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The clinical and histologic presentation of gingival squamous cell carcinoma: a study of 519 cases
Vol. 114 No. 4 October 2012
The clinical and histologic presentation of gingival squamous cell carcinoma: a study of 519 cases Sarah G. Fitzpatrick, DDS,a Ashley N. Neuman, DDS,b Donald M. Cohen, DMD, MS, MBA,b and Indraneel Bhattacharyya, DDS, MSD,b Cleveland, OH; and Gainesville, FL Objectives. Gingival squamous cell carcinoma (SCCA) often presents with benign features, which may lead to delay in treatment. This study describes the clinical and histologic characteristics of a series of gingival SCCA cases. Study Design. A retrospective consecutive case review was performed using the University of Florida College of Dentistry Biopsy service’s database, which yielded clinical and histologic information on 519 cases of gingival SCCA. Results. The average age of affected patients was 72.3 years. The most common site was the mandibular posterior gingiva. Approximately 72% of lesions were present for ⬎2 months at biopsy. The majority of clinicians considered a malignancy in their differential diagnosis (64%), although 15% considered only reactive lesions. Most of the carcinomas presented as exophytic masses and, histologically, were moderately differentiated. Conclusions. Gingival SCCA may present with varied clinical and histologic appearances and should be considered in the differential diagnosis of benign appearing lesions of the gingiva. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114: 509-515)
Squamous cell carcinoma (SCCA) of the gingiva has been reported to account for up to one quarter of cases of oral SCCA, although estimates range from ⬍10% to as high as 30%, depending on the study.1-4 Early diagnosis of gingival SCCA may pose significant challenges to the clinician because of its diverse clinical appearance and the many benign conditions that it may mimic, including periodontal disease, lichen planus, inflammatory reactive tumor-like lesions, and nonspecific granulation tissue. Consequently, delays in diagnosis and treatment may result. Gingival SCCA exhibits cervical node metastases in one-third or more of cases.5 In addition, early bony invasion is a frequent occurrence because of the close proximity of the underlying alveolar bone.6,7 This study reviews the clinical data from a large database of gingival squamous cell carcinomas during a 17-year period.
STUDY DESIGN The archives of the Oral and Maxillofacial Pathology Biopsy Service at the University of Florida College of Dentistry were reviewed to identify all subtypes of SCCA by searching for cases coded as SCCA or verrucous carcinoma from 1994 to 2011 with institutional review board approval. Subclassification a
Department of Oral Pathology, Case Western Reserve University School of Dental Medicine, Cleveland, OH. b Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL. Received for publication Apr 12, 2012; returned for revision Jun 8, 2012; accepted for publication Jun 11, 2012. © 2012 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.06.018
was performed by location, and only cases with a primary site of gingiva or alveolar mucosa were included. A total of 571 cases were initially identified within this date range. Cases were excluded if they involved the alveolar ridge predominantly by extension from an adjacent location (such as floor of mouth, buccal mucosa, palate). Cases were also excluded if the primary location listed was maxillary tuberosity or retromolar pad because of the potential of an extension from a tumor primarily involving Waldeyer’s ring or the palatine tonsillar areas, although lesions that originated on the gingiva but spread slightly to these locations were included. In addition, in instances in which 2 or more biopsies were present within the previous 1-year period in the same location, only the initial biopsy was included to eliminate the possibility of double counting any lesions that were first submitted for incisional biopsy and later submitted after total excision. Cases also were required to show evidence of surface involvement to avoid inclusion of cases of primary intraosseous carcinoma. Finally, cases were eliminated in the event of any information indicating the possibility of metastatic disease as the primary source.
Statement of Clinical Relevance This study characterizes the wide variation in clinical and histologic appearance of gingival squamous cell carcinoma. A significant delay in diagnosis is often seen due to the ability of these lesions to mimic common benign conditions.
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Fig. 1. Graph depicting patients’ age range.
The total final number of cases included in the study was 519. A database was constructed and information was gathered on each of the cases from the original biopsy report and the submitting clinician’s biopsy submission form. Any radiographs or clinical pictures submitted with the case were reviewed as well. Parameters evaluated included age, gender, location, time the lesion had been present at time of biopsy, color, clinical appearance, submitting clinician’s clinical impression of the lesion, any previous treatment, radiographic findings, histopathologic diagnosis, and histopathologic grade. This study did not include staging, treatment, or outcome because this information was not available.
