Vol. 118 No. 6 December 2014
Carcinoma cuniculatum of the oral mucosa: a potentially underdiagnosed entity in the absence of clinical correlation Ricardo J. Padilla, DDS,a and Valerie A. Murrah, DMD, MSb University of North Carolina, Chapel Hill, NC, USA
Objective. To delineate the features of carcinoma cuniculatum (CC), emphasizing potential management errors. Study Design. A retrospective study examined archival cases of CC. An analysis of clinical, microscopic, and management parameters was performed. Results. Ten cases were identified, and their clinical and microscopic features were summarized. CC exhibits a sessile pink/ red mildly papillary surface. Histologically, CC presents a tortuous invasive component with a more subtle papillary appearance than verrucous carcinoma. Conclusions. CC is an uncommon variant of squamous cell carcinoma distinct from verrucous carcinoma. Diagnostic delays result from misinterpretation of superficial samples or lack of awareness of the entity. Bland cytology and unusual architecture result in underdiagnosis of CC without clinicopathologic correlation. Clinicians should submit multiple deep samples of lesions displaying a cobblestone-like surface and provide a clinical photograph to the pathologist. Pathologists can avoid underdiagnosis by thorough sampling of biopsies and requesting additional tissue as needed. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:684-693)
In 1954, Aird et al.1 reported a series of cases of neoplastic proliferations of epidermal keratinocytes of the sole of the foot that shared some features of invasive/endophytic squamous cell carcinoma and verrucous carcinoma. Aird called it epithelioma cuniculatum. The terms have since evolved, and currently the entity is accepted as carcinoma cuniculatum (CC). The defining features used for this indolent and distinct variant of squamous cell carcinoma include: 1 The peculiar architecture of the neoplastic epithelium, exhibiting ramified sinuses and keratin-filled crypts resembling rabbit burrows (hence the term cuniculatum, from the Latin for rabbit) extending deep into the connective tissues 2 A relatively modest exophytic component that is broadly papillary 3 Well-differentiated keratinocytes without overt cytologic atypia2 Multiple other cases have been described in other anatomic locations since the original publication by Aird. However, fewer than 30 cases of CC of the upper aerodigestive tract and oral cavity have been reported in the English-language literature to date.2 Among the Part of this work was presented as a poster at the 2012 Annual Meeting of the American Academy of Oral and Maxillofacial Pathology, Minneapolis, MN, USA. a Clinical Associate Professor, Department of Diagnostic Sciences, University of North Carolina School of Dentistry. b Professor and Chair, Department of Diagnostic Sciences, University of North Carolina School of Dentistry. Received for publication May 21, 2013; returned for revision Aug 4, 2014; accepted for publication Aug 10, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.08.011
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fewer than 20 oral mucosal cases, the most common locations are the alveolar mucosa/gingiva and the hard palate.2 The youngest patient reported with oral CC to date was a 7-year-old girl.3 In 1979, Elzay and O’Keefe reported a case of an “unusual epithelial proliferation” in a 9-year-old boy, which they interpreted as “pseudoepitheliomatous hyperplasia with features of carcinoma.” This was treated by complete surgical excision, and no recurrence was detected after 2 years of followup. They interpreted this phenomenon as an atypical proliferation arising from an “aborted gingival cyst.” Photomicrograph 5 in their article is consistent with the architecture of a CC.4 Despite the fact that the architecture of the lesions suggests a human papillomavirus (HPV) etiology; Allon et al.5 found no evidence of HPV-6, -11, -16, or -18 DNA by polymerase chain reaction analysis in a gingival lesion exhibiting bone destruction. Clinically, the lesions most often present as erythroleukoplakias exhibiting a cobblestone-like surface architecture with induration, a significant endophytic component, and a modest exophytic component. Sometimes there is white-yellow keratin-like material
Statement of Clinical Relevance Without clinicopathologic correlation and proper sampling, carcinoma cuniculatum may be underdiagnosed and subsequently undertreated. The caveat is given for clinicians to obtain generous and deep biopsies of verrucous lesions, to sample multiple sites, and to advocate extensive specimen sectioning by pathologists.
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Table I. Summary of demographic data and anatomic location of our 10 cases of carcinoma cuniculatum of the oral cavity Case
Age (y)
Gender
1
65
M
2
38
F
3
72
M
4
81
F
5
67
F
6 7 8
79 88 75
M F F
9
69
F
10
85
F
Location Right mandibular attached gingiva Right mandibular gingiva, area of teeth 27-31 Right mandibular gingiva, area of teeth 23-28 Right anterior maxillary gingiva, palatal to tooth 9 Right mandible and buccal mucosa Left vestibule Left maxillary gingiva/ridge Mandibular right gingiva, ridge, and buccal mucosa Right mandibular gingiva, area of teeth 29-30 Mandibular gingiva, area of tooth 27
Age, gender, and location of cases of carcinoma cuniculatum from the University of North Carolina Oral and Maxillofacial Pathology Biopsy Service from July 2005 to November 2013.
that can be expressed from the orifices of the crypts as they approach the surface of the oral mucosa.2,6,7 Histologically, the neoplasm exhibits a slightly papillary-like exophytic surface architecture and a predominantly endophytic proliferation of keratinocytes that “burrow” into the supporting connective tissues, creating branching crypt-like structures filled with keratin. The cells usually exhibit minimal cytologic atypia.6 The cytologic features of the lesion have been compared with those observed in verrucous carcinoma (VC) owing to the lack of pleomorphism, atypical mitoses, altered nuclear-to-cytoplasmic ratio, or anaplasia. The architecture of the lesion is somewhat reminiscent of an inverted schneiderian papilloma of the sinonasal mucosa, and the “burrows” may remind the pathologist of the pseudohorn cysts that may be seen in a seborrheic keratosis of the skin. The invasive or endophytic component of CC has been reported to induce underlying bone loss.5 The lesions usually exhibit an indolent clinical course, and complete surgical removal is considered appropriate treatment. To date, there is no clear evidence that a neck dissection is required for management of the lesion, in light of the very low risk of metastasis by these tumors.8 No data regarding radiation therapy for oral CC were found in a review of the Englishlanguage literature to date. Suzuki et al.9 reported a case of a recurrent CC that was treated with docetaxel, but their patient died of aspiration pneumonia during treatment of his recurrent tumor.
