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J Oral Maxillofac Surg 61:895-897, 2003
Discussion Frozen Section Examination of the Margins for Resection of Squamous Cell Carcinoma of the Lower Lip Ellen Eisenberg, DMD Professor, Department of Oral Diagnosis, and Division Head, Oral and Maxillofacial Pathology, University of Connecticut School of Dental Medicine, Farmington, Connecticut; e-mail:
[email protected]
Is there a prognostic advantage gained by using intraoperative frozen section analysis during surgical resection of lower lip cancer? Is the outlook worse when the technique is not applied? With regard to squamous cell carcinoma of surface epithelium specifically, what information does histopathologic evaluation of surgical margins by either frozen section or conventional fixed permanent section analysis actually convey? In their case series report of 131 patients treated for squamous cell carcinoma of the lower lip, Gooris and coauthors1 attest to the reliability of intraoperative frozen section evaluation for determining the adequacy of surgical resection margins. They also address the limitations of frozen section analysis, which are, in many respects, similar to those associated with conventional light microscopic examination of well-fixed permanent tissue sections. Given the published body of evidence that suggests that local control of malignant disease is best achieved when surgical margins are tumor free,2,3 the overall results reported, the conclusions drawn, and the recommendations offered here are not at all surprising. In essence, they corroborate the prevailing wisdom on this subject, which is that frozen section analysis is a valuable adjunctive guide to surgical eradication of lower lip carcinoma. Nonetheless, despite the generally favorable light in which frozen section analysis is portrayed here, the technique is not infallible.4 It is well to note that among the presented findings that have the potential to instruct us, most are those that represent exceptions to the “rule.” Stated in a slightly different way, in this study, those cases whose outcome appears to deviate from that of the majority are the very ones we should examine more closely for insights they might reveal, rather than dismiss as mere oddities. On the basis of their observations, Gooris and associates admit that “a negative [surgical resection] margin based on frozen section examination does not necessarily exclude the [risk for] development of local recurrent tumor. . .” and that despite a negative margin, local recurrence [after treatment of squamous cell carcinoma of the lower lip] may still occur. . .”. This in fact was the case for several of the 131 patients in this report. Moreover, the recurrences developed less than 5 years after the initial frozen section– guided tumor resection procedure, and they were found within 2 cm of the site of the previously diagnosed primary lip cancer. The authors speculate that apparent failures to control local disease recurrence in these cases were attributable
to a margin that either was “not truly negative” or was “close” to the resected tumor, or, regardless of surgical technique, was a consequence of the phenomenon of “field cancerization.”1 In general, it is likely that to some extent, any and all of these postulated explanations can be implicated as reasons for postsurgical recurrent disease.4 Therefore, it is well worth taking a closer look at a specific aspect of the cases described in this report, namely, the character of their surgical margins as determined by frozen section evaluation. Of key significance here is the authors’ working definition of what constitutes “positive” and “negative” margins. In this study, a margin was considered to be “positive” only if invasive squamous carcinoma or carcinoma in situ was evident in the resection plane on intraoperative frozen section review. In contrast, in addition to those surgical margins that exhibited no demonstrable evidence of disease, ones that showed either epithelial dysplasia or presence of tumor within 0.5 cm of the resection surface (the latter termed a “close” margin) were regarded as “negative.” Presence of a “positive” margin prompted immediate surgical refinement (in essence, “re-resection”) during the same operative procedure, whereas a reportedly “negative” margin allowed for closure of the resection wound without any additional surgery. Although 114 individuals were found to have reportedly “negative” margins on intraoperative frozen section evaluation during the initial lip cancer resection, 7 of those patients experienced tumor recurrence within 5 to 35 months subsequent to that procedure. Admittedly, those 7 patients represent a relatively modest 6% of the 131 patients studied and comprise just 7% of the 114 individuals found to have “negative” margins initially.1 However, their disposition does pose a challenge to the notion that a surgical margin only 0.5 cm from a resected carcinoma, or one that exhibits significant intraepithelial maturation disturbance (dysplasia), is appropriately designated as “negative.” Let us explore this briefly. Epithelial dysplasia is a premalignant lesion.5 Among the more vexing frustrations surgeons frequently encounter in clinical practice are seemingly futile, repeated surgical attempts to eradicate cutaneous, lip vermilion, or oral mucosal epithelial dysplasias to prevent their progression to frank carcinomas. In some cases, dysplastic surface lesions seem to continually recur (albeit at rates that tend to vary among individual patients), even after they have undergone multiple, documented gross as well as microscopic excisions with conventional surgery or laser ablative treatment. This often leads the surgeon to question the efficacy of his or her surgical technique or to inquire as to whether there might not be other, perhaps more effective therapeutic alternatives available, presumably “guaranteed” to obviate any possibility of future recurrences.6,7 For the pathologist, whose primary responsibility it is to inform and advise his or her surgeon colleague about diagnoses and prognoses and, as appropriate, recommend approaches to therapy, frustration with the proclivity of epi-
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DISCUSSION
FIGURE 1. Graphic representation (not drawn to scale) illustrating that genotypic changes precede phenotypic changes along the “timeline” of malignant transformation of surface epithelium.