RESULTS Demographics and location The average age reported in our series was 72.3 years (of 515 cases in which the age was provided). The range was between 17 and 99 years (Fig. 1). Patients younger than 50 years of age comprised just 5% (27 patients) of the cases. Four cases, or ⬍1%, occurred in patients younger than 30 years of age, including 2 cases in patients younger than 20 (ages 17 and 19 years). Male subjects comprised a slightly greater percentage at 52% (271 patients). Gingival SCCA arose more commonly in the mandibular gingiva (69%, 358 patients). In 10 cases, the involved arch was not noted (Fig. 2). Clinical parameters Of the 365 cases in which the “lesion duration” was reported by the clinician, 72% were present for ⬎2 months (Table I). In summary, lesions present for less than 2 months accounted for 28% (101 of 365), 2 months to 1 year made up 55% (201 of 365), and ⬎1 year comprised 17% (63 cases). The most common color descriptor of the lesion was red (including erythematous and erythroplakia), in 169
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patients (33%), followed by mixed (red and white, erythroleukoplakia) in 141 (27%), white (leukoplakia) in 55 (10%), pink in 71 (14%), and other (9 patients or 2%). This information was not reported in 74 cases. Many cases (n ⫽ 117) included more than one term to describe the clinical presentation of the lesions. Examples of common clinical appearances are shown in Figure 3. The most common descriptors fell into a category describing an exophytic lesion (including pedunculated, fungating, or mass-like) in 105 cases. The next most commonly described category of lesions was verrucous, corrugated, or papillary in appearance (including rough, pebbly, granular, or cauliflower) at 103 responses. Ulcerated lesions were the third most commonly described appearances with 98 cases. Additional clinical descriptors included “painful” (38), “swollen” (36), “hemorrhagic” (32), “granulation tissue-like” (29), “leukoplakic” (21), “nonhealing” (19), “sessile or raised” (16), “rolled borders” (12), “fistula/suppurative/ abscess” (8), “erythroleukoplakia or mixed” (7), “inflamed or irritated” (7), “indurated” (6), “exposed bone” (5), “friable” (4), “aggressive or destructive,” (4) “fluctuant, soft, or edematous” (4), and “necrotic” (2). In 75 cases, no clinical description of the lesion was provided. Clinical impression The clinical impression listed by the submitting clinician varied, with many clinicians listing both benign and malignant entities in their differential diagnosis (Table II). In 64% of cases (333), the possibility of a malignant lesion was considered in the differential diagnosis or clinical impression, either as the primary clinical impression or as a secondary diagnosis (e.g., “primary diagnosis, rule out cancer”). In cases in which only a benign lesion was considered in the differential diagnosis, the most common entities included pyogenic granuloma, peripheral giant cell granuloma, peripheral ossifying fibroma, or nonspecific inflammatory or reactive lesions, which combined comprised 15% of the clinical diagnoses. Previous procedures and history Of the 519 cases, 127 reported some form of recent or previous treatment. Most common prior treatment included recent extraction (67 cases), and a previous biopsy in 32 cases (16 premalignant results, 7 benign results, 9 with unknown results). Thirteen cases reported recent periodontal therapy, including 4 cases with a previous history of surgical grafting to the area. In 6 cases, patients were empirically treated with several classes of drugs before obtaining a definite diagnosis, including antibiotics (6 cases), corticosteroids (3), and one case each with an antifungal, locally placed
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Fig. 2. Graph depicting location of gingival SCCA (expressed as percentages).
Table I. Duration of lesion prior to biopsy Duration of lesion
No. cases
Percent of total (519)
Unknown ⬍2 mo ⬎2-6 mo ⬎6 mo to 1 yr ⬎1-2 yr ⬎2-3 yr ⬎3-5 yr ⬎5 yr “Weeks” “Months” “Years”
154 91 127 41 15 13 12 4 10 33 19
30 17 24 8 3 3 2 ⬍1 2 6 4
antibiotic treatment (Arrestin; OraPharma, Inc., Horsham, PA), and Retin A gel. Eight patients had treatments that fit into more than one category. Thirty-two cases reported a previous history of oral SCCA or verrucous carcinoma, although the specific location was not always mentioned. One patient had a history of SCCA of the skin. Radiation therapy affecting the head and neck for a previous carcinoma was noted in 9 patients. In 3 cases, the clinician reported clinical lymphadenopathy at the time of the biopsy. A history of oral lichen planus was reported in 14 cases, and in 3 cases separate tissue was submitted in Michel’s solution for direct immunofluorescence study and results indicated a positive fibrinogen reaction at the basement membrane. Thirty-three cases were noted to present clinically as “denture sores,” with an additional 5 cases in which sores underneath fixed partial denture pontics were reported. Diagnosis and grading The final histopathologic diagnosis was SCCA in 79% of cases (409 cases) and verrucous carcinoma in 7% of cases (39 cases). Other SCCA variants included papil-
lary SCCA (12% or 61 cases), spindle cell or sarcomatoid carcinoma (1%, 6 cases), basaloid SCCA (2 cases), and one case each of acantholytic SCCA and adenosquamous carcinoma. In summary, the majority of cases were moderately differentiated carcinomas, with a diverse range from superficially invasive through poorly differentiated (Fig. 4). The cases that were not graded were all classified as verrucous carcinoma, which is considered to be well differentiated. Lesions were classified as superficially invasive in the presence of small or limited areas of focal invasion of dysplastic epithelium into the underlying connective tissue. Lesions were classified as well differentiated if they retained clear features of squamous epithelium versus poorly differentiated if they exhibited anaplastic features with little to no squamous differentiation. Moderately differentiated lesions were those that displayed overall features between well and poorly differentiated tumors. Lesions which exhibited areas of 2 different histologic grading categories were classified as “well to moderately” or “moderately to poorly” differentiated. Bone involvement Of the 519 cases, 134 had findings reported by the submitting clinician suggestive of bone involvement, including severe local periodontal disease, loose/mobile teeth, self-exfoliating teeth, or a nonhealing extraction site, had radiographic evidence of bony involvement, signs of bone invasion on the biopsy material examined, or other signs of bone invasion such as paresthesia or pathologic fracture (Fig. 5). A total of 43 patients had loose or mobile teeth, aggressive localized periodontal disease, or self-exfoliating teeth, and 33 cases presented as nonhealing extraction sites. Fiftytwo cases reported “bone involvement” clinically or had radiographic evidence of bone involvement on accompanying radiographs. Mandibular nerve pares-
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Fig. 3. Various clinical presentations of gingival SCCA. A, Gingival mass in a 17-year-old female patient mimicking a reactive gingival lesion. The biopsy revealed well-differentiated SCCA (photo courtesy of Dr. Avi Schetritt). B, Ulcerative lesion surrounding the gingival margin of teeth # 29 to 31 with a lichenoid appearance in a 54-year-old male patient. Biopsy revealed moderately well-differentiated SCCA (photo courtesy of Dr. Stephen Strout). C, Diffuse bulbous and erythematous gingival involvement of the mandibular left molar area. The biopsy revealed moderately differentiated SCCA (photo courtesy of Dr. Jason Lee). D, Papillary erythroleukoplakic lesion surrounding teeth # 26 to 28. The histologic diagnosis was atypical verrucoid epithelial proliferation consistent with early verrucous carcinoma (photo courtesy of Dr. James. Wilson).
