Victoria L. Woo DDS, Robert D. Kelsch DMD, Lan Su DMD, PhD, Taeyun Kim BS, David J. Zegarelli DDS,eLas Vegas, NV, New Hyde Park, NY, Westlake Village, CA, Los Angeles, CA, New York, NY
UNIVERSITY OF NEVADA LAS VEGAS, LONG ISLAND JEWISH MEDICAL CENTER, PRIVATE PRACTICE, UNIVERSITY OF CALIFORNIA LOS ANGELES SCHOOL OF MEDICINE, AND COLUMBIA UNIVERSITY COLLEGE OF DENTAL MEDICINE
Squamous cell carcinoma (SCC) is a rare finding in the adolescent population, with most cases occurring in patients with underlying heritable diseases or immunologic conditions. Moreover, the incidence of oral SCC in this age group is extremely low. While isolated cases of adolescent oral SCC have been documented, most have been primary tongue or lip lesions. We report 4 cases of gingival SCC occurring in otherwise healthy adolescent patients. The preliminary clinical impressions ranged from factitial injury to inflammatory tissue. Microscopic similarities, including overlap with pseudoepitheliomatous hyperplasia and keratoacanthoma, were seen. Review of the literature indicates that adolescent gingival SCC is extremely rare and a challenging diagnosis for the clinician and pathologist alike.
Diagnostic pitfalls, possible etiologic factors, and the prognostic outlook of this condition are discussed. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:92-99)
Squamous cell carcinoma (SCC) is the most common neoplasm of the maxillofacial region and an infrequent finding in patients under the age of 40.1 Oral SCC (OSCC) is likewise rare in patients younger than 40, with cited incidences of 0.4%2 to 6.6%.3 Intraorally, SCC of this younger population has a predilection for the tongue and lips4-8and gingival involvement is dis- tinctly unusual.
SCC in patients under 20 years of age (which we herein refer to as the adolescent population) is excep- tionally rare. Most reported cases have originated in the respiratory tract including the larynx, trachea, bronchi, and lungs; skin; and genital tract.9
In this study, we present 4 cases of gingival OSCC.
All 4 cases occurred in otherwise healthy adolescent patients. We also review the current literature on OSCC affecting the younger population, with specific focus on diagnostic challenges faced by clinicians and patholo-
gists, etiology, management considerations, and prog- nostic implications.
CASE REPORTS Case 1
A healthy 18-year-old white female was referred for eval- uation of gingival lesions with associated teeth mobility. Her medical and family histories were noncontributory; however, a 3.5-pack-year history of cigarette smoking was disclosed.
On intraoral examination, multiple white, nodular, and ulcer- ated growths were present upon the #22-27 facial and lingual gingiva. Radiographs of this region revealed 50% to 75%
horizontal bone loss (Fig. 1). The clinical impression included an atypical epithelial proliferation versus traumatic or factitial injury. A biopsy was performed and read as “epithelial pro- liferation suggestive of squamous odontogenic tumor-like proliferation.” Because of these equivocal findings, it was determined that a second biopsy was warranted. Microscopic examination of the second specimen showed a verrucous- appearing epithelial proliferation with a prominent endo- phytic growth pattern. The tumor was characterized by a central, keratin-filled crater with distinct lateral cupping and exhibited the overall architecture of a keratoacanthoma (Fig.
2). The epithelium was markedly dyskeratotic with mild cellular pleomorphism. Stromal invasion was identified to- ward the lesion base and several sections showed deep infil- tration into the bone, prompting consideration of a carcinoma cuniculatum. A diagnosis of well-differentiated squamous cell carcinoma was ultimately rendered. The patient was subsequently treated with a hemimandibulectomy and bilat- eral supraomohyoid neck dissections. The final pathologic diagnosis was well-differentiated squamous cell carcinoma.