thelial dysplasia for recurrences derives from a somewhat different perspective, namely, awareness that there is apparent dissonance between the biologic behavior of this disease and its presence or absence under the microscope.8 Simply stated, in the broad context of the evolution of a malignant surface epithelial lesion, visible histopathologic evidence of dysplasia, regardless of degree (eg. mild, moderate, or severe), can be compared with a photographic image of a person in their midlife, rather than in their youth or old age. Like a snapshot, which is essentially a kind of morphologic record of an object, animate or inanimate, at a particular point in time and space, the discernible light microscopic alterations in epithelial cytology and tissue architecture that comprise what is recognized as dysplasia, whether subtle or conspicuous, similarly constitute a kind of histomorphologic “snapshot” of an already well-established and probably irreversible array of molecular and genetic disturbances situated in the “midlife” of an advancing transformation continuum whose potential climax is invasive carcinoma. That these histomorphologic alterations can actually be seen and interpreted diagnostically is indication that the constellation of genetic changes that constitute neoplastic development must have already been progressing for some unspecified period of time, previously undetectable to both the surgeon’s and the pathologist’s eye (Fig 1). Carcinogenesis is a process that involves cumulative mutations in genes that control cell growth, development, differentiation, and intercellular communications.9 These genotypic alterations slowly and progressively accrue at the molecular level, well before there is any ostensible clinical or light microscopic evidence (in essence, phenotypic change) to indicate a deviation from normal. Furthermore, the process of malignant transformation of surface epithelium of both the lip as well as the oral mucosa requires considerable time, perhaps decades, to consummate. Therefore, it is highly likely that even morphologically flawlessappearing cells at the surgical margins of a resected squamous carcinoma are already genetically damaged, so that recurrence either of frank tumor or premalignant dysplasia,
even after an apparently “complete” surgical excision, is attributable to the presence of these genetically marred cells.8 The challenge of dealing with this phenomenon of “field cancerization” is especially acute when one considers that squamous cell carcinoma of the lower lip, like its counterpart on the oral mucosa, involves one of the body’s most anatomically accessible sites. Lip cancer, unlike intraoral squamous carcinoma, is etiologically linked to extreme or chronic long-term exposure to the ultraviolet spectrum of sunlight (actinic radiation). Yet the insult to DNA of lip surface epithelial cells and ultimately the clinical consequences of that molecular genetic injury, actinic cheilitis (actinic cheilosis), a condition with potential to eventuate in squamous carcinoma, can be considered analogous to that of transformed oral mucous membrane epithelium, whose genetic damage is perpetrated by the carcinogenic influences to which it is particularly susceptible.10,11 The rate at which these mutations agglomerate and ultimately culminate in a clinically or microscopically obvious surface lesion appears to be unique to the affected individual and is quite likely dependent on a multitude of intrinsic as well as extrinsic factors that have yet to be defined. Nonetheless, it is logical to consider that both mutation-driven factors and inherent genetic diversity could in part account for individual discrepancies in disease progression from epithelial dysplasia to carcinoma. Therefore, it is reasonable to assume that both premalignant surface lesions as well as invasive neoplasms that progress or recur