Table II. Summary of clinical impression or differential diagnosis Clinical impression
No. cases
Percent of total (519)
SCCA or verrucous carcinoma “Cancer” “Tumor” Dysplasia PVL or VPHK Benign lesions vs SCCA Reactive gingival lesion Nonspecific inflammatory/reactive Periodontal disease Viral papillary lesion Infective (fungal, viral) Lichen planus Hyperkeratosis OM, BRON, or ORN Gingival hyperplasia Other Unknown
209 25 6 14 13 66 41 35 14 12 11 8 7 6 6 13 33
40 5 1 3 2.5 12 8 7 3 2 2 1.5 1 1 1 4 6
BRON, bisphosphonate related osteonecrosis; OM, osteomyelitis; ORN, osteoradionecrosis; PVL, proliferative verrucous leukoplakia; SCCA, squamous cell carcinoma; VPHK, verrucopapillary hyperkeratosis.
thesia was noted in 4 cases. Three cases of pathologic fracture were reported. In 2 cases, histologic evidence of invasion into bone was evident. Three cases had multiple features suggestive of bone involvement.
Fig. 4. Histologic grade of gingival SCCAs, expressed as percentage.
DISCUSSION The average age of the patient of 72.3 years in this study was slightly higher than comparable studies, which have reported an average age between 61 and 68 years. This could be attributable to the demographics of the general population of Florida, which has a tendency to be older in general than many other areas.1,2,4,7-9 The age range in our case series (17-99 years) also included patients of both younger and older ages than the other
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Fig. 5. Radiographic features of gingival SCCA: A, Edentulous ridge with cupping erosion of the bone in the mandibular right posterior region. B, Mandibular left first molar with severe surrounding bone loss giving the appearance of a tooth “floating in air.” C, Mandibular left molar teeth with radiographic appearance of furcation involvement (radiograph courtesy of Dr. Stephen Wendt). D, Mandibular anterior teeth with severe localized bone loss (radiograph courtesy of Dr. Christopher S. Lee).
studies.1,8,9 Gingival SCCA occurring in patients younger than 20 years of age has only rarely been reported.10,11 In previous studies, the gender ratio has been reported to be more predominantly male, ranging from 75% to a slight male predominance.1,2,4,7,8,12 Barasch et al,13 however, noted a female predilection in gingival carcinomas in their study of 111 cases. In the current case series, ratio was nearly 1:1, with 52% of patients males. The bulk of the lesions (69%) were reported in the mandibular gingiva, which is within the range of previous studies.1,2,7 Exact location of the lesions was not noted in most previous studies, though one study reported a higher number of cases in the posterior mandible compared to the anterior mandible.2 Cady et al. also reported lesions to be more common in the posterior regions, which was consistent with our findings.12 In several previous studies, authors have evaluated the timeline to diagnosis in regards to gingival SCCA. Seoane et al.6 compared gingival SCCA to tongue or floor of the mouth SCCA and reported that gingival SCCA was diagnosed in ⬍6 weeks in 75% of cases. They did not find any statistically significant difference in the time to diagnosis when compared to the other oral locations. Another study reported duration of symptoms of ⬍3 months in 86% of gingival SCCA patients.2 Cady et al.12 in 1969 reported a broader duration range with 45% of patients complaining of
symptoms for 3 months or less and 54% for over 3 months. In contrast, in our study, in those cases in which duration of lesion was noted, 72% of cases were present over 2 months. However, accurate estimation of the time to diagnosis is problematic due to a wide variation in reported times. In prior studies, authors have evaluated the specific clinical presentation of gingival SCCA. Soo et al2 reported the most frequent symptoms associated with gingival SCCA as soreness or pain followed by ulceration, toothache or loose teeth, denture sore, or swelling or mass. Another study reported the most common presentation to be a swelling or mass, followed by ulceration and, rarely, pain or mobility of teeth.7 Makridis et al1 found the most common presentation to be that of an erythroplakic lesion, followed by ulceration and leukoplakia. Premalignant oral epithelial lesions have been shown to have a higher rate of transformation for red or mixed lesions than purely white lesions.14,15 Our findings that the most common clinical appearance was that of an exophytic or mass-like lesion is consistent with the Gomez et al. study.7 In addition, our study also identified the presence of ulceration as a common presenting feature. To the best of our knowledge, no previous study has examined the submitting provider’s clinical impression or differential diagnosis in regard to gingival SCCA. Much has been written, however, regarding the poten-
ORAL AND MAXILLOFACIAL PATHOLOGY 514 Fitzpatrick et al.