Perineural and lymphovascular invasion were absent and ex- cised lymph nodes were negative for carcinoma. She contin-
aAssociate Professor, Department of Biomedical Sciences, School of Dental Medicine, University of Nevada Las Vegas.
bAttending, Oral Pathology Division, North Shore-LIJ Health Sys- tem, Long Island Jewish Medical Center.
cPrivate practice; Lecturer, University of California Los Angeles School of Medicine; Associate Professor, Department of Head and Neck Surgery, University of California, Irvine School of Medicine.
dDDS Candidate 2009, Columbia University College of Dental Med- icine.
eProfessor and Chair, Division of Oral and Maxillofacial Pathology, Columbia University College of Dental Medicine.
Received for publication Mar 28, 2008; returned for revision Aug 29, 2008; accepted for publication Sep 2, 2008.
1079-2104/$ - see front matter
© 2009 All rights reserved.
doi:10.1016/j.tripleo.2008.09.003
92
ues to be without evidence of disease 51 months postopera- tively.
Case 2
A healthy 17-year-old white male was referred for evalu- ation of a white, nodular mass of the left posterior maxillary buccal gingiva, extending through the interproximal area to palatal tissues. His medical and family histories were non- contributory. His social history was negative for tobacco and alcohol products. Radiographic evidence of bone loss was noted between the involved molars. The clinical impression from the referring clinician was an abscess with granulation tissue. The initial biopsy revealed a squamous proliferation characterized by focal epithelial detachment, individual cell keratinization, and mild atypia (Fig. 3). After examination of multiple sections, the biopsy was read as “epithelial prolifer-
ation suspicious for well-differentiated squamous cell carci- noma.” It was further stated that distinction from pseudoepi- theliomatous hyperplasia (PEH) was difficult in this case. A second biopsy was performed and revealed features diagnos- tic of a well-differentiated squamous cell carcinoma. The patient underwent a left hemimaxillectomy with left suprao- mohyoid neck dissection and a final pathologic diagnosis of well-differentiated squamous cell carcinoma was rendered.
Perineural and lymphovascular invasion were absent and the excised lymph nodes were negative for carcinoma. Interest- ingly, the patient returned 6 months postoperatively com- plaining of pain in the malar region. CT imaging revealed mucosal thickening in the left maxillary sinus. Another bi- opsy was performed and showed the presence of atypical epithelium with one detached epithelial island. In conjunction with an outside consultant’s opinion, it was decided that definitive evidence of recurrent carcinoma was not present in this specimen. Both the primary and consulting pathologist agreed that the histologic interpretation was extremely chal- lenging and follow-up was strongly recommended. The pa- tient is without disease 46 months postoperatively.
Case 3
A healthy 11-year-old white female presented for evalua- tion of a nodulo-papillary growth of the right maxillary facial gingiva, noted by her parents after spontaneous exfoliation of the primary canine. Her medical, family, and social histories were noncontributory. The biopsy was diagnosed as well- differentiated squamous cell carcinoma. A right hemimaxil- lectomy was performed (Fig. 4) and also read as well-differ- entiated squamous cell carcinoma with keratoacanthoma-like features (Fig. 5). The patient continues to be without disease 6 months postoperatively.
Fig. 1. Case #1. Radiograph showing at least 50% horizontal bone loss in the anterior mandibular region.
Fig. 2. Case #1. Histologic section of a well-differentiated squamous cell carcinoma with keratoacanthoma-like features, including a central, keratin-filled invagination and lateral cupping (hematoxylin-eosin stain, magnification⫻20).
Fig. 3. Case #2. Histologic section of a well-differentiated squamous cell carcinoma composed of squamous islands with focal evidence of dyskeratosis and keratin pearl formation, reminiscent of pseudoepitheliomatous hyperplasia (hematox- ylin-eosin stain, magnification⫻100).
