- Email: [email protected]
An asymptomatic diffuse palatal mass
Accepted Manuscript An asymptomatic diffuse palatal mass Ahmed S. Sultan, BDS, Sook-Bin Woo, DMD, MMSc PII:
S2212-4403(17)30109-8
DOI:
10.1016/j.oooo.2017.03.005
Reference:
OOOO 1729
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 17 October 2016 Revised Date:
25 January 2017
Accepted Date: 5 March 2017
Please cite this article as: Sultan AS, Woo S-B, An asymptomatic diffuse palatal mass, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2017), doi: 10.1016/j.oooo.2017.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT An asymptomatic diffuse palatal mass
Ahmed S. Sultan, BDS a, b Sook-Bin Woo, DMD, MMSc a, b
Ahmed S. Sultan, BDS Email: [email protected] Tel: 617-943-1700
a
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Fax: 617-264-6312
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Corresponding Author:
Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA
b Department
of Oral Medicine, Infection and Immunity, Harvard School of Dental
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Medicine, Boston, MA
Manuscript word count: 2170 Number of Tables: 1 Number of Figures: 13 Funding sources: None. Conflicts of interest: None declared. This case was presented at the 10th annual Gorlin conference in Minneapolis, Minnesota on 10/15/16.
ACCEPTED MANUSCRIPT CLINICAL PRESENTATION An 82 year-old African-American woman presented for evaluation of “itchiness and tingling” of the palate and a poorly fitting maxillary denture of two months history. Her medical history was significant for hypertension, hyperlipidemia, atrial fibrillation,
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gout, gastroesophageal reflux disease and a history of left breast ductal carcinoma insitu (status-post excision and radiation therapy in 2008). Her medications included
diltiazem, pravastatin, allopurinol, colchicine, and omeprazole and she had no known
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drug allergies. She reported that she was a current cigarette smoker and had smoked 45 cigarettes a day for the last 50 years. She drinks three shots of liquor a week.
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Extra-oral examination revealed a 1.5 x 1.0 cm non-tender mobile right submandibular lymph node. There was no evidence of extraoral swelling, asymmetry or cutaneous fistula. Intra-oral examination revealed a 3.0 x 2.5 cm diffuse mass involving the right hard palatal mucosa that was firm on palpation but non-tender with 0.2-0.3 cm surface yellow papules (Figure 1A). The overlying mucosa also had pebbly nodular areas
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with multiple deep invaginations measuring 0.5-1 cm in depth (Figure 1B). Periodontal probing of the invaginations did not result in mucous secretion or hemorrhage. There was 2+ mobility of the maxillary right first permanent molar. CT imaging revealed a 3.4
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x 1.4 cm soft-tissue attenuating mass of the right hard palatal mucosa that extended across the midline, and into the hard palate (Figure 2A). There was no involvement of
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the pterygopalatine fossa, masticator space, orbit, or intracranial space. Complete opacification of the right maxillary sinus with mucoperiosteal thickening was also seen (Figure 2B).
ACCEPTED MANUSCRIPT DIFFERENTIAL DIAGNOSIS An important feature is that although the surface was pebbly, there was no ulceration and there was minimal involvement of the surface mucosa by leukoplakia or erythroplakia. It is also unlikely that this tumor had only been present for two months.
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The differential diagnoses include primarily malignant tumors because of involvement of the palatal bone.