Fig. 1. A, Photomicrograph of the incisional biopsy in case 1. Note the endophytic proliferation of surface epithelium and tunnels of neoplastic cells (hematoxylin-eosin, original magnification 20). B, Superficial wedge biopsy specimen of case 1 with prominent keratin-filled cuniculatum resembling the so-called pseudohorn cyst seen in seborrheic keratosis of the skin. C, Photomicrograph of case 1 at high magnification shows the complex endophytic architecture of the cuniculatum as well as the minimal cytologic atypia.
In this article, we present a case series of oral mucosa CC that to our knowledge is the largest to date. We emphasize the classic features of CC over a spectrum of patient presentations, with the goal of optimizing diagnostic and treatment decisions.
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Fig. 2. A, Photomicrograph of initial biopsy of case 2 showing neoplastic cells at the margins of the specimen. Note the keratin-filled “burrows” and the foreign body reaction to escaped keratin in the connective tissue to the left. In this field the connection of the cuniculata to the surface epithelium are not evident, but they were present in other fields of the specimen (not shown) (hematoxylin-eosin, original magnification 50). A high-resolution version of the image is available as eSlide: VM00322. B, Photomicrograph of case 2. Note the cuniculatum within the connective tissue. Some of them are filled with keratin, and others have lost it during processing. There is a distinct lack of cellular atypia (hematoxylin-eosin, original magnification 200). A high-resolution version of the image is available as eSlide: VM00322.
METHODS AND MATERIALS An electronic search of the archives of the University of North Carolina Oral and Maxillofacial Pathology Biopsy Service for the period of July 1, 2005, to November 2013 was performed using the key words “carcinoma cuniculatum.” A total of 10 cases were retrieved from our files. Material from all cases was reviewed, and the diagnosis was confirmed. The diagnostic criteria used were a slightly cobblestone-like exophytic surface and endophytic proliferation of
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Fig. 3. A, Photomicrograph of the biopsy specimen in case 3 showing the papillary/corrugated-like architecture of the lesion and the burrows filled with keratin extending into the connective tissues. Note the transition between normal surface epithelium at the left of the specimen and the lesion as it extends into the stroma (hematoxylin-eosin, original magnification 100). A high-resolution version of the image is available as eSlide: VM00323. B, Photomicrograph of case 3 showing the transition between surface epithelium and tumor. The tumor lacks significant atypia and shows the invasive burrows filled with keratin (hematoxylin-eosin, original magnification 200). A high-resolution version of the image is available as eSlide: VM00324. C, Incisional biopsy specimen of case 3 exhibiting a prominent endophytic architecture resembling inverted schneiderian papilloma. A high-resolution version of the image is available as eSlide: VM00324.
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Fig. 4. A, Photomicrograph of the incisional biopsy of case 4. This area shows the keratin-filled invaginations into the supporting connective tissue stroma. Note the lack of significant atypia of the neoplastic cells. A mild inflammatory cell infiltrate flanks the neoplastic cords (hematoxylin-eosin, original magnification 100). B, Specimen of case 4 exhibiting deep keratin-filled burrows and a complex endophytic architecture. C and D, Photomicrographs of case 4 illustrating the relatively blunt architecture of the exophytic component in CC; note also the presence of inflammatory cells at the periphery of the endophytic component of CC resembling VC (hematoxylin-eosin, original magnification 200). A high-resolution version of the image is available as eSlide: VM00325.
branching crypt-like epithelial structures filled with keratin (cuniculatum) extending into the connective tissue. Only minimal cytologic atypia was acceptable.
RESULTS All cases were reviewed for diagnostic accuracy and adequate follow-up. Patient age at presentation, gender, and location of the lesions were recorded and are presented in Table I. The average age of our patients was 71.9 years; there were 7 women and 3 men. The most common locations were the attached gingiva and vestibules. Case 1 A 65-year-old white man presented to a community oral and maxillofacial surgeon (OMFS) with a diffuse thick erythroleukoplakia on the facial gingiva of the right mandible. An incisional biopsy of the lesion was performed. This biopsy tissue was initially diagnosed as reactive epithelium with hyperkeratosis (Figure 1, A-C). A second opinion was requested, because the clinician felt that the lesion was suggestive of malignancy. The lesion was subsequently interpreted as CC
and treated by total excision. The excision specimen was definitively diagnostic of CC. Case 2 A 38-year-old white woman presented to a periodontist for evaluation of an exophytic red and white lesion of the right mandibular gingiva, which was noted 11 months previously when the patient was pregnant. The lesion was clinically interpreted as a benign proliferation, and a biopsy of the lesion was performed to confirm that impression. A diagnosis of CC was rendered, with mild dysplasia present at the margins (Figure 2, A). The clinician elected to perform definitive treatment by raising a full-thickness flap in the area of teeth 27 to 31. All interproximal tissue was removed with curettes and Cavitron (Dentsply, York, PA, USA); all periosteum was removed, and the bone was debrided with a piezoelectric unit. No bone abnormality was detected clinically during the procedure. Alloderm (LifeCell Corporation, Bridgewater, NJ, USA) was placed over denuded bone. The surgical specimen confirmed the diagnosis of CC. Figure 2, B, shows some of the cuniculata seen in this specimen. The patient was free of tumor after 26 months and subsequently was lost to follow-up.
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Fig. 5. A, Clinical presentation of case 5. Note the cobblestone surface of the erythroleukoplakic and indurated lesion of the mandibular gingiva that extends to the right buccal mucosa. The “keratin tunnels or burrows” sometimes produced white/yellow material that was evident on the surface as white/yellow dots. B, Photomicrograph of a high-magnification field of case 5 taken to depict the typical pseudopapillary architecture of the surface of carcinoma cuniculatum (hematoxylin-eosin, original magnification 400).
Case 3 A 72-year-old man presented to an OMFS with gingival enlargement in the area of teeth 23 to 28. The lesion was asymptomatic, and the patient did not recall how long it had been present. Incisional biopsy was performed, and the lesion was diagnosed as CC (Figure 3, A-C). The patient subsequently had a wide local excision of the lesion including periosteum. The patient is free of disease after 8 years. Case 4 An 81-year-old woman presented to a periodontist with a 3-month history of a swollen, granulation-tissue-like lesion growing out of the palatal sulcus of tooth 9. The tissue was described as very friable. An incisional biopsy was diagnosed as CC (Figure 4, A-D). The patient underwent an en bloc resection of teeth 8 and 9 with a 1-cm bone margin by an OMFS.