Case 4
A healthy 11-year-old white female presented for eval- uation of a white lesion of the right mandibular buccal gingiva. Her medical, family, and social histories were noncontributory. An excisional biopsy was performed and diagnosed as “fibroepithelial hyperplasia with multiple foci of retained odontogenic epithelial rests,” most consistent with a PEH-like process. Three years later, the patient returned with a similar lesion at the same site. A follow-up incisional biopsy revealed histologic features of a well- differentiated squamous cell carcinoma. The biopsy was reviewed by several oral and surgical pathologists, all of whom agreed with the diagnosis. The patient was treated with a marginal mandibulectomy and continues to be with- out disease 24 months postoperatively.
DISCUSSION Literature review
Thompson et al.5performed a retrospective review at the Armed Forces Institute of Pathology (AFIP) over a 30-year period and documented only 20 cases of OSCC in patients younger than 20 years of age. Although the total number of OSCCs was not stated, this review was an extension of a previous AFIP study,4 in which 14,253 OSCCs accessioned before 1970 were studied.
In the Thompson series, the most common sites of involvement were the tongue (9 cases) and the lips (6 cases); 4 patients had confirmed ipsilateral cervical metastases. The histologic grading ranged from well- to poorly differentiated and several tumors exhibited a papillary growth pattern. These patients had no re- ported hereditary or genetic predisposing factors. We performed a literature review and identified 63 pub- lished cases of adolescent OSCC in the English lan- guage, as summarized inTable I.3-5,7,9-25Of note, we also reviewed several papers that examined OSCC in patients under the age of 40.6,26-32 However, specific information regarding adolescent patients was often difficult to extrapolate from these studies: conse- quently, they are not included inTable I.
Adolescent OSCC originating in the gingiva is ex- ceptionally rare. To our knowledge, only 4 cases have been previously published. These cases are highlighted inTable Iand summarized inTable IIwith our present 4 cases. Of these 8 cases, the affected patients ranged from 4 to 18 years in age and a slight predilection for the maxillary gingiva was seen. Clinically, most tumors were described as white, nodular or exophytic, some- times granular or papillary-appearing proliferations.
The most common clinical impression was that of an inflammatory lesion. There was often difficulty in mi- croscopic interpretation of the biopsy specimens, with distinction from PEH posing a recurrent problem in several cases.21,23The final pathologic reading in 7 of the 8 cases was well-differentiated SCC.20-21,23
Clinical and histopathologic challenges
Diagnosing OSCC in the very young patient can be challenging, both on a clinical and microscopic level.
On the gingiva, clinically white lesions may be mis- taken for a wide array of benign epithelial proliferations such as a squamous papilloma, verruca vulgaris, and nonspecific epithelial hyperplasia. Lesions of traumatic origin such as frictional hyperkeratosis, chemical burns, or factitial injury may also be considered. Exophytic lesions may be misdiagnosed as reactive proliferations such as a pyogenic granuloma,33 fibroma, peripheral ossifying fibroma, or peripheral giant cell granuloma;
or inflammatory entities such as an abscess or parulis.21 Granular-appearing lesions may raise the possibility of Fig. 4. Case #3. Hemimaxillectomy specimen demonstrating
a yellow-white, nodular mass with a central crater.
Fig. 5. Case #3. Histologic section of a well-differentiated squamous cell carcinoma with keratoacanthoma-like features (hematoxylin-eosin stain, magnification⫻20).
a granulomatous process, including a foreign body re- action and less likely, a deep fungal infection or oral manifestation of tuberculosis or Crohn’s disease. In cases with intraosseous involvement, the differential diagnosis broadens and may include a central giant cell granuloma and Langerhans cell histiocytosis, among other entities.
Unfortunately, the microscopic diagnosis of OSCC in this young age group is equally challenging. The often bland histologic features of most adolescent OSCCs, par- ticularly those originating from the gingiva, can make distinction from reactive and benign neoplastic processes extremely difficult. Diagnostic pitfalls deserving mention include PEH, as illustrated by our second and fourth cases as well as others21,23; keratoacanthoma, as illustrated by our first and third cases and others21,23,33,34
; and squa- mous odontogenic tumor.