Lymphomas of the oral cavity represent the second most common oral
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malignancy and usually present as palatal swellings in 23% of cases,1 often with
minimal surface involvement. Most are primary tumors and approximately 5% of extra-
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nodal non-Hodgkin lymphomas occur in the head and neck.1 Non-Hodgkin lymphomas are typically seen in males in the sixth decade of life. One uncommon variant, the natural killer/T-cell variant presents as a destructive ulceration in the midline of the hard palate which is not the presentation in this case. Lymphadenopathy and the presence of B symptoms (fevers, night sweats, weight loss, and fatigue) are presenting symptoms in
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approximately 33% of patients which this patient did not report.2 Minor salivary gland tumors affect the palatal glands in 33-51% of cases and occur most commonly in adult women in the 5th and 6th decades of life.3 Pleomorphic
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adenoma and its variant myoepithelioma are the most common neoplasms accounting for 33% of cases.3 Pleomorphic adenomas are usually painless solitary slow-growing
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masses that generally do not involve the bone although long-standing lesions may cause saucerization. Malignant transformation is uncommon within minor salivary glands and occurs in approximately 3% of cases, and may lead to bone invasion.4 Three malignant salivary gland tumors are important in the differential
diagnosis and these also present as firm asymptomatic masses and may be slowgrowing. Mucoepidermoid carcinoma is the most common malignant salivary gland tumor and these are often cystic and openings of cysts may account for the presence of invaginations and tracts in this patient.5 The absence of mucous secretion following
ACCEPTED MANUSCRIPT probing does not favor mucoepidermoid carcinoma and suggests that the invaginations were likely surrounded by epithelium. Polymorphous low-grade adenocarcinoma is a slow-growing locally infiltrative tumor. Approximately half of cases arise in the palatal mucosa and feature perineural
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invasion and it may be that this was causing her symptoms of itching and tingling.6 Adenoid cystic carcinoma presents as a firm mass that may be more rapid in
growth and cause ulceration. Pain is a common presenting symptom because 67% of
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cases exhibit perineural invasion.7
Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive tumor of the
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sinonasal cavity of uncertain histogenesis. SNUC is more common in males with a median age of 51 years (range: 19-83 years) and usually presents at an advanced stage.8 Palatal perforation with a fungating mass may occur similar to this case. However, this is unlikely in our case considering that CT imaging revealed that the epicenter of the mass was in the palatal mucosa and not the sinonasal cavity. Approximately 64% of cases are
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associated with human papillomavirus.9
Squamous cell carcinoma (SCCa) presenting on the hard palatal mucosa is uncommon and represents approximately 2.5% of intra-oral SCCas.10 SCCas typically
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present as indurated masses, plaques or ulcers arising within an erythroplakia or leukoplakia. It would be unusual for SCCa to develop with minimal changes in the
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surface mucosa. However, this patient’s 50-year smoking history and alcohol consumption puts her at risk for this condition. Metastatic disease in the oral cavity typically presents in the fifth to seventh
decades of life.11 Intra-oral metastasis may be the presenting sign of an undiagnosed primary tumor in 23% of cases.11 The most common primary sites are the lung and breast for men and women, respectively. Breast cancer metastasis is a consideration in this case because of the patient’s previous diagnosis of breast ductal carcinoma in-situ. Metastatic disease most commonly occurs in the mandible while the gingiva is the most
ACCEPTED MANUSCRIPT common site of intra-oral soft tissue involvement; breast carcinoma metastasis accounts
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for 20/218 (9%) of oral soft tissue metastases.11
ACCEPTED MANUSCRIPT DIAGNOSIS AND MANAGEMENT At the second visit one week later, the palatal mucosa was noticeably more pebbly and nodular. An incisional biopsy of the right hard palatal mucosal mass was performed and sections revealed a SCCa with a complex endophytic and cystic
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architecture within the lamina propria (Figure 3A and 3B). There were multiple keratinfilled crypts with interconnecting burrows and cysts (Figure 3C). The epithelium lining these crypts consisted ofthin trabeculae of tumor cells that exhibited marked atypia
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characterized by basal cell hyperplasia, pleomorphism and nuclear hyperchromasia
(Figure 3D). The histopathology was consistent with carcinoma cuniculatum and the
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patient was referred for further staging and management.
PET-CT scan revealed a 4.2 x 2.0 cm FDG-avid mass of the right hard palatal mucosa with extension into the hard palate (Figure 4). There were multiple FDG-avid subcentimeter level IIA, IIB and V nodes. The patient was staged as a cT2N0M0, stage II SCCa. She underwent a right subtotal maxillectomy, right partial palatectomy and
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bilateral modified radical neck dissections. The sections of the excision specimens revealed a carcinoma cuniculatum similar to the original biopsy, with invasion of the hard palate as small tumor islands, but without penetration through bone into the
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maxillary sinus or lateral nasal wall; tumor cells were pleomorphic similar to conventional SCCa (Figure 5A-5C). The overlying epithelium showed evidence of
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dysplasia with large, bulbous rete ridges exhibiting basal cell hyperplasia, pleomorphism, dyskeratosis and keratin pearl formation (Figure 5D). Tumor was present at the posterior margins. No lymphovascular or perineural invasion was present. Forty-seven lymph nodes (right neck; 33 nodes, left neck; 14 nodes) from the bilateral neck dissections were negative for nodal metastasis. She was staged as pT3N0M0 (stage III) and because she also had tumor at the posterior margins of resection, she received adjuvant radiation therapy (total dose of 60 Gy). A palatal obturator was fabricated and
ACCEPTED MANUSCRIPT delivered by an oral and maxillofacial prosthodontics. At 12-month follow-up she was
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disease-free.