The resection specimen confirmed the diagnosis of CC, and the margins were free of tumor. At the time of this report, the patient had been free of disease for 2.5 years, and the dentition had been restored with a removable partial denture. Case 5 A 67-year-old woman had a 30-year history of lichen planus. She recently developed an ulcerative, red and white, “pebbly” oral lesion of the right mandibular gingiva and buccal mucosa that was not responsive to lichen planus management (Figure 5, A). The clinical differential diagnosis of the referring clinician for the gingival lesion was lichen planus vs carcinoma. An incisional biopsy was performed before our evaluation, and the lesion was diagnosed as “inflamed papilloma with fungal hyphae; no atypia or malignancy present” by an outside pathologist. The clinician requested a second opinion, because he felt
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Fig. 6. Photomicrograph of the biopsy specimen of case 6. The architecture of carcinoma cuniculatum is evident as well as a chronic inflammatory cell infiltrate that is similar to the one often seen in VC (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00326.
that the clinical presentation was not consistent with that diagnosis. Upon review of the case, a diagnosis of CC was strongly suspected, and the lesion was sampled further, confirming the diagnosis of CC. The second specimen exhibited typical features of CC. Figure 5, B, is a representative high-magnification photomicrograph that shows the papillary architecture of the lesions. The patient was subsequently referred to a head and neck surgeon for definitive treatment. The lesion was widely excised with clear margins. No neck dissection was performed. The patient was lost to follow-up after this treatment. Case 6 A 79-year-old man presented for evaluation of a red and white pebbly lesion of the mandibular gingiva. The patient had a distant history of smokeless tobacco use but had discontinued her habit over 30 years prior. A panoramic radiograph showed evidence of erosion of the superficial cortical bone. An incisional biopsy was diagnosed as CC with superficial bone involvement. Figure 6 represents an area of the biopsy with typical CC features and a prominent chronic inflammatory cell infiltrate associated with the neoplasm. This inflammatory cell infiltrate is reminiscent of the one commonly seen in VC. The patient underwent a wide local excision of the soft tissue and bloc resection of the area with preservation of the inferior alveolar nerve canal and inferior border of the mandible. The patient was free of disease during the following 5 years and subsequently was lost to follow-up. Case 7 An 88-year-old woman presented with a 2-cm red and white mass of the left maxillary gingiva. Radiographic
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Fig. 7. Photomicrograph of case 7. The cuniculata are evident and able to be tracked in multiple sections to the surface of the lesion. Multiple different burrows are seen in different tangential sections and orientations. Levels of the block showed connection between most of these tunnels with the surface (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00327.
evaluation of the area did not show evidence of cortical bone erosion. An excisional biopsy was performed, and the lesion was diagnosed as CC with evidence of carcinoma at the margins (Figure 7, A, B). The patient underwent subsequent wide local excision, which achieved margins free of tumor. At the time of this report, the patient had been followed up for 10 months postoperatively, with no sign of recurrence. Case 8 A 75-year-old woman presented with a fungating and ulcerated lesion of the edentulous ridge at the sites of teeth 29 to 31 that extended to her right buccal mucosa. She had a 120-pack-year history of smoking but had quit 18 years earlier. She underwent an incisional biopsy of the lesion of the right mandibular gingiva. The specimen was fragmented and measured 0.4 cm in largest diameter. It was interpreted at an outside institution as “hyperkeratosis, epithelial atrophy, and dyskeratosis.” The OMFS was informed that the specimen was fragmented and that owing to the presence of dyskeratosis and epithelial atrophy and given the appearance of the lesion in the clinical photograph, the possibility of neoplasia could not be excluded. A deeper biopsy or excision of the entire lesion was recommended to provide additional diagnostic information.
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Fig. 8. Photomicrograph of second biopsy of case 8. Notice the burrowing of the tunnel into the connective tissue. The amount of keratin in this case decreased in the deeper portions of the tunnels. However, the overall architecture of the lesion was consistent with carcinoma cuniculatum (hematoxylineosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00328.
Two additional deeper incisional biopsies of the lesion were obtained, one of the mandibular gingiva and another of the buccal mucosa. We evaluated these specimens and made a diagnosis of carcinoma cuniculatum (Figure 8). The patient then underwent a composite resection of the lesion, achieving clear bone and soft tissue margins. She was free of disease at 9-month follow-up. Case 9 A 69-year-old woman had a history of periodontal bone grafting in the area of tooth 31. The site healed uneventfully. She continued routine dental visits with no evidence of lesions in the area. Five years after the initial surgery, the patient presented with a “spongy” lesion between teeth 29 and 30 (Figure 9, A). At the time it was managed briefly as potentially traumatic, but the lesion persisted. A course of antibiotics was instituted to no avail. Subsequently, a biopsy of the area was taken and a diagnosis of CC was made (Figure 9, B, C). The patient then underwent a block resection and extraction of teeth in the area. At the time of this report 6 months postoperatively, there was no evidence of disease. Case 10 An 85-year-old woman presented with an exophytic and hyperplastic-appearing lesion associated with teeth 26 to 28. The lesion had a pebbly appearance, and purulence was seen in the area. Tooth 27 was extracted, and a biopsy was obtained (Figure 10, A-C). The pathology specimen was diagnosed as CC. The patient
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declined any further treatment and has since been lost to follow-up. Representative clinical photographs of the appearance of our cases 5 and 9 of CC are presented in Figures 5, A, and 9, A, respectively. Note the frequent pink to red/white cobblestoned surface appearance of the lesions. This clinical presentation is representative of the majority of our cases. Some of them also exhibited small white-yellow pustule-like areas as a minor component. Suzuki et al.9 also have reported CC presenting clinically as a leukoplakia. Histologically, the lesions invariably showed a short and blunt papillated surface architecture with proliferation of bland-appearing keratinocytes into the supporting connective tissues. The characteristic cuniculatum were present in every lesion to a variable extent. The pathologic features also included spongiosis, inflammatory cell exocytosis, and dyskeratosis within the surface stratified squamous epithelium, although not all our cases had all of these secondary features. Within the supporting connective tissue of some of our cases, there was a reactive chronic inflammatory cell infiltrate. The inflammatory cells were mainly lymphocytes and plasma cells. In some cases, scattered eosinophils were observed near the epithelialconnective tissue interface. The characteristic histologic features of CC are described in earlier paragraphs and are further illustrated in Figures 1, A-C; 3, C; 4, B-D; 7, A; and 9, C.