tial for diagnostic delay because of the clinical similarity of gingival SCCA to benign conditions such as periodontal disease. The majority of our biopsy submissions come from dental specialists, especially oral surgeons and periodontists, but in many cases the biopsy submission sheet mentioned previous evaluation before referral by general dentists or other providers. The majority of the lesions in our study evoked at least the consideration of a malignant process in the differential diagnosis (69% of cases in which a clinical impression was provided), which is encouraging. The most common benign group of pathologies considered were gingival reactive growths, particularly in those lesions that presented with an exophytic component. When the response “gingival reactive growth” is combined with “other reactive/inflammatory lesions,” the percentage of clinicians considering only this in their differential diagnosis approached 15% of cases. The consideration of other groups of lesions, such as periodontal disease, viral mediated benign papillary lesions, infective fungal or viral lesions, denture sores, or chronic ulcers, point to the importance of considering gingival SCCA in any cases in which lesions present with an atypical appearance or are unresponsive to therapy. Several studies note that gingival SCCA becomes evident in patients immediately after undergoing extractions. We found that extraction of a tooth preceded identification of the gingival lesion in approximately 13% of the patients. In contrast, for Cady et al12 almost one third of their cases of gingival SCCA were associated with a preceding extraction of teeth. Twenty years later, Soo et al2 noted that tooth extractions preceded diagnosis of carcinoma in 20% of their patients. This decrease over time may indicate an increased awareness among clinicians of the importance of including gingival SCCA in the differential diagnosis of localized aggressive or atypical periodontal disease. Some forms of oral lichen planus have been correlated with an increased risk of developing oral SCCA, particularly the erosive or ulcerated types. However, this association remains the subject of controversy because this phenomenon may be represent a true malignant transformation or an overlap of clinical and histologic presentation.16 Several features in our study were of interest in this respect. First is the relatively low rate of patients in which the clinician reported a history of oral lichen planus (14 patients or 3% of the total cases). In addition, 3 of the 14 cases in our study showed positivity to fibrinogen along the basement membrane zone on direct immunofluorescence. A total of 33 submitting clinicians (6% of total) in our study reported that their patients presented with denture sores. Gomez et al 7 reported a much higher
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rate, at nearly one quarter of cases. The development of carcinoma in edentulous or partially edentulous patients who develop gingival SCCA is a potentially interesting area to explore further, especially given the propensity for denture sores to clinically mimic gingival SCCA. Campbell et al17 concluded in a 1997 study that there was no support for a causative link between denture use and gingival/alveolar SCCA. Although the majority of cases of SCCA in this case series represented common histologic subtypes of oral SCCA, rarer subtypes were also found, in particular papillary SCCA (12% of cases). This form of oral SCCA has been shown to be less aggressive than other types of head and neck SCCA.18 The histologic grading scale of our cases was very similar to other studies. Soo et al2 and Poeschl et al8 found that the most common histologic grade of gingival SCCA was moderately differentiated or grade II. In contrast, however, another study noted the vast majority of their cases comprised well differentiated SCCA.7 The true rate of bony involvement associated with these cases could not be fully assessed due to a lack of access to radiographic or other diagnostic information in many of these cases. Our estimate of 26% of cases (n ⫽ 134) demonstrating either frank bony invasion or features suggestive of bone involvement should represent a minimum level of bony involvement in this series. Since our study did not involve access to the postdiagnosis treatment records of these cases, no information on staging, treatment, or outcome could be assessed.
CONCLUSIONS In this study we aimed to more fully characterize the clinical presentation of gingival SCCA, an entity that may pose significant clinical challenges for the clinician. Gingival SCCA may present over a wide age range and may present in any area of the dentate or edentulous jaws. The clinical presentation is wide-ranging, mimicking many common benign lesions. This may lead to a delay in diagnosis. Similarly, the histologic presentation of the SCCA itself may be varied, encompassing a wide range of histologic grades and potential behavior. Therefore, the clinical presentation of a largely benign appearing gingival lesion should evoke suspicion, especially in the presence of any atypical features or a poor response to conservative therapy. REFERENCES 1. Makridis SD, Mellado JR, Freedman AL, Salkin LM, Stein MD. Squamous cell carcinoma of gingiva and edentulous alveolar ridge: a clinicopathologic study. Int J Periodontics Restorative Dent 1998;18:292-8. 2. Soo KC, Spiro RH, King W, Harvey W, Strong EW. Squamous carcinoma of the gums. Am J Surg 1988;156:281-5.
OOOO Volume 114, Number 4 3. Rautava J, Luukkaa M, Heikinheimo K, Alin J, Grenman R, Happonen RP. Squamous cell carcinomas arising from different types of oral epithelia differ in their tumor and patient characteristics and survival. Oral Oncol 2007;43:911-9. 4. Shingaki S, Nomura T, Takada M, Kobayashi T, Suzuki I, Nakajima T. Squamous cell carcinomas of the mandibular alveolus: analysis of prognostic factors. Oncology 2002;62:17-24. 5. Lubek J, El-Hakim M, Salama AR, Liu X, Ord RA. Gingival carcinoma: retrospective analysis of 72 patients and indications for elective neck dissection. Br J Oral Maxillofac Surg 2011;49:182-5. 6. Seoane J, Varela-Centelles PI, Walsh TF, Lopez-Cedrun JL, Vazquez I. Gingival squamous cell carcinoma: diagnostic delay or rapid invasion? J Periodontol 2006;77:1229-33. 7. Gomez D, Faucher A, Picot V, Siberchicot F, Renaud-Salis JL, Bussières E, Pinsolle J. Outcome of squamous cell carcinoma of the gingiva: a follow-up study of 83 cases. J Craniomaxillofac Surg 2000;28:331-5. 8. Poeschl PW, Russmueller G, Seemann R, Klug C, Poeschl E, Sulzbacher I, Ewers R. Staging and grading as prognostic factors in maxillary squamous cell carcinoma. J Oral Maxillofac Surg 2011;69:3038-44. 9. Nomura T, Shibahara T, Cui NH, Noma H. Patterns of mandibular invasion by gingival squamous cell carcinoma. J Oral Maxillofac Surg 2005;63:1489 –13. 10. Woo VL, Kelsch RD, Su L, Kim T, Zegarelli DJ. Gingival squamous cell carcinoma in adolescence. Oral Med oral Pathol oral Radiol. J Endod 2009;107:92-9. 11. Ribeiro CM, Gueiros LA, Leon JE, do Carmo Abreu e Lima M, de Almeida OP, Leão JC. Oral squamous cell carcinoma in a
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7-year-old Brazilian boy. Int J Oral Maxillofac Surg 2011;40: 994-7. Cady B, Catlin D. Epidermoid carcinoma of the gum. A 20-year survey. Cancer 1969;23:551-69. Barasch A, Gofa A, Krutchkoff DJ, Eisenberg E. Squamous cell carcinoma of the gingiva: a case series analysis. Oral Med Oral Pathol Oral Radiol Endod 1995;80:183-7. Lapthanasupkul P, Poomsawat S, Punyasingh J. A clinicopathologic study of oral leukoplakia and erythroplakia in a Thai population. Quintessence Int 2007;38:e448-55. Van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009;45:317-23. Muller S. Oral manifestations of dermatologic disease: a focus on lichenoid lesions. Head and neck. Pathologe 2011;5:36-40. Campbell BH, Mark DH, Soneson EA, Freije JE, Schultz CJ. The role of dental prostheses in alveolar ridge squamous carcinomas. Arch Otolaryngol Head Neck Surg 1997;123:1112-5. Colby C, Klein AM. Papillary squamous cell carcinoma of the larynx. Ear Nose Throat J 2011;90:E13-E5.
