk RK, Ratz JL, Bailin PL, Wheeland RG.Trends in the presentation and treatment of basal cell carcinoma. Dermatol Surg Oncol 1986;12:860-5. 4. Koplin L, Zarem HA. Recurrent basal cell carcinoma: a review concerning the incidence, behavior, and management of recurrent basal cell carcinoma, with emphasis on the incompletely excised lesion. Plast Reconstr Surg 1980;65:656-64. 5. Orengo IF, Salasche SJ, Fewkes J, Khan J, Thornby J, Rubin F. Correlation of histologic subtypes of primary basal cell carcinoma and number of Mohs stages required to achieve a tumorfree plane.J Am Acad Dermato11997;37:395-7. 6. Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma and treatment implications. J Am Acad Dermato11990;23:1118-26. 7. Johnson TM,Tromovitch TA, Swanson NA. Combined curettage and excision: a treatment method for primary basal cell carcinoma.J Am Acad Dermato11991;24:613-7. 8. Salasche SJ, Amonette PA. Morpheaform basal cell epitheliomas, a study of subclinical extensions in a series of 51 cases. J Dermatol Surg Onco11981;7:387-94. 9. Bieley HC, Krisner RS, Reyes BA, Garland LD.The use of Mohs micrographic surgery for determination of residual tumor in incompletely excised basal cell carcinoma.J Am Acad Dermatol 1992;26:754-6. I0. Hauben DJ, Zirkin H, Mahler D, Sacks M.The biologic behavior of basal cell carcinoma: analysis of recurrence in excised basal cell carcinoma: part II. Plast Reconstr Surg 1982;69:110-6. 1 I. Edens BL, Bartlow GA, Haghighi P, Astarita RW, Davidson TM. Effectiveness of curettage and electrodesiccation in the removal of basal cell carcinoma. J Am Acad Dermatol 1983;9: 383-8. 12. Dellon AL, DeSilva S, Connolly M, Ross A. Prediction of recurrence in incompletely excised basal cell carcinoma. Plast Reconstr Surg 1985;75:860-71. 13. Spencer JM, Tannenbaum A, Sloan L, Amonette PA. Does inflammation contribute to the eradication of basal cell carcinoma following curettage and electrodesiccation? Dermatol Surg 1997;23:625-31. 14. Richmond JM, Davie RM. The significance of incomplete excision in patients with basal cell carcinoma. Br J Plast Surg 1987; 40:63-7. 15. Sussman LAE, Liggins DR Incompletely excised basal cell carcinoma:A management dilemma? Aust NZ J Surg 1996;66:276-8. 16. Park AJ, Strick M,Watson JD. Basal cell carcinomas: Do they need to be followed up? J R Coll Surg Edinb 1994;39:109-I I. 17. Liu FF, Maki E, Warde P, Payne D, Fitzpatrick P. A management approach to incompletely excised basal cell carcinomas of skin. Int J Radiat Oncol Biol Phys 1991;20:423-8. 18. De Silva SP,Dellon AL. Recurrence rate of positive margin basal cell carcinoma: results of a five-year prospective study. J Surg Oncol 1985;28:72-4.
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19. Gooding CA, White G, Yatsuhashi M. Significance of marginal extension in excised basal-cell carcinoma. N Engl J Med 1965; 273:923-4. 20. Pascal RR, Hobby LW, Lattes R, Crikelair GF. Prognosis of"incompletely excised" versus "completely excised" basal cell carcinoma. Plast Reconstr Surg 1968;41:328-32. 21. Taylor GA, Barisoni B.Ten years experience in the surgical treatment of basal cell carcinoma. Br J Surg 1973;60:522-5. 22. Silverman MK, Kopf AW, Grin CM, Bart RS, Levenstein MJ. Recurrence rates of treated basal cell carcinomas part 1: overview. J Dermatol Surg Oncol 1991 ;17:713-8. 23. Sarma DR Griffing CC, Weilbaecher TG. Observations on the inadequately excised basal cell carcinomas.J Surg Onco11984; 25:79-80.
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24. Knox JM, Lyles TW, Shapiro EM, Martin RD. Curettage and electrodesiccation in the treatment of skin cancer. Arch Dermatol 1960;82:197-204. 25. Dzubow LM. False-negative tumor-free margins following Mohs surgery. J Dermatol Surg Oncol 1988;14:600-2. 26. Eliezri YD, Cohen PR. Cancer recurrence following Mohs micrographic surgery: a mechanism of tumor persistence. Plast Reconstr Surg 1992;90:121-5. 27. Menn H, Robins P, Kopf A, et aI.The recurrent basal cell epithelioma: a study of 100 cases of recurrent, re-treated basal cell epitheliomas. Arch Dermatol 1971;103:628-31.