in a seemingly relentless manner after treatment are probably genetically distinct from lesions that appear phenotypically identical to them, but progress in a more indolent manner or recur at slower rates or, in some cases, fail to advance altogether.9 What is the significance of these observations and conjectures? Do they serve to diminish the diagnostic usefulness of light microscopy in general or undermine the value of frozen section evaluation in particular? The answer is that for all practical purposes, light microscopy (and the many diverse and versatile techniques for histopathologic evaluation that have been adapted to its use, including simple
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ELLEN EISENBERG frozen section analysis) remains the single most important and reliable method for diagnosing carcinoma and dysplasia. Therefore, irrespective of its acknowledged limitations, at least for the foreseeable future it will continue to serve as the mainstay of diagnostic tissue assessment. Still, with regard to the actual biology of neoplastic development, what must be borne in mind is that what can be seen under the microscope is only an incomplete representation of an intricate, complex, and dynamic process orchestrated by ongoing genetic mutations that have been propagating largely sight unseen over extended periods of time.8 What is the prognostic inference of all of this? Simply this: when an intraoperative frozen section examination during resection of lower lip cancer (or any other surface epithelial cancer) reveals dysplasia at a surgical margin, or a “close” margin (according to the criteria applied by Gooris and co-authors in their report1), to designate such a margin as “negative” may at best be an exaggeration. At worst, it may be ill advised. And even a margin with no visible evidence of disease may not be truly negative in the long run.8 Therefore, as recommended so astutely by Gooris et al,1 it would seem that the only sense of security that is real in these cases is the one that derives from close, ongoing clinical vigilance.
References 1. Gooris PJJ, Vermey B, deVisscher JGAM, et al: Frozen section examination of the margins for resection of squamous cell carcinoma of the lower lip. J Oral Maxillofac Surg 61:890, 2003 2. Veness M: Lip cancer: Important management issues. Austr J Dermatol 42:30, 2001
3. Zitsch RP, Park CW, Renner GJ, et al: Outcome analysis for lip carcinoma. Otolaryngol Head Neck Surg 113:589, 1995 4. Ord RA, Aisner S: Accuracy of frozen sections in assessing margins in oral cancer resection. J Oral Maxillofac Surg 55:663, 1997 5. Krutchkoff DJ, Eisenberg E, Anderson C: Dysplasia of oral mucosa: A unified approach to proper evaluation. Mod Pathol 4:113, 1991 6. Chen TY, Emrich LJ, Driscoll DL: The clinical significance of pathological findings in surgicially resected margins of the primary tumor in head and neck carcinoma. Arch Otolaryngol Head Neck Surg 112:863, 1986 7. Byers RM, Bland KI, Borlase B, et al: The prognostic and therapeutic value of frozen section determinations of squamous cell carcinoma of the head and neck. Am J Surg 136:525, 1978 8. Westra WH, Sidransky D: Phenotypic and genotypic disparity in premalignant lesions: Of calm water and crocodiles. J Natl Cancer Inst 90:1500, 1998 9. Rosin MP, Cheng X, Poh C, et al: Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 6:357, 2000 10. Kaugars GE, Pillion T, Svirsky JA, et al: Actinic cheilitis: A review of 152 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 88:181, 1997 11. Neville BW, Damm DD, Allen CM, et al: Epithelial pathology: Actinic cheilosis; squamous cell carcinoma, in Neville BW, Damm DD, Allen CM, et al (eds): Oral and Maxillofacial Pathology (ed 2). Philadelphia, PA, Saunders, 2002, pp 337-346, 353-354
© 2003 American Association of Oral and Maxillofacial Surgeons doi:10.1016/S0278-2391(03)00246-5