Reprint requests: Dr. Indraneel Bhattacharyya Associate Professor and Residency Program Director Division of Oral Pathology Department of Oral and Maxillofacial Diagnostic Sciences University of Florida College of Dentistry PO Box 100414 JHMHC Gainesville, FL 32610-0414 [email protected]
The clinical and histologic presentation of gingival squamous cell carcinoma: a study of 519 cases Sarah G. Fitzpatrick, DDS,a Ashley N. Neuman, DDS,b Donald M. Cohen, DMD, MS, MBA,b and Indraneel Bhattacharyya, DDS, MSD,b Cleveland, OH; and Gainesville, FL Objectives. Gingival squamous cell carcinoma (SCCA) often presents with benign features, which may lead to delay in treatment. This study describes the clinical and histologic characteristics of a series of gingival SCCA cases. Study Design. A retrospective consecutive case review was performed using the University of Florida College of Dentistry Biopsy service’s database, which yielded clinical and histologic information on 519 cases of gingival SCCA. Results. The average age of affected patients was 72.3 years. The most common site was the mandibular posterior gingiva. Approximately 72% of lesions were present for ⬎2 months at biopsy. The majority of clinicians considered a malignancy in their differential diagnosis (64%), although 15% considered only reactive lesions. Most of the carcinomas presented as exophytic masses and, histologically, were moderately differentiated. Conclusions. Gingival SCCA may present with varied clinical and histologic appearances and should be considered in the differential diagnosis of benign appearing lesions of the gingiva. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114: 509-515)
Squamous cell carcinoma (SCCA) of the gingiva has been reported to account for up to one quarter of cases of oral SCCA, although estimates range from ⬍10% to as high as 30%, depending on the study.1-4 Early diagnosis of gingival SCCA may pose significant challenges to the clinician because of its diverse clinical appearance and the many benign conditions that it may mimic, including periodontal disease, lichen planus, inflammatory reactive tumor-like lesions, and nonspecific granulation tissue. Consequently, delays in diagnosis and treatment may result. Gingival SCCA exhibits cervical node metastases in one-third or more of cases.5 In addition, early bony invasion is a frequent occurrence because of the close proximity of the underlying alveolar bone.6,7 This study reviews the clinical data from a large database of gingival squamous cell carcinomas during a 17-year period.
STUDY DESIGN The archives of the Oral and Maxillofacial Pathology Biopsy Service at the University of Florida College of Dentistry were reviewed to identify all subtypes of SCCA by searching for cases coded as SCCA or verrucous carcinoma from 1994 to 2011 with institutional review board approval. Subclassification a
Department of Oral Pathology, Case Western Reserve University School of Dental Medicine, Cleveland, OH. b Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL. Received for publication Apr 12, 2012; returned for revision Jun 8, 2012; accepted for publication Jun 11, 2012. © 2012 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.06.018
was performed by location, and only cases with a primary site of gingiva or alveolar mucosa were included. A total of 571 cases were initially identified within this date range. Cases were excluded if they involved the alveolar ridge predominantly by extension from an adjacent location (such as floor of mouth, buccal mucosa, palate). Cases were also excluded if the primary location listed was maxillary tuberosity or retromolar pad because of the potential of an extension from a tumor primarily involving Waldeyer’s ring or the palatine tonsillar areas, although lesions that originated on the gingiva but spread slightly to these locations were included. In addition, in instances in which 2 or more biopsies were present within the previous 1-year period in the same location, only the initial biopsy was included to eliminate the possibility of double counting any lesions that were first submitted for incisional biopsy and later submitted after total excision. Cases also were required to show evidence of surface involvement to avoid inclusion of cases of primary intraosseous carcinoma. Finally, cases were eliminated in the event of any information indicating the possibility of metastatic disease as the primary source.
Statement of Clinical Relevance This study characterizes the wide variation in clinical and histologic appearance of gingival squamous cell carcinoma. A significant delay in diagnosis is often seen due to the ability of these lesions to mimic common benign conditions.
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Fig. 1. Graph depicting patients’ age range.
The total final number of cases included in the study was 519. A database was constructed and information was gathered on each of the cases from the original biopsy report and the submitting clinician’s biopsy submission form. Any radiographs or clinical pictures submitted with the case were reviewed as well. Parameters evaluated included age, gender, location, time the lesion had been present at time of biopsy, color, clinical appearance, submitting clinician’s clinical impression of the lesion, any previous treatment, radiographic findings, histopathologic diagnosis, and histopathologic grade. This study did not include staging, treatment, or outcome because this information was not available.