ACCEPTED MANUSCRIPT DISCUSSION Aird et al.12 first described three cases of carcinoma cuniculatum (then termed “epithelioma cuniculatum”) of the foot in 1954. Clinically, the tumors were characterized by the presence of numerous sinuses that exuded foul-smelling greasy
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material. Histologically, there was “massive keratinization within the tumors, multiple small keratinous cysts and anastomosing crypts lined by squamous epithelium” which were filled with decomposing keratin.12 Due to the extensive nature of the tumors,
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amputation of the foot was required in all cases.12 In 1981, McKee et al.13 reported 19 cases of carcinoma cuniculatum concluding that the plantar surface of the foot is the
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most commonly involved site. The mean age was 54 years and almost all patients (17/19, 90%) were males. Patients commonly complained of the development of “holes” on the soles of their feet. Clinically, the plantar lesions resembled verrucous keratotic masses and were often initially diagnosed as “warts” or “corns” typically resulting in delay in diagnosis even as they enlarged over time, with a mean duration of 13 years.
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One case was described as arising in a sinus tract caused by osteomyelitis. Histologically, the tumors had both an endophytic and papillomatous exophytic component that were usually covered by orthokeratin or parakeratin. The squamous epithelium was well-
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differentiated and consisted of sinuses filled with keratin or parakeratin. Mitotic activity was confined to the basal layers and was generally low and invasion of the
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subcutaneous tissue was a frequent finding.13 Some of the illustrations are consistent with features of verrucous carcinoma with deep ramifying keratin-filled crypts. Intra-orally, carcinoma cuniculatum represents approximately 2.7% of all oral
SCCa.14 Similar to cutaneous lesions, oral carcinoma cuniculatum most commonly presents in males in the fifth to sixth decade with more than 85% occurring on the hard palatal mucosa, gingiva and alveolar ridge mucosa.15-17 It is a slow-growing but locally invasive tumor that clinically presents as an endophytic mass that may be preceded by a precursor lesion (i.e. leukoplakia, erythroplakia, or erythroleukoplakia) or result in
ACCEPTED MANUSCRIPT tooth mobility (as seen in this case).14,17 Approximately 36% of cases are associated with cigarette smoking.14,18 Histologically, this tumor is considered a low-grade variant of SCCa with characteristic deep ramifying irregular keratin filled cystic spaces, and a distinct endophytic architecture with thin trabecular and ribbon-like proliferation of
nodes from a bilateral neck dissection were negative for tumor.
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squamous epithelium.19 In keeping with the low-grade nature of this lesion, 47 lymph
Carcinoma cuniculatum has often been compared to verrucous carcinoma and to
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well-differentiated papillary SCCa because of the papillary morphology of these lesions
leading to deep furrows that may ramify. However, there are clinical and histopathologic
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differences, and the World Health Organization (WHO) classification of head and neck tumors included carcinoma cuniculatum as a distinct entity in 2005, characterized by keratin-filled crypts lined by epithelium that lack features of overt malignancy.19 Keratin-filled cyst-like spaces may be seen in both verrucous carcinoma and welldifferentiated papillary SCCa because of deep crypts and from oblique planes of section.
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Carcinoma cuniculatum is also not as overtly verrucous and exophytic but rather has a pebbly, nodular surface. The pertinent clinical and histopathologic features between carcinoma cuniculatum, verrucous carcinoma and well-differentiated papillary SCCa are
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listed in Table 1. Padilla and Murrah summarized the features of carcinoma cuniculatum as follows: 1) modest exophytic component, 2) ramifying keratin-filled crypts and
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sinuses, 3) well-differentiated keratinocytes without overt atypia.15 Similar to other cases reported in the literature, the tumor reported here had a pebbly/nodular surface, with yellow papules corresponding to superficially located keratin-filled burrows and crypts. Tumors with an exophytic cauliflower-like mass are more likely to be verrucous or papillary carcinoma. However, the cytopathologic features of the carcinoma cuniculatum reported here is one of a conventional SCCa rather than one with minimal atypia as has been reported.15,19 It may be difficult to identify areas of conventional single cell or small island infiltration.