DISCUSSION We consider carcinoma cuniculatum (CC) of the oral cavity to be a distinct low-grade variant of squamous cell carcinoma (SCC), which presents clinically as a pink to red exophytic lesion with a cobblestone-like surface. Microscopically it is has a predominantly endophytic/invasive architecture with short and blunt papillated surface. The characteristic burrows were present in every lesion to a variable extent, as well as areas of spongiosis, inflammatory cell exocytosis, and dyskeratosis. Some cases had eosinophils near the epithelial-connective tissue interface. CC has frequently been compared with VC and diagnosed as such. We believe that these lesions represent different variants of SCC, and the major distinguishing features between them are discussed here and in Table II: 1. Clinically, CC exhibits a sessile pink to red mildly papillary surface, whereas VC typically presents as a white warty lesion with more distinctive surface projections. 2. Histologically, the presence of a tortuous invasive component in CC contrasts with the more subtle “invasive front/pushing border” presentation of VC.
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Fig. 9. A, Clinical photograph of case 9. The lesion presented as a cobblestone erythroplakia with induration on the posterior mandibular facial gingiva. Five years prior, the area had received a periodontal graft, which healed well. B, Photomicrograph of case 9 showing a papillary surface architecture, keratin-filled burrows, and a reactive inflammatory cell infiltrate at the tumorstroma interface (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00330.
Fig. 10. Photomicrographs of case 10. This incisional biopsy was fragmented. A-C, Representative microscopic fields, which show the typical architecture of carcinoma cuniculatum (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00331.
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Table II. Differential features between carcinoma cuniculatum and verrucous carcinoma of the oral mucosa Features
Carcinoma cuniculatum
Verrucous carcinoma
Broad, pink, red, or white, mildly papillary/cobblestonelike surface
White, warty lesion with prominent filiform surface projections
Blunt papillary or cobblestone-like architecture of the exophytic component Tortuous invasive component with keratin plugging (cuniculata)
Predominantly exophytic growth with a verrucous/frondlike hyperkeratotic surface More restrained “invasive front/ pushing border”
Clinical
Microscopic
3. Histologically, CC presents with a more subtle papillary or corrugated-like appearance, whereas the hallmark of VC is its predominant exophytic growth with a verrucous/frond-like hyperkeratotic surface (Figure 11). In some of our cases, the consulting pathologists did not have access to clinical correlation when examining the cases microscopically, which prevented them from reaching a diagnosis of CC in the first specimen or as the initial diagnosis. Often it was only after the referring surgeon insisted that the clinical appearance of the lesion did not match the diagnosis, and either requested a second opinion or obtained additional tissue for evaluation, that the diagnosis of CC was reached. When a superficial or limited biopsy specimen of CC is examined, the lack of cytologic atypia and the presence of keratin-filled burrows may mislead the examining pathologist to underdiagnose the lesion as either reactive or hyperplastic. A common underdiagnosis rendered in some of the cases we have reviewed has been “verrucous hyperplasia with hyperkeratosis.” Another misdiagnosis rendered in the cases we reviewed was VC. We believe that the histopathologic features of CC distinguish it from VC by virtue of its endophytic “burrowing” growth pattern and less verruciform surface. However, we also realize that the evaluation of a poorly oriented, too superficial, or too small sample makes distinction between these entities extremely difficult or impossible. Therefore, the clinical description of an erythematous, pebbly, or cobblestonelike lesion is a critical and very useful piece of information to aid in the interpretation of CC vs VC. A clinical photograph can often make the difference between accurate diagnosis and misdiagnosis.
Fig. 11. Diagram illustrating the architectural between carcinoma cuniculatum and verrucous The purple represents the surface epithelium, represents the keratin of the epithelium, and the sents the supporting connective tissue stroma.
differences carcinoma. the orange pink repre-
CONCLUSIONS 1. CC is a distinct, uncommon, and low-grade variant of squamous cell carcinoma of the oral cavity that exhibits architectural features reminiscent of inverted schneiderian papilloma and cytologic features similar to verrucous carcinoma. 2. We consider VC and CC to be separate variants of SCC based on their respective histopathologic and clinical presentations. 3. Most importantly, owing to its bland cytology and unusual architecture, CC may frequently be underdiagnosed in the absence of thorough clinicopathologic correlation. This is especially critical for superficial biopsies. In light of these conclusions, the clinician would be well-advised to submit multiple deep samples of gingival lesions displaying a cobblestone-like surface and to provide a clinical photo to the pathologist. The pathologist would be well advised to avoid underdiagnosis by thorough sampling of submitted gingival biopsies with a cobblestone-like, corrugated, or papillary description and to request additional tissue as needed before making a final diagnosis in such cases. REFERENCES 1. Aird I, Johnson HD, Lennox B, et al. Epithelioma cuniculatum: a variety of squamous carcinoma peculiar to the foot. Br J Surg. 1954;42:245-250. 2. Pons Y, Kerrary S, Cox A, et al. Mandibular cuniculatum carcinoma: apropos of 3 cases and literature review. Head Neck. 2010;34:291-295. 3. Hutton A, McKaig S, Bardsley P, Monaghan A, Parmar S. Oral carcinoma cuniculatum in a young child. J Clin Pediatr Dent. 2010;35:89-94.
OOOO Volume 118, Number 6 4. Elzay RP, O’Keefe EM. Unusual gingival epithelial proliferation: primary pseudoepitheliomatous hyperplasia. Oral Surg. 1979;47: 436-440. 5. Allon D, Kaplan I, Manor R, Calderon S. Carcinoma cuniculatum of the jaw: a rare variant of oral carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:601-608. 6. Thavaraj S, Cobb A, Kalavrezos N, Beale T, Walker DM, Jay A. Carcinoma cuniculatum arising in the tongue. Head Neck Pathol. 2012;6:130-134. 7. Sun Y, Kuyama K, Burkhardt A, Yamamoto H. Clinicopathological evaluation of carcinoma cuniculatum: a variant of oral squamous cell carcinoma. J Oral Pathol Med. 2012;41: 303-308.
