Vol. 116 No. 4 October 2013
Oral carcinoma cuniculatum: two cases illustrative of a diagnostic challenge Felipe Paiva Fonseca, DDS, MSc,a Hélder Antônio Rebelo Pontes, DDS, PhD,b Flávia Sirotheau Corrêa Pontes, DDS, PhD,b Pedro Luiz de Carvalho, DDS, PhD,b Marcondes Sena-Filho, DDS, MSc,a Jacks Jorge, DDS, PhD,a Alan Roger Santos-Silva, DDS, PhD,a and Oslei Paes de Almeida, DDS, PhDa Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil and João de Barros Barreto University Hospital, Federal University of Pará, Belém, Brazil
Carcinoma cuniculatum is a rare variant of squamous cell carcinoma originally described on the sole of the foot and for a long time believed to be restricted to the skin. However, since its first description in 1954, several cases have been reported at other sites. Carcinoma cuniculatum characteristically invades the underlying subcutaneous, submucosal, or bone tissues, forming so-called “rabbit burrows,” with crypts filled with keratin that are of utmost importance for distinguishing this neoplasm from other variants of squamous cell carcinoma. Oral carcinoma cuniculatum is an even rarer entity that is frequently misdiagnosed initially, a phenomenon described in about one-third of previously reported cases. The aim of this report is: (1) to describe the clinicopathologic features of 2 new cases of oral carcinoma cuniculatum, initially misdiagnosed as infected orthokeratinized cyst and abscess, respectively; and (2) to review the related English language literature. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:457-463)
Carcinoma cuniculatum is a rare well-differentiated, lowgrade variant of squamous cell carcinoma first described by Aird et al. in 1954.1 Originally called epithelioma cuniculatum, it was believed to be restricted to cutaneous tissue, more specifically the plantar surface of the foot. However, since its first description, it has been reported at noncutaneous anatomic sites, including the esophagus, larynx, penis, and oral mucosa.2-4 Carcinoma cuniculatum has a distinctive histomorphology characterized by cuniculatum architecture, similar in appearance to “rabbit burrows,” with keratinfilled channels and cores lined by well-differentiated squamous epithelium. Clinical and histologic diagnosis is difficult, as carcinoma cuniculatum may mimic reactive or benign lesions, such as abscess and keratinforming cysts.3,4 Although carcinoma cuniculatum was included in the 2005 World Health Organization classification of head and neck tumors,5 its distinction from verrucous carcinoma remains controversial since some authors consider carcinoma cuniculatum as a variant of verrucous carcinoma, whereas others have suggested that carcinoma cuniculatum represents a distinct entity with potential for local aggressiveness.3,6 Carcinoma cuniculatum affecting oral structures represents an even a
Department of Oral Diagnosis (Semiology and Pathology), Piracicaba Dental School, State University of Campinas. b Service of Surgery and Oral Pathology, João de Barros Barreto University Hospital, Federal University of Pará. Received for publication Apr 8, 2013; returned for revision Jun 2, 2013; accepted for publication Jun 5, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.06.006
rarer clinical presentation of this entity, with very few reports published in the English language literature, and its clinicopathologic features remain to be fully addressed. Therefore, the aim of this report is to describe the clinicopathologic features of 2 additional cases of oral carcinoma cuniculatum, with emphasis on the challenges involved in arriving at a correct diagnosis.
CASE REPORTS Case 1 A 62-year-old female presented to our department complaining of a painful swelling in the anterior region of the mandible of almost 2 months duration. The patient’s past medical and dental histories were noncontributory and she denied tobacco and alcohol use. Extra-oral examination revealed a cutaneous fistula secreting a yellowish, foul-smelling material (Figure 1A). Intraorally the attached gingiva of the lower right incisors and canine was reddish and swollen, presenting foci of purulent secretion (Figure 1B). Panoramic radiography showed an ill-defined osteolytic area on the right side of the mandible, extending from the incisors to the ascending ramus (Figure 1C). Incisional biopsy revealed fragments of orthokeratinized epithelium with large amounts of keratin throughout the specimen (Figure 2). The initial diagnosis was infected orthokeratinized keratocyst and the patient underwent surgical resection for removal of the lesion. The patient returned after 2 years of surgery, presenting with an aggressive, painful, reddish lesion with numerous whitish areas and small nodules, mainly involving the buccal aspect of the anterior mandible and extending to the left side. Radiographically, the left side of the mandible was invaded by the tumor, which extended up to the molar region, causing extensive bone destruction (Figure 3). No palpable cervical lymph nodes were found. The results of a large incisional biopsy revealed a predominantly papillomatous squamous epithelial growth, with multiple keratin-filled branches,
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Fig. 1. Clinical and radiographic features of case 1. (A) The mental area was enlarged, erythematous, with a cutaneous fistula with yellowish discharge, suggestive of an abscess. (B) Intra-orally, the lower teeth showed alveolar bone involvement and small gingival nodules suggestive of dental fistula. (C) Radiographically, there was an extensive irregular radiolucency involving the anterior teeth and the posterior region of the right side of the mandible.