Pseudoepitheliomatous hyperplasia (PEH). PEH is characterized histologically by elongation of rete ridges
and pseudo-invasion of the stroma by squamous epi- thelium. The epithelial islands often exhibit jagged or irregular outlines with variable keratin pearl formation and mitotic activity.23In contrast to OSCC, the pseudo-
“invasive” islands of PEH are comprised of cytologi- cally benign cells with a distinct absence of atypical mitotic figures or individual cell keratinization.23,35,36
Keratoacanthoma (KA). KA is a controversial entity with purported unique behavioral and microscopic characteristics. Involvement of the oral mucosa, so called solitary intraoral KA, has been documented in isolated case reports.33,34,37,38
The histologic hallmarks of KA include a central, keratin-filled invagination sur- rounded by hyperplastic and dyskeratotic squamous epithelium; broad, pushing rete ridges that undermine the adjacent non-neoplastic mucosa, imparting the ap- pearance of acute lateral “lipping”; sheets and islands of epithelium within the stroma; keratin pearl forma- tion; and infrequent mitotic figures.33,36 Somewhat Table I. Summary of reported adolescent oral squamous cell carcinoma cases
Author Year No. of cases Age in years Gender Site
Frank et al.10 1936 1 Newborn M Tongue
Saleeby et al.11 1940 11 Newborn (2)
聿15 (4)
NS Tongue
New and Hertz12 1940 1 13 M L margin and base of tongue
Merrifield et al.13 1955 1 5 F FOM
Frazell and Lucas14 1962 1 19 F Lateral tongue
Venables and Craft15 1966 1 17 F R border of tongue
Pichler et al.16 1972 1 19 M R lateral tongue
Turner and Snitzer7 1974 1 12 M R dorsal, lateral, ventral tongue
Byers17 1975 4 17 NS NS
19 19 19
Patel and Dave18 1976 5 ⬍20 Anterior tongue
Krolls and Hoffman4 1976 (?-1973) 3* 14 M Tongue
14 F Tongue
14 M Lower lip
16* 15-19 NS
Thompson et al.5 1999 (1966-1999) 20 ⬍20 10 M Tongue (9 cases)
10 F Lip (6 cases)
Soni and Chatterji19 1982 1 11 M L tongue
Son and Kapp20 1985 1 10 M R maxillary alveolus
1 17 F R buccal
1 18 M R anterior tongue
1 19 M L anterior tongue
Earle et al.9 1985 1 7 M R anterior maxillary gingiva
Sacks et al.21 1985 1 13 M Maxillary alveolar mucosa
Usenius et al.22 1987 1 14 M L lateral tongue
Bill et al.23 2001 1 14 L mandibular premolar gingiva
Sasaki et al.3 2005 1 19 F NS
O’Regan et al.24 2006 2 16-20 M NS
F
Sturgis et al.25 2005 2 18 M Tongue
16 F Tongue
M, male; F, female; NS, not specified; L, left; R, right; FOM, floor of mouth.
*These 19 cases were subsequently included in the review by Thompson et al.
worrisome features such as individual cell keratiniza- tion33and mild cytologic atypia39may also be seen. In contrast to OSCC, true stromal invasion should not be present. Furthermore, the “classic” clinical course of KAs (i.e., rapid onset followed by regression) is not expected in OSCC. To date, the issue of whether KA warrants separate designation from SCC or if it simply represents a very well differentiated SCC remains de- batable.
Squamous odontogenic tumor (SOT). SOT or SOT- like proliferations are composed microscopically of bland squamous epithelial islands with smooth periph- eral borders.40 The islands may occasionally undergo central cystic change and dystrophic calcification. In contrast to OSCC, the constituent cells of SOT do not demonstrate cytologic atypia or increased mitotic ac- tivity. Furthermore, true SOTs are predominantly in- traosseous lesions.