ORIGINAL ARTICLE Padilla and Murrah 693 8. Kruse AL, Graetz KW. Carcinoma cuniculatum: a rare entity in the oral cavity. J Craniofac Surg. 2009;20:1270-1272. 9. Suzuki J, Hashimoto S, Watanabe K, Takahashi K, Usubuchi H, Suzuki H. Carcinoma cuniculatum mimicking leukoplakia of the mandibular gingiva. Auris Nasus Larynx. 2012;39:321-325. Reprint requests: Ricardo J. Padilla, DDS CB 7450, University of North Carolina School of Dentistry Chapel Hill, NC 27599-7450 USA [email protected]
Carcinoma cuniculatum of the oral mucosa: a potentially underdiagnosed entity in the absence of clinical correlation Ricardo J. Padilla, DDS,a and Valerie A. Murrah, DMD, MSb University of North Carolina, Chapel Hill, NC, USA
Objective. To delineate the features of carcinoma cuniculatum (CC), emphasizing potential management errors. Study Design. A retrospective study examined archival cases of CC. An analysis of clinical, microscopic, and management parameters was performed. Results. Ten cases were identified, and their clinical and microscopic features were summarized. CC exhibits a sessile pink/ red mildly papillary surface. Histologically, CC presents a tortuous invasive component with a more subtle papillary appearance than verrucous carcinoma. Conclusions. CC is an uncommon variant of squamous cell carcinoma distinct from verrucous carcinoma. Diagnostic delays result from misinterpretation of superficial samples or lack of awareness of the entity. Bland cytology and unusual architecture result in underdiagnosis of CC without clinicopathologic correlation. Clinicians should submit multiple deep samples of lesions displaying a cobblestone-like surface and provide a clinical photograph to the pathologist. Pathologists can avoid underdiagnosis by thorough sampling of biopsies and requesting additional tissue as needed. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:684-693)
In 1954, Aird et al.1 reported a series of cases of neoplastic proliferations of epidermal keratinocytes of the sole of the foot that shared some features of invasive/endophytic squamous cell carcinoma and verrucous carcinoma. Aird called it epithelioma cuniculatum. The terms have since evolved, and currently the entity is accepted as carcinoma cuniculatum (CC). The defining features used for this indolent and distinct variant of squamous cell carcinoma include: 1 The peculiar architecture of the neoplastic epithelium, exhibiting ramified sinuses and keratin-filled crypts resembling rabbit burrows (hence the term cuniculatum, from the Latin for rabbit) extending deep into the connective tissues 2 A relatively modest exophytic component that is broadly papillary 3 Well-differentiated keratinocytes without overt cytologic atypia2 Multiple other cases have been described in other anatomic locations since the original publication by Aird. However, fewer than 30 cases of CC of the upper aerodigestive tract and oral cavity have been reported in the English-language literature to date.2 Among the Part of this work was presented as a poster at the 2012 Annual Meeting of the American Academy of Oral and Maxillofacial Pathology, Minneapolis, MN, USA. a Clinical Associate Professor, Department of Diagnostic Sciences, University of North Carolina School of Dentistry. b Professor and Chair, Department of Diagnostic Sciences, University of North Carolina School of Dentistry. Received for publication May 21, 2013; returned for revision Aug 4, 2014; accepted for publication Aug 10, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.08.011
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fewer than 20 oral mucosal cases, the most common locations are the alveolar mucosa/gingiva and the hard palate.2 The youngest patient reported with oral CC to date was a 7-year-old girl.3 In 1979, Elzay and O’Keefe reported a case of an “unusual epithelial proliferation” in a 9-year-old boy, which they interpreted as “pseudoepitheliomatous hyperplasia with features of carcinoma.” This was treated by complete surgical excision, and no recurrence was detected after 2 years of followup. They interpreted this phenomenon as an atypical proliferation arising from an “aborted gingival cyst.” Photomicrograph 5 in their article is consistent with the architecture of a CC.4 Despite the fact that the architecture of the lesions suggests a human papillomavirus (HPV) etiology; Allon et al.5 found no evidence of HPV-6, -11, -16, or -18 DNA by polymerase chain reaction analysis in a gingival lesion exhibiting bone destruction. Clinically, the lesions most often present as erythroleukoplakias exhibiting a cobblestone-like surface architecture with induration, a significant endophytic component, and a modest exophytic component. Sometimes there is white-yellow keratin-like material
Statement of Clinical Relevance Without clinicopathologic correlation and proper sampling, carcinoma cuniculatum may be underdiagnosed and subsequently undertreated. The caveat is given for clinicians to obtain generous and deep biopsies of verrucous lesions, to sample multiple sites, and to advocate extensive specimen sectioning by pathologists.
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Table I. Summary of demographic data and anatomic location of our 10 cases of carcinoma cuniculatum of the oral cavity Case
Age (y)
Gender
1
65
M
2
38
F
3
72
M
4
81
F
5
67
F
6 7 8
79 88 75
M F F
9
69
F
10
85
F
Location Right mandibular attached gingiva Right mandibular gingiva, area of teeth 27-31 Right mandibular gingiva, area of teeth 23-28 Right anterior maxillary gingiva, palatal to tooth 9 Right mandible and buccal mucosa Left vestibule Left maxillary gingiva/ridge Mandibular right gingiva, ridge, and buccal mucosa Right mandibular gingiva, area of teeth 29-30 Mandibular gingiva, area of tooth 27
Age, gender, and location of cases of carcinoma cuniculatum from the University of North Carolina Oral and Maxillofacial Pathology Biopsy Service from July 2005 to November 2013.
that can be expressed from the orifices of the crypts as they approach the surface of the oral mucosa.2,6,7 Histologically, the neoplasm exhibits a slightly papillary-like exophytic surface architecture and a predominantly endophytic proliferation of keratinocytes that “burrow” into the supporting connective tissues, creating branching crypt-like structures filled with keratin. The cells usually exhibit minimal cytologic atypia.6 The cytologic features of the lesion have been compared with those observed in verrucous carcinoma (VC) owing to the lack of pleomorphism, atypical mitoses, altered nuclear-to-cytoplasmic ratio, or anaplasia. The architecture of the lesion is somewhat reminiscent of an inverted schneiderian papilloma of the sinonasal mucosa, and the “burrows” may remind the pathologist of the pseudohorn cysts that may be seen in a seborrheic keratosis of the skin. The invasive or endophytic component of CC has been reported to induce underlying bone loss.5 The lesions usually exhibit an indolent clinical course, and complete surgical removal is considered appropriate treatment. To date, there is no clear evidence that a neck dissection is required for management of the lesion, in light of the very low risk of metastasis by these tumors.8 No data regarding radiation therapy for oral CC were found in a review of the Englishlanguage literature to date. Suzuki et al.9 reported a case of a recurrent CC that was treated with docetaxel, but their patient died of aspiration pneumonia during treatment of his recurrent tumor.