Fig. 2. Histopathologic features obtained at first biopsy of case 1. (A) Several small fragments of markedly orthokeratinized epithelium (hematoxylin-eosin (H&E), 50). (B) Higher magnification showing abundant formation of keratin by the welldifferentiated epithelium (H&E, 100). The diagnosis was infected orthokeratinized keratocyst.
cores, and crypts, without evidence of cytologic atypia. The subjacent connective tissue contained an intense chronic inflammatory infiltrate, with areas rich in neutrophils (Figure 4). Immunohistochemical reaction for Ki67 in tissue samples of the first and second biopsies revealed a proliferative
index lower than 5% (Figure 5). The final diagnosis was oral carcinoma cuniculatum. The patient was submitted to additional surgical procedures and after 18 months of follow-up there was no evidence of recurrence.
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CASE REPORT Fonseca et al. 459
Fig. 3. Clinical and radiographic presentation of case 1 two years after initial therapy. (A) Large mass with whitish areas involving the left side of the mandible premolars and molars in the area had extensive mobility. The floor of the mouth also shows an elevated area covered by a whitish surface. Small nodules can be observed on the alveolar ridge. (B) Radiographically, there was massive involvement of the mandible, extending up to the medial surface of the left second molar.
Fig. 4. Microscopic appearance of a sample obtained from case 1 at recurrence. (A) Neoplastic tissue was composed of welldifferentiated squamous epithelium, showing prominent burrows covered by a thick layer of keratin. Cellular atypia and mitoses were only rarely found. (B) Chronically inflamed areas with foci of neutrophilic abscesses could also be seen close to the neoplastic epithelium (H&E, 100). The diagnosis was oral carcinoma cuniculatum.
Fig. 5. Immunoexpression of Ki67 was consistently low in the (A) first and (B) second biopsies of case 1 (streptavidinbiotin, 400).
Case 2 A 47-year-old female patient was referred to our department complaining of painful ulcers of her maxillary gingiva for approximately 7 years. Because of the presence of cutaneous fistulas on the left nasolabial fold region and a previous diagnosis of osteomyelitis, the patient had been treated with antibiotics for several weeks. Additional past medical and dental histories were noncontributory, and she reported no use of tobacco or alcohol. Clinically, the patient presented with 3 cutaneous fistulas on the left nasolabial fold (Figure 6A) and a large erythematous ulceration affecting the palate and the upper left alveolar mucosa, with areas producing a yellowish secretion (Figure 6B). Panoramic radiography revealed extensive destruction of the left maxilla with ill-defined borders (Figure 6C). An incisional biopsy showed fragments of well-differentiated squamous
epithelium with multiple keratin-filled branches and cores that proliferated toward the underlying connective tissue, but with little cytologic atypia and few mitoses. Areas of chronic inflammatory infiltrate and neutrophil microabscesses were also identified in the subjacent connective tissue. The Ki67 proliferative index was lower than 5% (Figure 7). On the basis of the clinical and histologic characteristics, a diagnosis of oral carcinoma cuniculatum was rendered. The patient underwent surgical procedure followed up by adjunct radiotherapy and is currently free of tumor after 6 years of follow-up.
DISCUSSION Since its first description, carcinoma cuniculatum has been considered to represent a low-grade variant of
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Fig. 6. Clinical and radiographic features of case 2. (A) The patient presented with 3 cutaneous fistulas of the left nasolabial fold with a yellowish discharge. (B) Extensive erythematous ulceration with areas of yellowish secretion affecting the left palate and alveolar mucosa (C) extensive ill-defined maxillary destruction is evident radiographically.