ACCEPTED MANUSCRIPT A keratocystic odontogenic tumor (odontogenic keratocyst) or even carcinoma that arose within an odontogenic cyst, that perforates the cortical plate may appear similar to a carcinoma cuniculatum with bone invasion, but in such a case, the epicenter of the lesion is within the jawbone as opposed to being in the overlying mucosal
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tumor.17,20 Because the vast majority (over 85%) of carcinoma cuniculatum arise on the gingival or palatal mucosa, erosion and infiltration of the underlying bone by such tumors must be differentiated from central odontogenic lesions that perforate the
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Less than 40 cases of oral carcinoma cuniculatum have been reported.14,17,18 The
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majority of cases have an indolent course with a relatively good prognosis with only five cases (13%) with recurrences reported in the literature, similar to verrucous carcinoma. They may be successfully managed with surgical resection alone.14,16-18,20 Regional lymph node involvement and distant metastasis are infrequent with five cases (13%) exhibiting regional nodal involvement and only two cases (5%) with distant
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metastasis.14,17,18 In this case, 47 lymph nodes were histologically negative for nodal metastasis and these were FDG-avid level IIA, IIB and V nodes on PET-CT. They most likely represent reactive lymphadenitis, which is a common occurrence in the head and
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neck and may lead to false positive findings on PET-CT.21 Because the tumor was staged as pT3N0M0 (stage III) and she had tumor at the posterior margin, she received
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adjuvant radiation therapy.22
ACCEPTED MANUSCRIPT CONCLUSIONS This is a case of the rare carcinoma cuniculatum, a low-grade variant of SCCa. Carcinoma cuniculatum should be considered within the differential diagnosis of a mass with a relatively smooth surface especially if there is expression of keratin-like material
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from surface pits and tracts. The endophytic architecture with multiple keratin filled crypts and interconnecting burrows is classic for carcinoma cuniculatum. Clinicopathologic correlation is important to differentiate this tumor from verrucous
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(odontogenic keratocyst).
ACCEPTED MANUSCRIPT FIGURE LEGENDS Fig. 1A. There was a 3.0 x 2.5 cm mass involving almost the entire right hard palatal mucosa with overlying pebbly, nodular areas, 0.2-0.3 cm surface yellow papules (arrow) and deep pits and fissures (first visit).
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Fig. 1B. One of many deep pits measuring at least 0.6 cm in depth (second visit). Fig. 2A. CT image revealed a 3.4 x 1.4 cm soft-tissue attenuating mass of the right hard palatal mucosa without involvement of the pterygopalatine fossa, masticator space,
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orbit, or intracranial space.
Fig. 2B. CT image revealed complete opacification of the right maxillary sinus with
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mucoperiosteal thickening.
Fig. 3A. Squamous cell carcinoma with a complex endophytic architecture and keratinfilled cysts within the lamina propria. (x20) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03807.
Fig. 3B. Thinly parakeratinized surface epithelium exhibits the usually pattern of
keratin. (x100)
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maturation; large and small tumor islands are present with abscesses and abundant
Fig. 3C. Multiple keratin filled cysts lined by atypical epithelium with a mild lymphocytic
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infiltrate. (x100)
Fig. 3D. Tumor cells exhibit marked atypia characterized by basal cell hyperplasia,
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pleomorphism and nuclear hyperchromasia. (x400) Fig. 4. PET-CT scan revealed a 4.2 x 2.0 cm FDG-avid mass of the right hard palatal mucosa with extension into the hard palate. Fig. 5A. The excision specimen consists of a carcinoma cuniculatum similar to the original biopsy with keratin-filled cystic islands of tumor cells, arising from dysplastic epithelium. (x40) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03808.
ACCEPTED MANUSCRIPT Fig. 5B. Cystic tumor islands exhibit basal cell hyperplasia, pleomorphism, and hyperchromasia; there is stromal infiltration present and a mild lymphocytic infiltrate. (x200) Fig. 5C. Tumor islands are present within bone. (x100)
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Fig. 5D. The overlying epithelium showed dysplasia with large, bulbous rete ridges exhibiting basal cell hyperplasia, pleomorphism, dyskeratosis and keratin pearl
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formation. (x200)
ACCEPTED MANUSCRIPT Table 1. Clinical and histopathologic features of carcinoma cuniculatum, verrucous carcinoma and well-differentiated papillary squamous cell carcinoma 14,17,19,23-25
Verrucous carcinoma
•
white exophytic verrucous/warty mass keratin-filled crypts in between exophytic papillary fronds
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white/red exophytic papillary mass
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Welldifferentiated papillary squamous cell carcinoma
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Histopathologic features • parakeratin, orthokeratin or both • variable papillary morphology with endophytic squamous proliferation forming thin trabecular and ribbon-like proliferation of atypical squamous epithelium lining deep ramifying keratinfilled cystic spaces that are connected to the surface • blunt pushing margin but may also see conventional infiltration • variable cytologic atypia • parakeratin • papillary exophytic and endophytic squamous proliferation • bulbous frond-like rete ridges with parakeratin plugging within crypts • bluntly-invasive, broad pushing tumor front without conventional infiltration • minimal cytologic atypia and low mitotic rate • parakeratin, orthokeratin or both • papillary exophytic and endophytic squamous proliferation • microabscesses at tips of rete ridges are often present • bluntly-invasive, broad pushing tumor front or invades as single cells or small islands of tumor cells • substantial cytologic atypia present
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Clinical features • poorly demarcated mass with a pebbly surface • yellow cheesy material may be expressed from surface pits and sinuses
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Carcinoma type Carcinoma cuniculatum
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carcinoma of the palate: A rare case report. J Indian Soc Periodontol. 2016;20:203-6. Elhakim MT, Breinholt H, Godballe C, Andersen LJ, Primdahl H, Kristensen CA, et
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al. Polymorphous low-grade adenocarcinoma: A Danish national study. Oral Oncol. 2016;55:6-10.