Fig. 1. A, Photomicrograph of the incisional biopsy in case 1. Note the endophytic proliferation of surface epithelium and tunnels of neoplastic cells (hematoxylin-eosin, original magnification 20). B, Superficial wedge biopsy specimen of case 1 with prominent keratin-filled cuniculatum resembling the so-called pseudohorn cyst seen in seborrheic keratosis of the skin. C, Photomicrograph of case 1 at high magnification shows the complex endophytic architecture of the cuniculatum as well as the minimal cytologic atypia.
In this article, we present a case series of oral mucosa CC that to our knowledge is the largest to date. We emphasize the classic features of CC over a spectrum of patient presentations, with the goal of optimizing diagnostic and treatment decisions.
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Fig. 2. A, Photomicrograph of initial biopsy of case 2 showing neoplastic cells at the margins of the specimen. Note the keratin-filled “burrows” and the foreign body reaction to escaped keratin in the connective tissue to the left. In this field the connection of the cuniculata to the surface epithelium are not evident, but they were present in other fields of the specimen (not shown) (hematoxylin-eosin, original magnification 50). A high-resolution version of the image is available as eSlide: VM00322. B, Photomicrograph of case 2. Note the cuniculatum within the connective tissue. Some of them are filled with keratin, and others have lost it during processing. There is a distinct lack of cellular atypia (hematoxylin-eosin, original magnification 200). A high-resolution version of the image is available as eSlide: VM00322.
METHODS AND MATERIALS An electronic search of the archives of the University of North Carolina Oral and Maxillofacial Pathology Biopsy Service for the period of July 1, 2005, to November 2013 was performed using the key words “carcinoma cuniculatum.” A total of 10 cases were retrieved from our files. Material from all cases was reviewed, and the diagnosis was confirmed. The diagnostic criteria used were a slightly cobblestone-like exophytic surface and endophytic proliferation of
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Fig. 3. A, Photomicrograph of the biopsy specimen in case 3 showing the papillary/corrugated-like architecture of the lesion and the burrows filled with keratin extending into the connective tissues. Note the transition between normal surface epithelium at the left of the specimen and the lesion as it extends into the stroma (hematoxylin-eosin, original magnification 100). A high-resolution version of the image is available as eSlide: VM00323. B, Photomicrograph of case 3 showing the transition between surface epithelium and tumor. The tumor lacks significant atypia and shows the invasive burrows filled with keratin (hematoxylin-eosin, original magnification 200). A high-resolution version of the image is available as eSlide: VM00324. C, Incisional biopsy specimen of case 3 exhibiting a prominent endophytic architecture resembling inverted schneiderian papilloma. A high-resolution version of the image is available as eSlide: VM00324.
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Fig. 4. A, Photomicrograph of the incisional biopsy of case 4. This area shows the keratin-filled invaginations into the supporting connective tissue stroma. Note the lack of significant atypia of the neoplastic cells. A mild inflammatory cell infiltrate flanks the neoplastic cords (hematoxylin-eosin, original magnification 100). B, Specimen of case 4 exhibiting deep keratin-filled burrows and a complex endophytic architecture. C and D, Photomicrographs of case 4 illustrating the relatively blunt architecture of the exophytic component in CC; note also the presence of inflammatory cells at the periphery of the endophytic component of CC resembling VC (hematoxylin-eosin, original magnification 200). A high-resolution version of the image is available as eSlide: VM00325.
branching crypt-like epithelial structures filled with keratin (cuniculatum) extending into the connective tissue. Only minimal cytologic atypia was acceptable.
RESULTS All cases were reviewed for diagnostic accuracy and adequate follow-up. Patient age at presentation, gender, and location of the lesions were recorded and are presented in Table I. The average age of our patients was 71.9 years; there were 7 women and 3 men. The most common locations were the attached gingiva and vestibules. Case 1 A 65-year-old white man presented to a community oral and maxillofacial surgeon (OMFS) with a diffuse thick erythroleukoplakia on the facial gingiva of the right mandible. An incisional biopsy of the lesion was performed. This biopsy tissue was initially diagnosed as reactive epithelium with hyperkeratosis (Figure 1, A-C). A second opinion was requested, because the clinician felt that the lesion was suggestive of malignancy. The lesion was subsequently interpreted as CC
and treated by total excision. The excision specimen was definitively diagnostic of CC. Case 2 A 38-year-old white woman presented to a periodontist for evaluation of an exophytic red and white lesion of the right mandibular gingiva, which was noted 11 months previously when the patient was pregnant. The lesion was clinically interpreted as a benign proliferation, and a biopsy of the lesion was performed to confirm that impression. A diagnosis of CC was rendered, with mild dysplasia present at the margins (Figure 2, A). The clinician elected to perform definitive treatment by raising a full-thickness flap in the area of teeth 27 to 31. All interproximal tissue was removed with curettes and Cavitron (Dentsply, York, PA, USA); all periosteum was removed, and the bone was debrided with a piezoelectric unit. No bone abnormality was detected clinically during the procedure. Alloderm (LifeCell Corporation, Bridgewater, NJ, USA) was placed over denuded bone. The surgical specimen confirmed the diagnosis of CC. Figure 2, B, shows some of the cuniculata seen in this specimen. The patient was free of tumor after 26 months and subsequently was lost to follow-up.
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Fig. 5. A, Clinical presentation of case 5. Note the cobblestone surface of the erythroleukoplakic and indurated lesion of the mandibular gingiva that extends to the right buccal mucosa. The “keratin tunnels or burrows” sometimes produced white/yellow material that was evident on the surface as white/yellow dots. B, Photomicrograph of a high-magnification field of case 5 taken to depict the typical pseudopapillary architecture of the surface of carcinoma cuniculatum (hematoxylin-eosin, original magnification 400).
Case 3 A 72-year-old man presented to an OMFS with gingival enlargement in the area of teeth 23 to 28. The lesion was asymptomatic, and the patient did not recall how long it had been present. Incisional biopsy was performed, and the lesion was diagnosed as CC (Figure 3, A-C). The patient subsequently had a wide local excision of the lesion including periosteum. The patient is free of disease after 8 years. Case 4 An 81-year-old woman presented to a periodontist with a 3-month history of a swollen, granulation-tissue-like lesion growing out of the palatal sulcus of tooth 9. The tissue was described as very friable. An incisional biopsy was diagnosed as CC (Figure 4, A-D). The patient underwent an en bloc resection of teeth 8 and 9 with a 1-cm bone margin by an OMFS.