RESULTS Demographics and location The average age reported in our series was 72.3 years (of 515 cases in which the age was provided). The range was between 17 and 99 years (Fig. 1). Patients younger than 50 years of age comprised just 5% (27 patients) of the cases. Four cases, or ⬍1%, occurred in patients younger than 30 years of age, including 2 cases in patients younger than 20 (ages 17 and 19 years). Male subjects comprised a slightly greater percentage at 52% (271 patients). Gingival SCCA arose more commonly in the mandibular gingiva (69%, 358 patients). In 10 cases, the involved arch was not noted (Fig. 2). Clinical parameters Of the 365 cases in which the “lesion duration” was reported by the clinician, 72% were present for ⬎2 months (Table I). In summary, lesions present for less than 2 months accounted for 28% (101 of 365), 2 months to 1 year made up 55% (201 of 365), and ⬎1 year comprised 17% (63 cases). The most common color descriptor of the lesion was red (including erythematous and erythroplakia), in 169
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patients (33%), followed by mixed (red and white, erythroleukoplakia) in 141 (27%), white (leukoplakia) in 55 (10%), pink in 71 (14%), and other (9 patients or 2%). This information was not reported in 74 cases. Many cases (n ⫽ 117) included more than one term to describe the clinical presentation of the lesions. Examples of common clinical appearances are shown in Figure 3. The most common descriptors fell into a category describing an exophytic lesion (including pedunculated, fungating, or mass-like) in 105 cases. The next most commonly described category of lesions was verrucous, corrugated, or papillary in appearance (including rough, pebbly, granular, or cauliflower) at 103 responses. Ulcerated lesions were the third most commonly described appearances with 98 cases. Additional clinical descriptors included “painful” (38), “swollen” (36), “hemorrhagic” (32), “granulation tissue-like” (29), “leukoplakic” (21), “nonhealing” (19), “sessile or raised” (16), “rolled borders” (12), “fistula/suppurative/ abscess” (8), “erythroleukoplakia or mixed” (7), “inflamed or irritated” (7), “indurated” (6), “exposed bone” (5), “friable” (4), “aggressive or destructive,” (4) “fluctuant, soft, or edematous” (4), and “necrotic” (2). In 75 cases, no clinical description of the lesion was provided. Clinical impression The clinical impression listed by the submitting clinician varied, with many clinicians listing both benign and malignant entities in their differential diagnosis (Table II). In 64% of cases (333), the possibility of a malignant lesion was considered in the differential diagnosis or clinical impression, either as the primary clinical impression or as a secondary diagnosis (e.g., “primary diagnosis, rule out cancer”). In cases in which only a benign lesion was considered in the differential diagnosis, the most common entities included pyogenic granuloma, peripheral giant cell granuloma, peripheral ossifying fibroma, or nonspecific inflammatory or reactive lesions, which combined comprised 15% of the clinical diagnoses. Previous procedures and history Of the 519 cases, 127 reported some form of recent or previous treatment. Most common prior treatment included recent extraction (67 cases), and a previous biopsy in 32 cases (16 premalignant results, 7 benign results, 9 with unknown results). Thirteen cases reported recent periodontal therapy, including 4 cases with a previous history of surgical grafting to the area. In 6 cases, patients were empirically treated with several classes of drugs before obtaining a definite diagnosis, including antibiotics (6 cases), corticosteroids (3), and one case each with an antifungal, locally placed
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Fig. 2. Graph depicting location of gingival SCCA (expressed as percentages).
Table I. Duration of lesion prior to biopsy Duration of lesion
No. cases
Percent of total (519)
Unknown ⬍2 mo ⬎2-6 mo ⬎6 mo to 1 yr ⬎1-2 yr ⬎2-3 yr ⬎3-5 yr ⬎5 yr “Weeks” “Months” “Years”
154 91 127 41 15 13 12 4 10 33 19
30 17 24 8 3 3 2 ⬍1 2 6 4
antibiotic treatment (Arrestin; OraPharma, Inc., Horsham, PA), and Retin A gel. Eight patients had treatments that fit into more than one category. Thirty-two cases reported a previous history of oral SCCA or verrucous carcinoma, although the specific location was not always mentioned. One patient had a history of SCCA of the skin. Radiation therapy affecting the head and neck for a previous carcinoma was noted in 9 patients. In 3 cases, the clinician reported clinical lymphadenopathy at the time of the biopsy. A history of oral lichen planus was reported in 14 cases, and in 3 cases separate tissue was submitted in Michel’s solution for direct immunofluorescence study and results indicated a positive fibrinogen reaction at the basement membrane. Thirty-three cases were noted to present clinically as “denture sores,” with an additional 5 cases in which sores underneath fixed partial denture pontics were reported. Diagnosis and grading The final histopathologic diagnosis was SCCA in 79% of cases (409 cases) and verrucous carcinoma in 7% of cases (39 cases). Other SCCA variants included papil-
lary SCCA (12% or 61 cases), spindle cell or sarcomatoid carcinoma (1%, 6 cases), basaloid SCCA (2 cases), and one case each of acantholytic SCCA and adenosquamous carcinoma. In summary, the majority of cases were moderately differentiated carcinomas, with a diverse range from superficially invasive through poorly differentiated (Fig. 4). The cases that were not graded were all classified as verrucous carcinoma, which is considered to be well differentiated. Lesions were classified as superficially invasive in the presence of small or limited areas of focal invasion of dysplastic epithelium into the underlying connective tissue. Lesions were classified as well differentiated if they retained clear features of squamous epithelium versus poorly differentiated if they exhibited anaplastic features with little to no squamous differentiation. Moderately differentiated lesions were those that displayed overall features between well and poorly differentiated tumors. Lesions which exhibited areas of 2 different histologic grading categories were classified as “well to moderately” or “moderately to poorly” differentiated. Bone involvement Of the 519 cases, 134 had findings reported by the submitting clinician suggestive of bone involvement, including severe local periodontal disease, loose/mobile teeth, self-exfoliating teeth, or a nonhealing extraction site, had radiographic evidence of bony involvement, signs of bone invasion on the biopsy material examined, or other signs of bone invasion such as paresthesia or pathologic fracture (Fig. 5). A total of 43 patients had loose or mobile teeth, aggressive localized periodontal disease, or self-exfoliating teeth, and 33 cases presented as nonhealing extraction sites. Fiftytwo cases reported “bone involvement” clinically or had radiographic evidence of bone involvement on accompanying radiographs. Mandibular nerve pares-
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Fig. 3. Various clinical presentations of gingival SCCA. A, Gingival mass in a 17-year-old female patient mimicking a reactive gingival lesion. The biopsy revealed well-differentiated SCCA (photo courtesy of Dr. Avi Schetritt). B, Ulcerative lesion surrounding the gingival margin of teeth # 29 to 31 with a lichenoid appearance in a 54-year-old male patient. Biopsy revealed moderately well-differentiated SCCA (photo courtesy of Dr. Stephen Strout). C, Diffuse bulbous and erythematous gingival involvement of the mandibular left molar area. The biopsy revealed moderately differentiated SCCA (photo courtesy of Dr. Jason Lee). D, Papillary erythroleukoplakic lesion surrounding teeth # 26 to 28. The histologic diagnosis was atypical verrucoid epithelial proliferation consistent with early verrucous carcinoma (photo courtesy of Dr. James. Wilson).