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outcomes and prognostic factors, including human papillomavirus, for sinonasal undifferentiated carcinoma: a retrospective review. Head Neck. 2015;37:366-74.
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Bouquot, J.E., Slootweg, P.J. Carcinoma cuniculatum. In: Barnes L, Eveson, JW, Reichart, P.,
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Fitzpatrick SG, Neuman AN, Cohen DM, Bhattacharyya I. Papillary variant of
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ACCEPTED MANUSCRIPT Table 1. Clinical and histopathologic features of carcinoma cuniculatum, verrucous carcinoma and well-differentiated papillary squamous cell carcinoma 14,17,19,23-25
Verrucous carcinoma
•
white exophytic verrucous/warty mass keratin-filled crypts in between exophytic papillary fronds
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white/red exophytic papillary mass
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Welldifferentiated papillary squamous cell carcinoma
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•
Histopathologic features • parakeratin, orthokeratin or both • variable papillary morphology with endophytic squamous proliferation forming thin trabecular and ribbon-like proliferation of atypical squamous epithelium lining deep ramifying keratinfilled cystic spaces that are connected to the surface • blunt pushing margin but may also see conventional infiltration • variable cytologic atypia • parakeratin • papillary exophytic and endophytic squamous proliferation • bulbous frond-like rete ridges with parakeratin plugging within crypts • bluntly-invasive, broad pushing tumor front without conventional infiltration • minimal cytologic atypia and low mitotic rate • parakeratin, orthokeratin or both • papillary exophytic and endophytic squamous proliferation • microabscesses at tips of rete ridges are often present • bluntly-invasive, broad pushing tumor front or invades as single cells or small islands of tumor cells • substantial cytologic atypia present
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Clinical features • poorly demarcated mass with a pebbly surface • yellow cheesy material may be expressed from surface pits and sinuses
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Carcinoma type Carcinoma cuniculatum
ACCEPTED MANUSCRIPT FIGURE LEGENDS Fig. 1A. There was a 3.0 x 2.5 cm mass involving almost the entire right hard palatal mucosa with overlying pebbly, nodular areas, 0.2-0.3 cm surface yellow papules (arrow) and deep pits and fissures (first visit).
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Fig. 1B. One of many deep pits measuring at least 0.6 cm in depth (second visit). Fig. 2A. CT image revealed a 3.4 x 1.4 cm soft-tissue attenuating mass of the right hard palatal mucosa without involvement of the pterygopalatine fossa, masticator space,
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orbit, or intracranial space.
Fig. 2B. CT image revealed complete opacification of the right maxillary sinus with
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mucoperiosteal thickening.
Fig. 3A. Squamous cell carcinoma with a complex endophytic architecture and keratinfilled cysts within the lamina propria. (x20) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03807.
Fig. 3B. Thinly parakeratinized surface epithelium exhibits the usually pattern of
keratin. (x100)
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maturation; large and small tumor islands are present with abscesses and abundant
Fig. 3C. Multiple keratin filled cysts lined by atypical epithelium with a mild lymphocytic
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infiltrate. (x100)
Fig. 3D. Tumor cells exhibit marked atypia characterized by basal cell hyperplasia,
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pleomorphism and nuclear hyperchromasia. (x400) Fig. 4. PET-CT scan revealed a 4.2 x 2.0 cm FDG-avid mass of the right hard palatal mucosa with extension into the hard palate. Fig. 5A. The excision specimen consists of a carcinoma cuniculatum similar to the original biopsy with keratin-filled cystic islands of tumor cells, arising from dysplastic epithelium. (x40) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03808.