The resection specimen confirmed the diagnosis of CC, and the margins were free of tumor. At the time of this report, the patient had been free of disease for 2.5 years, and the dentition had been restored with a removable partial denture. Case 5 A 67-year-old woman had a 30-year history of lichen planus. She recently developed an ulcerative, red and white, “pebbly” oral lesion of the right mandibular gingiva and buccal mucosa that was not responsive to lichen planus management (Figure 5, A). The clinical differential diagnosis of the referring clinician for the gingival lesion was lichen planus vs carcinoma. An incisional biopsy was performed before our evaluation, and the lesion was diagnosed as “inflamed papilloma with fungal hyphae; no atypia or malignancy present” by an outside pathologist. The clinician requested a second opinion, because he felt
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Fig. 6. Photomicrograph of the biopsy specimen of case 6. The architecture of carcinoma cuniculatum is evident as well as a chronic inflammatory cell infiltrate that is similar to the one often seen in VC (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00326.
that the clinical presentation was not consistent with that diagnosis. Upon review of the case, a diagnosis of CC was strongly suspected, and the lesion was sampled further, confirming the diagnosis of CC. The second specimen exhibited typical features of CC. Figure 5, B, is a representative high-magnification photomicrograph that shows the papillary architecture of the lesions. The patient was subsequently referred to a head and neck surgeon for definitive treatment. The lesion was widely excised with clear margins. No neck dissection was performed. The patient was lost to follow-up after this treatment. Case 6 A 79-year-old man presented for evaluation of a red and white pebbly lesion of the mandibular gingiva. The patient had a distant history of smokeless tobacco use but had discontinued her habit over 30 years prior. A panoramic radiograph showed evidence of erosion of the superficial cortical bone. An incisional biopsy was diagnosed as CC with superficial bone involvement. Figure 6 represents an area of the biopsy with typical CC features and a prominent chronic inflammatory cell infiltrate associated with the neoplasm. This inflammatory cell infiltrate is reminiscent of the one commonly seen in VC. The patient underwent a wide local excision of the soft tissue and bloc resection of the area with preservation of the inferior alveolar nerve canal and inferior border of the mandible. The patient was free of disease during the following 5 years and subsequently was lost to follow-up. Case 7 An 88-year-old woman presented with a 2-cm red and white mass of the left maxillary gingiva. Radiographic
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Fig. 7. Photomicrograph of case 7. The cuniculata are evident and able to be tracked in multiple sections to the surface of the lesion. Multiple different burrows are seen in different tangential sections and orientations. Levels of the block showed connection between most of these tunnels with the surface (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00327.
evaluation of the area did not show evidence of cortical bone erosion. An excisional biopsy was performed, and the lesion was diagnosed as CC with evidence of carcinoma at the margins (Figure 7, A, B). The patient underwent subsequent wide local excision, which achieved margins free of tumor. At the time of this report, the patient had been followed up for 10 months postoperatively, with no sign of recurrence. Case 8 A 75-year-old woman presented with a fungating and ulcerated lesion of the edentulous ridge at the sites of teeth 29 to 31 that extended to her right buccal mucosa. She had a 120-pack-year history of smoking but had quit 18 years earlier. She underwent an incisional biopsy of the lesion of the right mandibular gingiva. The specimen was fragmented and measured 0.4 cm in largest diameter. It was interpreted at an outside institution as “hyperkeratosis, epithelial atrophy, and dyskeratosis.” The OMFS was informed that the specimen was fragmented and that owing to the presence of dyskeratosis and epithelial atrophy and given the appearance of the lesion in the clinical photograph, the possibility of neoplasia could not be excluded. A deeper biopsy or excision of the entire lesion was recommended to provide additional diagnostic information.
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Fig. 8. Photomicrograph of second biopsy of case 8. Notice the burrowing of the tunnel into the connective tissue. The amount of keratin in this case decreased in the deeper portions of the tunnels. However, the overall architecture of the lesion was consistent with carcinoma cuniculatum (hematoxylineosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00328.
Two additional deeper incisional biopsies of the lesion were obtained, one of the mandibular gingiva and another of the buccal mucosa. We evaluated these specimens and made a diagnosis of carcinoma cuniculatum (Figure 8). The patient then underwent a composite resection of the lesion, achieving clear bone and soft tissue margins. She was free of disease at 9-month follow-up. Case 9 A 69-year-old woman had a history of periodontal bone grafting in the area of tooth 31. The site healed uneventfully. She continued routine dental visits with no evidence of lesions in the area. Five years after the initial surgery, the patient presented with a “spongy” lesion between teeth 29 and 30 (Figure 9, A). At the time it was managed briefly as potentially traumatic, but the lesion persisted. A course of antibiotics was instituted to no avail. Subsequently, a biopsy of the area was taken and a diagnosis of CC was made (Figure 9, B, C). The patient then underwent a block resection and extraction of teeth in the area. At the time of this report 6 months postoperatively, there was no evidence of disease. Case 10 An 85-year-old woman presented with an exophytic and hyperplastic-appearing lesion associated with teeth 26 to 28. The lesion had a pebbly appearance, and purulence was seen in the area. Tooth 27 was extracted, and a biopsy was obtained (Figure 10, A-C). The pathology specimen was diagnosed as CC. The patient
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declined any further treatment and has since been lost to follow-up. Representative clinical photographs of the appearance of our cases 5 and 9 of CC are presented in Figures 5, A, and 9, A, respectively. Note the frequent pink to red/white cobblestoned surface appearance of the lesions. This clinical presentation is representative of the majority of our cases. Some of them also exhibited small white-yellow pustule-like areas as a minor component. Suzuki et al.9 also have reported CC presenting clinically as a leukoplakia. Histologically, the lesions invariably showed a short and blunt papillated surface architecture with proliferation of bland-appearing keratinocytes into the supporting connective tissues. The characteristic cuniculatum were present in every lesion to a variable extent. The pathologic features also included spongiosis, inflammatory cell exocytosis, and dyskeratosis within the surface stratified squamous epithelium, although not all our cases had all of these secondary features. Within the supporting connective tissue of some of our cases, there was a reactive chronic inflammatory cell infiltrate. The inflammatory cells were mainly lymphocytes and plasma cells. In some cases, scattered eosinophils were observed near the epithelialconnective tissue interface. The characteristic histologic features of CC are described in earlier paragraphs and are further illustrated in Figures 1, A-C; 3, C; 4, B-D; 7, A; and 9, C.