Table II. Summary of clinical impression or differential diagnosis Clinical impression
No. cases
Percent of total (519)
SCCA or verrucous carcinoma “Cancer” “Tumor” Dysplasia PVL or VPHK Benign lesions vs SCCA Reactive gingival lesion Nonspecific inflammatory/reactive Periodontal disease Viral papillary lesion Infective (fungal, viral) Lichen planus Hyperkeratosis OM, BRON, or ORN Gingival hyperplasia Other Unknown
209 25 6 14 13 66 41 35 14 12 11 8 7 6 6 13 33
40 5 1 3 2.5 12 8 7 3 2 2 1.5 1 1 1 4 6
BRON, bisphosphonate related osteonecrosis; OM, osteomyelitis; ORN, osteoradionecrosis; PVL, proliferative verrucous leukoplakia; SCCA, squamous cell carcinoma; VPHK, verrucopapillary hyperkeratosis.
thesia was noted in 4 cases. Three cases of pathologic fracture were reported. In 2 cases, histologic evidence of invasion into bone was evident. Three cases had multiple features suggestive of bone involvement.
Fig. 4. Histologic grade of gingival SCCAs, expressed as percentage.
DISCUSSION The average age of the patient of 72.3 years in this study was slightly higher than comparable studies, which have reported an average age between 61 and 68 years. This could be attributable to the demographics of the general population of Florida, which has a tendency to be older in general than many other areas.1,2,4,7-9 The age range in our case series (17-99 years) also included patients of both younger and older ages than the other
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Fig. 5. Radiographic features of gingival SCCA: A, Edentulous ridge with cupping erosion of the bone in the mandibular right posterior region. B, Mandibular left first molar with severe surrounding bone loss giving the appearance of a tooth “floating in air.” C, Mandibular left molar teeth with radiographic appearance of furcation involvement (radiograph courtesy of Dr. Stephen Wendt). D, Mandibular anterior teeth with severe localized bone loss (radiograph courtesy of Dr. Christopher S. Lee).
studies.1,8,9 Gingival SCCA occurring in patients younger than 20 years of age has only rarely been reported.10,11 In previous studies, the gender ratio has been reported to be more predominantly male, ranging from 75% to a slight male predominance.1,2,4,7,8,12 Barasch et al,13 however, noted a female predilection in gingival carcinomas in their study of 111 cases. In the current case series, ratio was nearly 1:1, with 52% of patients males. The bulk of the lesions (69%) were reported in the mandibular gingiva, which is within the range of previous studies.1,2,7 Exact location of the lesions was not noted in most previous studies, though one study reported a higher number of cases in the posterior mandible compared to the anterior mandible.2 Cady et al. also reported lesions to be more common in the posterior regions, which was consistent with our findings.12 In several previous studies, authors have evaluated the timeline to diagnosis in regards to gingival SCCA. Seoane et al.6 compared gingival SCCA to tongue or floor of the mouth SCCA and reported that gingival SCCA was diagnosed in ⬍6 weeks in 75% of cases. They did not find any statistically significant difference in the time to diagnosis when compared to the other oral locations. Another study reported duration of symptoms of ⬍3 months in 86% of gingival SCCA patients.2 Cady et al.12 in 1969 reported a broader duration range with 45% of patients complaining of
symptoms for 3 months or less and 54% for over 3 months. In contrast, in our study, in those cases in which duration of lesion was noted, 72% of cases were present over 2 months. However, accurate estimation of the time to diagnosis is problematic due to a wide variation in reported times. In prior studies, authors have evaluated the specific clinical presentation of gingival SCCA. Soo et al2 reported the most frequent symptoms associated with gingival SCCA as soreness or pain followed by ulceration, toothache or loose teeth, denture sore, or swelling or mass. Another study reported the most common presentation to be a swelling or mass, followed by ulceration and, rarely, pain or mobility of teeth.7 Makridis et al1 found the most common presentation to be that of an erythroplakic lesion, followed by ulceration and leukoplakia. Premalignant oral epithelial lesions have been shown to have a higher rate of transformation for red or mixed lesions than purely white lesions.14,15 Our findings that the most common clinical appearance was that of an exophytic or mass-like lesion is consistent with the Gomez et al. study.7 In addition, our study also identified the presence of ulceration as a common presenting feature. To the best of our knowledge, no previous study has examined the submitting provider’s clinical impression or differential diagnosis in regard to gingival SCCA. Much has been written, however, regarding the poten-
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tial for diagnostic delay because of the clinical similarity of gingival SCCA to benign conditions such as periodontal disease. The majority of our biopsy submissions come from dental specialists, especially oral surgeons and periodontists, but in many cases the biopsy submission sheet mentioned previous evaluation before referral by general dentists or other providers. The majority of the lesions in our study evoked at least the consideration of a malignant process in the differential diagnosis (69% of cases in which a clinical impression was provided), which is encouraging. The most common benign group of pathologies considered were gingival reactive growths, particularly in those lesions that presented with an exophytic component. When the response “gingival reactive growth” is combined with “other reactive/inflammatory lesions,” the percentage of clinicians considering only this in their differential diagnosis approached 15% of cases. The consideration of other groups of lesions, such as periodontal disease, viral mediated benign papillary lesions, infective fungal or viral lesions, denture sores, or chronic ulcers, point to the importance of considering gingival SCCA in any cases in which lesions present with an atypical appearance or are unresponsive to therapy. Several