Last, a rare entity known as carcinoma cuniculatum (CC) also deserves mention as it was a histologic con- sideration for our first case. CC is considered to be either a variant of a well-differentiated SCC or verru- cous carcinoma as it bears clinical and histologic re- semblance to both. A slow-growing lesion with a ten- dency toward deep osseous invasion, CC is characterized architecturally by branching, keratin- filled crypts alternating with prominently keratinized papillary projections.41There is broad invasion of the stroma by islands of minimally atypical squamous cells that may exhibit microabscess formation.41 Most CC originate from the gingival or palatal mucosa although the bulk of the tumor mass may be found within bone.41 Because of difficulties in clinical and microscopic interpretation of adolescent OSCC, it has been sug- gested that lesions exhibiting unusual behavior, such as delayed healing, continued enlargement, and/or osse- ous destruction, be re-biopsied or excised with ade- quate margins.23 A similar approach is recommended for lesions demonstrating histologic ambiguity on ini- tial biopsy.
Etiology
The etiologic basis of OSCC affecting young patients has long been debated. The “classic” environmental risk factors most strongly implicated in OSCC devel- opment (e.g., tobacco smoking, alcohol consumption, and betel quid use30) are of questionable etiologic sig- nificance in this population. Many authors have re- marked that these habits are infrequent in younger individuals and that the shorter exposure times may be insufficient to induce carcinogenesis.3,24,31,42,43
Schantz et al.44 postulated that tumorigenesis is not only dependent on the type and level of carcinogen exposure but genetic sensitivity of the individual as TableII.SummaryofreportedcasesadolescentgingivalSCCcases AuthorAge/ GenderSiteClinicalimpressionInitialdiagnosisNo.of biopsiesFinal diagnosisTreatmentFollow-up SonandKapp2010/MRmxalveolusNSNSNSSCC,well“Surgery”274moNED Earleetal.96/MAntmxgingivaNS1NSSCC,modHemimx30moNED Sacksetal.2113/MLmxgingiva“abscess”PEH1SCC,wellPartialmaxillecHemimx24moNED Billetal.2314/MLmngingiva“inflammatory”Atypicalepithelial proliferation“multiple”SCC,wellExcision;Marginalmandibulec36moNED Present18/FAntMngingivaAtypicalepithelialproliferation; traumatic/factitialinjurySOT-like proliferation2SCC,wellHemimn⫹neck(bilatSOH)51moNED Present17/MLPostmxgingivaAbscessPEH2SCC,wellHemimx⫹neck(LSOH)At6mo,atypicalepithelial Proliferationinsinus;46 moNED Present11/FRAntMxgingivaNSSCC,well1SCC,wellHemimx6moNED Present11/FRMngingivaNSPEH-like2SCC,wellMarginalmandibulec24moNED M,male;R,right;L,left;Ant,anterior;Mn,mandible;Mx,maxilla;NS,notspecified;PEH,pseudoepitheliomatoushyperplasia;SCC.squamouscellcarcinoma;mod,moderately;Hemimx, hemimaxillectomy;Hemimn,hemimandibulectomy;Maxillec,maxillectomy;Mandibulec,mandibulectomy;bilat,bilateral;SOH,supraomohyoidneckdissection;mo,months;NED,noevidenceof disease.
well. Their group found that young adults with SCCs of the upper aerodigestive tract exhibited increased sus- ceptibility to mutagen-induced chromosomal damage.44 OSCC in this young age group has also been linked to several heritable conditions, including the familial ge- nodermatoses and chromosomal instability syndromes (Table III).9,23,46-50Furthermore, systemic factors lead- ing to immunologic deficiencies, such as solid organ transplantation, bone marrow transplant, and long-term immunosuppressive therapy, have been documented in some cases.45,46,51,52
All 4 patients in our study were healthy and well, with no suggestion of such predis- posing factors.