DISCUSSION We consider carcinoma cuniculatum (CC) of the oral cavity to be a distinct low-grade variant of squamous cell carcinoma (SCC), which presents clinically as a pink to red exophytic lesion with a cobblestone-like surface. Microscopically it is has a predominantly endophytic/invasive architecture with short and blunt papillated surface. The characteristic burrows were present in every lesion to a variable extent, as well as areas of spongiosis, inflammatory cell exocytosis, and dyskeratosis. Some cases had eosinophils near the epithelial-connective tissue interface. CC has frequently been compared with VC and diagnosed as such. We believe that these lesions represent different variants of SCC, and the major distinguishing features between them are discussed here and in Table II: 1. Clinically, CC exhibits a sessile pink to red mildly papillary surface, whereas VC typically presents as a white warty lesion with more distinctive surface projections. 2. Histologically, the presence of a tortuous invasive component in CC contrasts with the more subtle “invasive front/pushing border” presentation of VC.
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Fig. 9. A, Clinical photograph of case 9. The lesion presented as a cobblestone erythroplakia with induration on the posterior mandibular facial gingiva. Five years prior, the area had received a periodontal graft, which healed well. B, Photomicrograph of case 9 showing a papillary surface architecture, keratin-filled burrows, and a reactive inflammatory cell infiltrate at the tumorstroma interface (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00330.
Fig. 10. Photomicrographs of case 10. This incisional biopsy was fragmented. A-C, Representative microscopic fields, which show the typical architecture of carcinoma cuniculatum (hematoxylin-eosin, original magnification 40). A high-resolution version of the image is available as eSlide: VM00331.
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Table II. Differential features between carcinoma cuniculatum and verrucous carcinoma of the oral mucosa Features
Carcinoma cuniculatum
Verrucous carcinoma
Broad, pink, red, or white, mildly papillary/cobblestonelike surface
White, warty lesion with prominent filiform surface projections
Blunt papillary or cobblestone-like architecture of the exophytic component Tortuous invasive component with keratin plugging (cuniculata)
Predominantly exophytic growth with a verrucous/frondlike hyperkeratotic surface More restrained “invasive front/ pushing border”
Clinical
Microscopic
3. Histologically, CC presents with a more subtle papillary or corrugated-like appearance, whereas the hallmark of VC is its predominant exophytic growth with a verrucous/frond-like hyperkeratotic surface (Figure 11). In some of our cases, the consulting pathologists did not have access to clinical correlation when examining the cases microscopically, which prevented them from reaching a diagnosis of CC in the first specimen or as the initial diagnosis. Often it was only after the referring surgeon insisted that the clinical appearance of the lesion did not match the diagnosis, and either requested a second opinion or obtained additional tissue for evaluation, that the diagnosis of CC was reached. When a superficial or limited biopsy specimen of CC is examined, the lack of cytologic atypia and the presence of keratin-filled burrows may mislead the examining pathologist to underdiagnose the lesion as either reactive or hyperplastic. A common underdiagnosis rendered in some of the cases we have reviewed has been “verrucous hyperplasia with hyperkeratosis.” Another misdiagnosis rendered in the cases we reviewed was VC. We believe that the histopathologic features of CC distinguish it from VC by virtue of its endophytic “burrowing” growth pattern and less verruciform surface. However, we also realize that the evaluation of a poorly oriented, too superficial, or too small sample makes distinction between these entities extremely difficult or impossible. Therefore, the clinical description of an erythematous, pebbly, or cobblestonelike lesion is a critical and very useful piece of information to aid in the interpretation of CC vs VC. A clinical photograph can often make the difference between accurate diagnosis and misdiagnosis.
Fig. 11. Diagram illustrating the architectural between carcinoma cuniculatum and verrucous The purple represents the surface epithelium, represents the keratin of the epithelium, and the sents the supporting connective tissue stroma.
differences carcinoma. the orange pink repre-
CONCLUSIONS 1. CC is a distinct, uncommon, and low-grade variant of squamous cell carcinoma of the oral cavity that exhibits architectural features reminiscent of inverted schneiderian papilloma and cytologic features similar to verrucous carcinoma. 2. We consider VC and CC to be separate variants of SCC based on their respective histopathologic and clinical presentations. 3. Most importantly, owing to its bland cytology and unusual architecture, CC may frequently be underdiagnosed in the absence of thorough clinicopathologic correlation. This is especially critical for superficial biopsies. In light of these conclusions, the clinician would be well-advised to submit multiple deep samples of gingival lesions displaying a cobblestone-like surface and to provide a clinical photo to the pathologist. The pathologist would be well advised to avoid underdiagnosis by thorough sampling of submitted gingival biopsies with a cobblestone-like, corrugated, or papillary description and to request additional tissue as needed before making a final diagnosis in such cases. REFERENCES 1. Aird I, Johnson HD, Lennox B, et al. Epithelioma cuniculatum: a variety of squamous carcinoma peculiar to the foot. Br J Surg. 1954;42:245-250. 2. Pons Y, Kerrary S, Cox A, et al. Mandibular cuniculatum carcinoma: apropos of 3 cases and literature review. Head Neck. 2010;34:291-295. 3. Hutton A, McKaig S, Bardsley P, Monaghan A, Parmar S. Oral carcinoma cuniculatum in a young child. J Clin Pediatr Dent. 2010;35:89-94.
OOOO Volume 118, Number 6 4. Elzay RP, O’Keefe EM. Unusual gingival epithelial proliferation: primary pseudoepitheliomatous hyperplasia. Oral Surg. 1979;47: 436-440. 5. Allon D, Kaplan I, Manor R, Calderon S. Carcinoma cuniculatum of the jaw: a rare variant of oral carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:601-608. 6. Thavaraj S, Cobb A, Kalavrezos N, Beale T, Walker DM, Jay A. Carcinoma cuniculatum arising in the tongue. Head Neck Pathol. 2012;6:130-134. 7. Sun Y, Kuyama K, Burkhardt A, Yamamoto H. Clinicopathological evaluation of carcinoma cuniculatum: a variant of oral squamous cell carcinoma. J Oral Pathol Med. 2012;41: 303-308.
ORIGINAL ARTICLE Padilla and Murrah 693 8. Kruse AL, Graetz KW. Carcinoma cuniculatum: a rare entity in the oral cavity. J Craniofac Surg. 2009;20:1270-1272. 9. Suzuki J, Hashimoto S, Watanabe K, Takahashi K, Usubuchi H, Suzuki H. Carcinoma cuniculatum mimicking leukoplakia of the mandibular gingiva. Auris Nasus Larynx. 2012;39:321-325. Reprint requests: Ricardo J. Padilla, DDS CB 7450, University of North Carolina School of Dentistry Chapel Hill, NC 27599-7450 USA [email protected]