Fig. 7. Histopathologic features of case 2. (A) Well-differentiated epithelial proliferation infiltrating toward the underlying connective tissue (H&E, 0). (B) Characteristic low-grade neoplasia with keratin-filled crypts and cores (H&E, 100). (C) Areas of neutrophilic microabscesses could also be identified throughout the sample (H&E, 200). (D) Low Ki67 immunoexpression (streptavidin-biotin, 400).
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Table I. Clinicopathologic features of carcinoma cuniculatum of the oral cavity previously described in the English literature Authors
No. of patients
Fonseca et al. (present study)
2
Pons et al.7
3
Thavaraj et al.14 Suzuki et al.15
1 1
Sun et al.4
Kruse et al.6 Hutton et al.16 Raguse et al.17 Allon et al.8
15
1 1 1 1
Sex
Age
Site
Bone involvement
Tobacco use
Alcohol intake
Misdiagnosis
Recurrence*
Regional/distant metastases
Treatment
Follow-up (months)
F
62
Mandible
Yes
No
No
Keratocyst
No
No/no
Surgery
18; FOD
F M M M M M
47 72 82 43 61 68
Maxilla Mandible Mandible Mandible Tongue Gingiva
Yes Yes Yes Yes No Yes
No No No No NS Yes
No No No No NS Yes
No No No No No Yes
No/no No/no No/no No/no No/no No/no
Surgery/radiotherapy Surgery Surgery Surgery Surgery Surgery
72; FOD 24; FOD 4; DUC 12; FOD 24; FOD 14; DOD
7M/8F
67y
Yes (5) No (10)
Yes (5) No (10)
Yes (6) No (9)
Yes (3)
Yes (3)/yes (1)
Surgery (15)
F F F M
74 7 81 56
Tongue (8) Mandible (6) Vestibule (1) Maxilla Maxilla Mandible Maxilla
Abscess Abscess Cyst Keratocyst No Osteomyelitis with leukoplakia NS
Yes Yes Yes Yes
No No No Yes
No No No No
No Abscess Osteomyelitis No
No No Yes No
No/no No/no No/no No/no
Surgery Surgery Surgery Surgery
45z; DOC (1) FOD (14) 24; FOD 24; FOD 24; FOD 20; FOD
F, female; M, male; NS, not specified; FOD, free of disease; DOD, dead of the disease; DUC, dead of unknown cause; DOC, dead of other cause. *After correct diagnosis. y Mean age. z Mean time of follow-up.
CASE REPORT Fonseca et al. 461
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squamous cell carcinoma restricted to the plantar surface of the feet, presenting histologic features resembling rabbit burrows or cuniculus, formed by ramified keratinfilled crypts.6,7 Many other terms have been used to describe this entity, including epithelioma cuniculatum, verrucous carcinoma of the foot, papillomatosis cutis, carcinoides of Gottron, giant condyloma acuminatum of the genitalia, BuschkeeLowenstein tumor, and oral florid papillomatosis.8,9 Oral carcinoma cuniculatum is a very rare subtype of squamous cell carcinoma first described by Flieger and Owinski in 1977.10 Thereafter, several additional reports were published, several in the non-English literature.11-13 To date, only 24 cases of carcinoma cuniculatum affecting the oral cavity have been published in the English literature (Table I), revealing a slight male preponderance (13 males/11 females) and predominantly affecting older patients in the sixth and seventh decades of life.14,15 As in the skin and other anatomical sites, oral carcinoma cuniculatum is a slow-growing but locally aggressive tumor, infiltrating the subjacent connective tissue and bone that may or may not be preceded by an area of leukoplakia.4,15 It can also cause tooth loosening and mimic an abscess, as illustrated in both cases described.7,14 In case 1, the radiolucency was associated with a cutaneous yellowish, foul-smelling discharge, and no evidence of malignancy in the few epithelial fragments obtained at incisional biopsy, led to a misdiagnosis of infected orthokeratinized keratocyst. Interestingly, Pons et al.7 also highlighted this possible misdiagnosis in 2 of their case series, with the lesions initially considered to represent cysts. Moreover, cases of oral carcinoma cuniculatum misdiagnosed as abscess
and initially treated with antibiotics, as in case 2, have also been described in the literature.7,16,17 By reviewing all cases of oral carcinoma cuniculatum in the English literature, it can be seen that about one-third of the cases were initially misdiagnosed, delaying the appropriate management of these patients. Therefore, acquiring adequate tissue sample for microscopic evaluation is of utmost importance for diagnosis and correct clinicopathologic correlation is essential to avoid the possibility of misdiagnosis. Sun et al.4 reported that oral carcinoma cuniculatum represented 2.7% of all oral squamous cell carcinomas in their series. However, because of numerous clinical and histologic similarities between this variant and the more widely described verrucous carcinoma, the true