Although the molecular pathogenesis of adolescent OSCC is of interest, the paucity of reported cases has precluded extensive study on this subject. In contrast, OSCC in patients between the ages of 20 and 40 has garnered considerable research attention in recent years. Factors of probable relevance include viral in- fections and a wide array of genetic markers.
Viral infections. Human papillomavirus (HPV) ap- pears to be of controversial significance in OSCC af- fecting persons under the age of 40 years. Koch et al.53 stated that HPV of the oral mucosa was exceptionally rare in preadolescent children prior to sexual activity.
Similarly, El-Mofty and Lu54found 0/15 (0%) OSCCs in patients under 40 were positive for HPV-16 by polymerase chain reaction (PCR).
Genetic markers. Lingen et al.28 explored p53 ex- pression in SCCs of patients 40 and under with no identifiable risk factors. This group found that 17/21 (81%) of the tumors studied overexpressed p53 via immunohistochemistry (IHC). This percentage was re- portedly equal to or higher than p53 expression in SCCs of older patients with traditional risk factors.55Trem- blay et al.56confirmed significantly lower expression level of GSTP1 and the Fanconi’s anemia gene, FANCA, in OSCCs samples of their younger cohort compared to their older cohort. Zheng et al.57concluded that cyclin D1 gene polymorphism is associated with early-onset head and neck SCCs, especially in young individuals without smok- ing or drinking histories. Last, Wang et al.58found tongue cancers in their younger demographic to have higher frequencies of microsatellite instability, the variable short- ening or lengthening of short tandem repeats attributable
to DNA repair defects.58
These studies highlight possible differences in the molecular and genetic mechanisms driving oral carci- nogenesis in younger patients compared to the older population. Whether OSCC in the younger population represents an entity distinct from its adult counterpart remains unresolved at this time.
Clinical management and prognosis
Undoubtedly, treating adolescent patients with OSCC can pose challenges as well. In this very young population, special consideration must be given to op- timizing esthetics, prosthetic reconstruction and modi- fication, psychological implications, and follow-up. In most cases, a comprehensive medical/dental team will be required for proper management. In the very limited number of cases published, treatment has consisted predominantly of wide surgical excision with or with- out neck dissection. Some of these patients have also undergone adjuvant radiation therapy and/or chemo- therapy.5,20,25 Gingival OSCC cases have been man- aged with a hemimaxillectomy or segmental/marginal resection, with the neck being addressed if deemed necessary. Fortunately, most reported patients have had long disease-free intervals with no recurrence.20,21,23
Interestingly, conflicting data exist regarding the prognosis of young patients with OSCC. Some authors contend that OSCCs affecting patients younger than 40 pursue a more aggressive course with early metasta- sis15,17 and poorer survival outcomes.17,20,59 In con- trast, other groups have found either comparable or improved 5-year survival rates when compared with older patients with OSCC.1,31,60-65 Goldstein and Irish66 and Friedlander et al.67 found that younger in- dividuals with OSCC exhibited higher locoregional re- currence, although this did not portend to a poorer survival outcome. Myers et al.68 correlated decreased survival with presence of perineural invasion, lympho- vascular invasion, and surgical margins of less than 5 mm. Meticulous long-term follow-up appears war- ranted in all cases, including thorough evaluation for second primaries and cervical metastasis.6,59
In summary, we present 4 cases of gingival OSCC occurring in otherwise healthy adolescents. Moreover, we have reviewed common difficulties encountered in the clinical and microscopic interpretation of such cases. It is encouraging that significant strides have been achieved in understanding the molecular pathoe- tiology of OSCC in the younger population. However, it is also clear that little is known about OSCC in the adolescent patient. Ultimately, continued study of this unique patient population may help in establishing di- agnostic parameters and management guidelines.
Table III. Hereditary conditions associated with ado- lescent-onset oral squamous cell carcinoma
1. Xeroderma pigmentosum 2. Fanconi anemia 3. Epidermolysis bullosa 4. Juvenile papillomatosis 5. Dyskeratosis congenita
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