ACCEPTED MANUSCRIPT Fig. 5B. Cystic tumor islands exhibit basal cell hyperplasia, pleomorphism, and hyperchromasia; there is stromal infiltration present and a mild lymphocytic infiltrate. (x200) Fig. 5C. Tumor islands are present within bone. (x100)
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Fig. 5D. The overlying epithelium showed dysplasia with large, bulbous rete ridges exhibiting basal cell hyperplasia, pleomorphism, dyskeratosis and keratin pearl
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S2212-4403(17)30109-8
DOI:
10.1016/j.oooo.2017.03.005
Reference:
OOOO 1729
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 17 October 2016 Revised Date:
25 January 2017
Accepted Date: 5 March 2017
Please cite this article as: Sultan AS, Woo S-B, An asymptomatic diffuse palatal mass, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2017), doi: 10.1016/j.oooo.2017.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT An asymptomatic diffuse palatal mass
Ahmed S. Sultan, BDS a, b Sook-Bin Woo, DMD, MMSc a, b
Ahmed S. Sultan, BDS Email: [email protected] Tel: 617-943-1700
a
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Fax: 617-264-6312
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Corresponding Author:
Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Boston, MA
b Department
of Oral Medicine, Infection and Immunity, Harvard School of Dental
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Medicine, Boston, MA
Manuscript word count: 2170 Number of Tables: 1 Number of Figures: 13 Funding sources: None. Conflicts of interest: None declared. This case was presented at the 10th annual Gorlin conference in Minneapolis, Minnesota on 10/15/16.
ACCEPTED MANUSCRIPT CLINICAL PRESENTATION An 82 year-old African-American woman presented for evaluation of “itchiness and tingling” of the palate and a poorly fitting maxillary denture of two months history. Her medical history was significant for hypertension, hyperlipidemia, atrial fibrillation,
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gout, gastroesophageal reflux disease and a history of left breast ductal carcinoma insitu (status-post excision and radiation therapy in 2008). Her medications included
diltiazem, pravastatin, allopurinol, colchicine, and omeprazole and she had no known
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drug allergies. She reported that she was a current cigarette smoker and had smoked 45 cigarettes a day for the last 50 years. She drinks three shots of liquor a week.
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Extra-oral examination revealed a 1.5 x 1.0 cm non-tender mobile right submandibular lymph node. There was no evidence of extraoral swelling, asymmetry or cutaneous fistula. Intra-oral examination revealed a 3.0 x 2.5 cm diffuse mass involving the right hard palatal mucosa that was firm on palpation but non-tender with 0.2-0.3 cm surface yellow papules (Figure 1A). The overlying mucosa also had pebbly nodular areas
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with multiple deep invaginations measuring 0.5-1 cm in depth (Figure 1B). Periodontal probing of the invaginations did not result in mucous secretion or hemorrhage. There was 2+ mobility of the maxillary right first permanent molar. CT imaging revealed a 3.4
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x 1.4 cm soft-tissue attenuating mass of the right hard palatal mucosa that extended across the midline, and into the hard palate (Figure 2A). There was no involvement of
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the pterygopalatine fossa, masticator space, orbit, or intracranial space. Complete opacification of the right maxillary sinus with mucoperiosteal thickening was also seen (Figure 2B).
ACCEPTED MANUSCRIPT DIFFERENTIAL DIAGNOSIS An important feature is that although the surface was pebbly, there was no ulceration and there was minimal involvement of the surface mucosa by leukoplakia or erythroplakia. It is also unlikely that this tumor had only been present for two months.
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The differential diagnoses include primarily malignant tumors because of involvement of the palatal bone.