studies note that gingival SCCA becomes evident in patients immediately after undergoing extractions. We found that extraction of a tooth preceded identification of the gingival lesion in approximately 13% of the patients. In contrast, for Cady et al12 almost one third of their cases of gingival SCCA were associated with a preceding extraction of teeth. Twenty years later, Soo et al2 noted that tooth extractions preceded diagnosis of carcinoma in 20% of their patients. This decrease over time may indicate an increased awareness among clinicians of the importance of including gingival SCCA in the differential diagnosis of localized aggressive or atypical periodontal disease. Some forms of oral lichen planus have been correlated with an increased risk of developing oral SCCA, particularly the erosive or ulcerated types. However, this association remains the subject of controversy because this phenomenon may be represent a true malignant transformation or an overlap of clinical and histologic presentation.16 Several features in our study were of interest in this respect. First is the relatively low rate of patients in which the clinician reported a history of oral lichen planus (14 patients or 3% of the total cases). In addition, 3 of the 14 cases in our study showed positivity to fibrinogen along the basement membrane zone on direct immunofluorescence. A total of 33 submitting clinicians (6% of total) in our study reported that their patients presented with denture sores. Gomez et al 7 reported a much higher
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rate, at nearly one quarter of cases. The development of carcinoma in edentulous or partially edentulous patients who develop gingival SCCA is a potentially interesting area to explore further, especially given the propensity for denture sores to clinically mimic gingival SCCA. Campbell et al17 concluded in a 1997 study that there was no support for a causative link between denture use and gingival/alveolar SCCA. Although the majority of cases of SCCA in this case series represented common histologic subtypes of oral SCCA, rarer subtypes were also found, in particular papillary SCCA (12% of cases). This form of oral SCCA has been shown to be less aggressive than other types of head and neck SCCA.18 The histologic grading scale of our cases was very similar to other studies. Soo et al2 and Poeschl et al8 found that the most common histologic grade of gingival SCCA was moderately differentiated or grade II. In contrast, however, another study noted the vast majority of their cases comprised well differentiated SCCA.7 The true rate of bony involvement associated with these cases could not be fully assessed due to a lack of access to radiographic or other diagnostic information in many of these cases. Our estimate of 26% of cases (n ⫽ 134) demonstrating either frank bony invasion or features suggestive of bone involvement should represent a minimum level of bony involvement in this series. Since our study did not involve access to the postdiagnosis treatment records of these cases, no information on staging, treatment, or outcome could be assessed.
CONCLUSIONS In this study we aimed to more fully characterize the clinical presentation of gingival SCCA, an entity that may pose significant clinical challenges for the clinician. Gingival SCCA may present over a wide age range and may present in any area of the dentate or edentulous jaws. The clinical presentation is wide-ranging, mimicking many common benign lesions. This may lead to a delay in diagnosis. Similarly, the histologic presentation of the SCCA itself may be varied, encompassing a wide range of histologic grades and potential behavior. Therefore, the clinical presentation of a largely benign appearing gingival lesion should evoke suspicion, especially in the presence of any atypical features or a poor response to conservative therapy. REFERENCES 1. Makridis SD, Mellado JR, Freedman AL, Salkin LM, Stein MD. Squamous cell carcinoma of gingiva and edentulous alveolar ridge: a clinicopathologic study. Int J Periodontics Restorative Dent 1998;18:292-8. 2. Soo KC, Spiro RH, King W, Harvey W, Strong EW. Squamous carcinoma of the gums. Am J Surg 1988;156:281-5.
OOOO Volume 114, Number 4 3. Rautava J, Luukkaa M, Heikinheimo K, Alin J, Grenman R, Happonen RP. Squamous cell carcinomas arising from different types of oral epithelia differ in their tumor and patient characteristics and survival. Oral Oncol 2007;43:911-9. 4. Shingaki S, Nomura T, Takada M, Kobayashi T, Suzuki I, Nakajima T. Squamous cell carcinomas of the mandibular alveolus: analysis of prognostic factors. Oncology 2002;62:17-24. 5. Lubek J, El-Hakim M, Salama AR, Liu X, Ord RA. Gingival carcinoma: retrospective analysis of 72 patients and indications for elective neck dissection. Br J Oral Maxillofac Surg 2011;49:182-5. 6. Seoane J, Varela-Centelles PI, Walsh TF, Lopez-Cedrun JL, Vazquez I. Gingival squamous cell carcinoma: diagnostic delay or rapid invasion? J Periodontol 2006;77:1229-33. 7. Gomez D, Faucher A, Picot V, Siberchicot F, Renaud-Salis JL, Bussières E, Pinsolle J. Outcome of squamous cell carcinoma of the gingiva: a follow-up study of 83 cases. J Craniomaxillofac Surg 2000;28:331-5. 8. Poeschl PW, Russmueller G, Seemann R, Klug C, Poeschl E, Sulzbacher I, Ewers R. Staging and grading as prognostic factors in maxillary squamous cell carcinoma. J Oral Maxillofac Surg 2011;69:3038-44. 9. Nomura T, Shibahara T, Cui NH, Noma H. Patterns of mandibular invasion by gingival squamous cell carcinoma. J Oral Maxillofac Surg 2005;63:1489 –13. 10. Woo VL, Kelsch RD, Su L, Kim T, Zegarelli DJ. Gingival squamous cell carcinoma in adolescence. Oral Med oral Pathol oral Radiol. J Endod 2009;107:92-9. 11. Ribeiro CM, Gueiros LA, Leon JE, do Carmo Abreu e Lima M, de Almeida OP, Leão JC. Oral squamous cell carcinoma in a
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Reprint requests: Dr. Indraneel Bhattacharyya Associate Professor and Residency Program Director Division of Oral Pathology Department of Oral and Maxillofacial Diagnostic Sciences University of Florida College of Dentistry PO Box 100414 JHMHC Gainesville, FL 32610-0414 [email protected]