incidence of oral carcinoma cuniculatum may have been underestimated. Although the 2 variants show clinical and microscopic overlap, being grossly characterized as well-differentiated tumors with the absence of cellular atypia, in verrucous carcinoma the growth pattern is both exophytic and downward “pushing” or endophytic, whereas carcinoma cuniculatum’s growth pattern is chiefly endophytic and infiltrative and is characterized by the presence of complex branching keratin-filled crypts (Table II). The presence of a yellowish, foul-smelling secretion is a typical finding in carcinoma cuniculatum and has not been described in verrucous carcinoma. Moreover, verrucous carcinoma may eventually cause superficial bone erosion, but it does not penetrate deeply into the surrounding submucosa and bone, unlike carcinoma cuniculatum.3,6,8 The recently described solid variant of keratocystic odontogenic tumor (KOT) could also cause some diagnostic difficulties in the microscopic
Table II. Clinical, radiographic, and microscopic features of oral carcinoma cuniculatum and its most important differential diagnoses Tumors
Clinical features
Carcinoma cuniculatum
- Slow-growing, locally destructive tumor - Growth pattern is mainly infiltrative - Presence of yellowish secretion
- Bony destruction with ill-defined borders
- Malignant neoplasia containing welldifferentiated squamous epithelium - Absence of evident cellular atypia and mitoses - Presence of multiple keratin-filled branching and cores infiltrating adjacent tissues - Presence of neutrophil microabscesses
Verrucous carcinoma
- Slow-growing tumor - Growth pattern is mainly exophytic - Exhibit a papillaryverrucous surface
- Superficial bone erosion
- Malignant neoplasia containing welldifferentiated squamous epithelium - Absence of evident cellular atypia and mitoses - Mostly exophytic growth with downward “pushing”
Solid KOT
- Poorly understood clinical behavior with aggressive and indolent cases being reported
- Uni or multilocular radiolucency with well- or ill-defined borders
- Solid benign tumor containing multiple cystic spaces with the presence of a thin, flat odontogenic epithelium, a delicate parakeratin layer, and palisading of the basal cells
KOT, keratocystic odontogenic tumor.
Radiographic features
Microscopic features
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differential diagnosis with carcinoma cuniculatum.18 Given its rarity, the exact clinical behavior of solid KOT is controversial.18-20 Histopathologically, the identification of odontogenic epithelium with a superficial thin layer of parakeratin and a palisading basal cell layer is an important clue for the diagnosis of solid KOT. Moreover, areas of microabscesses that are frequently seen in carcinoma cuniculatum have not been described in solid KOT. Thavaraj et al.14 observed an increased expression of Ki67 in their carcinoma cuniculatum cases, indicating the moderate proliferative potential of this entity. However, we failed to confirm these findings, with both of our cases exhibiting a consistently low Ki67 immunoexpression, in accordance with other previous reports.6,8 Different etiologic factors have been speculated to contribute to the development of carcinoma cuniculatum, including local trauma, inflammation, and radiation. Human papillomavirus has been shown to be present in some cases affecting cutaneous tissue, but numerous authors failed to corroborate any correlation with its oral counterpart.4,6,8 Known oral cancer risk factors such as tobacco and alcohol use have also been speculated as etiologic agents; however, most of the affected patients were nonusers of tobacco and alcohol.7 Surgery procedure is the cornerstone therapeutic approach for patients with oral carcinoma cuniculatum, although the efficiency of radiotherapy and chemotherapy remains to be fully investigated. Despite its local aggressiveness, regional and distant metastasis is very rare and the overall prognosis is good.4,7,15 Given its distinct clinical and histopathologic features, clinicians and pathologists must be aware of its clinicopathologic characteristics so that the correct diagnosis is rendered, and appropriate treatment initiated.
CASE REPORT Fonseca et al. 463
6. 7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
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Reprint requests: Hélder Antônio Rebelo Pontes, DDS, PhD Service of Oral Pathology João de Barros Barreto University Hospital Federal University of Pará, Dos Mundurucus Street No. 4487, 66073-000 Guamá Belém, Pará, Brazil
[email protected]