Lymphomas of the oral cavity represent the second most common oral
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malignancy and usually present as palatal swellings in 23% of cases,1 often with
minimal surface involvement. Most are primary tumors and approximately 5% of extra-
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nodal non-Hodgkin lymphomas occur in the head and neck.1 Non-Hodgkin lymphomas are typically seen in males in the sixth decade of life. One uncommon variant, the natural killer/T-cell variant presents as a destructive ulceration in the midline of the hard palate which is not the presentation in this case. Lymphadenopathy and the presence of B symptoms (fevers, night sweats, weight loss, and fatigue) are presenting symptoms in
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approximately 33% of patients which this patient did not report.2 Minor salivary gland tumors affect the palatal glands in 33-51% of cases and occur most commonly in adult women in the 5th and 6th decades of life.3 Pleomorphic
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adenoma and its variant myoepithelioma are the most common neoplasms accounting for 33% of cases.3 Pleomorphic adenomas are usually painless solitary slow-growing
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masses that generally do not involve the bone although long-standing lesions may cause saucerization. Malignant transformation is uncommon within minor salivary glands and occurs in approximately 3% of cases, and may lead to bone invasion.4 Three malignant salivary gland tumors are important in the differential
diagnosis and these also present as firm asymptomatic masses and may be slowgrowing. Mucoepidermoid carcinoma is the most common malignant salivary gland tumor and these are often cystic and openings of cysts may account for the presence of invaginations and tracts in this patient.5 The absence of mucous secretion following
ACCEPTED MANUSCRIPT probing does not favor mucoepidermoid carcinoma and suggests that the invaginations were likely surrounded by epithelium. Polymorphous low-grade adenocarcinoma is a slow-growing locally infiltrative tumor. Approximately half of cases arise in the palatal mucosa and feature perineural
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invasion and it may be that this was causing her symptoms of itching and tingling.6 Adenoid cystic carcinoma presents as a firm mass that may be more rapid in
growth and cause ulceration. Pain is a common presenting symptom because 67% of
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cases exhibit perineural invasion.7
Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive tumor of the
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sinonasal cavity of uncertain histogenesis. SNUC is more common in males with a median age of 51 years (range: 19-83 years) and usually presents at an advanced stage.8 Palatal perforation with a fungating mass may occur similar to this case. However, this is unlikely in our case considering that CT imaging revealed that the epicenter of the mass was in the palatal mucosa and not the sinonasal cavity. Approximately 64% of cases are
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associated with human papillomavirus.9
Squamous cell carcinoma (SCCa) presenting on the hard palatal mucosa is uncommon and represents approximately 2.5% of intra-oral SCCas.10 SCCas typically
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present as indurated masses, plaques or ulcers arising within an erythroplakia or leukoplakia. It would be unusual for SCCa to develop with minimal changes in the
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surface mucosa. However, this patient’s 50-year smoking history and alcohol consumption puts her at risk for this condition. Metastatic disease in the oral cavity typically presents in the fifth to seventh
decades of life.11 Intra-oral metastasis may be the presenting sign of an undiagnosed primary tumor in 23% of cases.11 The most common primary sites are the lung and breast for men and women, respectively. Breast cancer metastasis is a consideration in this case because of the patient’s previous diagnosis of breast ductal carcinoma in-situ. Metastatic disease most commonly occurs in the mandible while the gingiva is the most
ACCEPTED MANUSCRIPT common site of intra-oral soft tissue involvement; breast carcinoma metastasis accounts
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for 20/218 (9%) of oral soft tissue metastases.11
ACCEPTED MANUSCRIPT DIAGNOSIS AND MANAGEMENT At the second visit one week later, the palatal mucosa was noticeably more pebbly and nodular. An incisional biopsy of the right hard palatal mucosal mass was performed and sections revealed a SCCa with a complex endophytic and cystic
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architecture within the lamina propria (Figure 3A and 3B). There were multiple keratinfilled crypts with interconnecting burrows and cysts (Figure 3C). The epithelium lining these crypts consisted ofthin trabeculae of tumor cells that exhibited marked atypia
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characterized by basal cell hyperplasia, pleomorphism and nuclear hyperchromasia
(Figure 3D). The histopathology was consistent with carcinoma cuniculatum and the
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patient was referred for further staging and management.
PET-CT scan revealed a 4.2 x 2.0 cm FDG-avid mass of the right hard palatal mucosa with extension into the hard palate (Figure 4). There were multiple FDG-avid subcentimeter level IIA, IIB and V nodes. The patient was staged as a cT2N0M0, stage II SCCa. She underwent a right subtotal maxillectomy, right partial palatectomy and
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bilateral modified radical neck dissections. The sections of the excision specimens revealed a carcinoma cuniculatum similar to the original biopsy, with invasion of the hard palate as small tumor islands, but without penetration through bone into the
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maxillary sinus or lateral nasal wall; tumor cells were pleomorphic similar to conventional SCCa (Figure 5A-5C). The overlying epithelium showed evidence of
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dysplasia with large, bulbous rete ridges exhibiting basal cell hyperplasia, pleomorphism, dyskeratosis and keratin pearl formation (Figure 5D). Tumor was present at the posterior margins. No lymphovascular or perineural invasion was present. Forty-seven lymph nodes (right neck; 33 nodes, left neck; 14 nodes) from the bilateral neck dissections were negative for nodal metastasis. She was staged as pT3N0M0 (stage III) and because she also had tumor at the posterior margins of resection, she received adjuvant radiation therapy (total dose of 60 Gy). A palatal obturator was fabricated and
ACCEPTED MANUSCRIPT delivered by an oral and maxillofacial prosthodontics. At 12-month follow-up she was
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disease-free.
ACCEPTED MANUSCRIPT DISCUSSION Aird et al.12 first described three cases of carcinoma cuniculatum (then termed “epithelioma cuniculatum”) of the foot in 1954. Clinically, the tumors were characterized by the presence of numerous sinuses that exuded foul-smelling greasy
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material. Histologically, there was “massive keratinization within the tumors, multiple small keratinous cysts and anastomosing crypts lined by squamous epithelium” which were filled with decomposing keratin.12 Due to the extensive nature of the tumors,
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amputation of the foot was required in all cases.12 In 1981, McKee et al.13 reported 19 cases of carcinoma cuniculatum concluding that the plantar surface of the foot is the
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most commonly involved site. The mean age was 54 years and almost all patients (17/19, 90%) were males. Patients commonly complained of the development of “holes” on the soles of their feet. Clinically, the plantar lesions resembled verrucous keratotic masses and were often initially diagnosed as “warts” or “corns” typically resulting in delay in diagnosis even as they enlarged over time, with a mean duration of 13 years.
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One case was described as arising in a sinus tract caused by osteomyelitis. Histologically, the tumors had both an endophytic and papillomatous exophytic component that were usually covered by orthokeratin or parakeratin. The squamous epithelium was well-
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differentiated and consisted of sinuses filled with keratin or parakeratin. Mitotic activity was confined to the basal layers and was generally low and invasion of the
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subcutaneous tissue was a frequent finding.13 Some of the illustrations are consistent with features of verrucous carcinoma with deep ramifying keratin-filled crypts. Intra-orally, carcinoma cuniculatum represents approximately 2.7% of all oral
SCCa.14 Similar to cutaneous lesions, oral carcinoma cuniculatum most commonly presents in males in the fifth to sixth decade with more than 85% occurring on the hard palatal mucosa, gingiva and alveolar ridge mucosa.15-17 It is a slow-growing but locally invasive tumor that clinically presents as an endophytic mass that may be preceded by a precursor lesion (i.e. leukoplakia, erythroplakia, or erythroleukoplakia) or result in
ACCEPTED MANUSCRIPT tooth mobility (as seen in this case).14,17 Approximately 36% of cases are associated with cigarette smoking.14,18 Histologically, this tumor is considered a low-grade variant of SCCa with characteristic deep ramifying irregular keratin filled cystic spaces, and a distinct endophytic architecture with thin trabecular and ribbon-like proliferation of
nodes from a bilateral neck dissection were negative for tumor.
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squamous epithelium.19 In keeping with the low-grade nature of this lesion, 47 lymph
Carcinoma cuniculatum has often been compared to verrucous carcinoma and to
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well-differentiated papillary SCCa because of the papillary morphology of these lesions
leading to deep furrows that may ramify. However, there are clinical and histopathologic
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differences, and the World Health Organization (WHO) classification of head and neck tumors included carcinoma cuniculatum as a distinct entity in 2005, characterized by keratin-filled crypts lined by epithelium that lack features of overt malignancy.19 Keratin-filled cyst-like spaces may be seen in both verrucous carcinoma and welldifferentiated papillary SCCa because of deep crypts and from oblique planes of section.
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Carcinoma cuniculatum is also not as overtly verrucous and exophytic but rather has a pebbly, nodular surface. The pertinent clinical and histopathologic features between carcinoma cuniculatum, verrucous carcinoma and well-differentiated papillary SCCa are
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listed in Table 1. Padilla and Murrah summarized the features of carcinoma cuniculatum as follows: 1) modest exophytic component, 2) ramifying keratin-filled crypts and
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sinuses, 3) well-differentiated keratinocytes without overt atypia.15 Similar to other cases reported in the literature, the tumor reported here had a pebbly/nodular surface, with yellow papules corresponding to superficially located keratin-filled burrows and crypts. Tumors with an exophytic cauliflower-like mass are more likely to be verrucous or papillary carcinoma. However, the cytopathologic features of the carcinoma cuniculatum reported here is one of a conventional SCCa rather than one with minimal atypia as has been reported.15,19 It may be difficult to identify areas of conventional single cell or small island infiltration.
ACCEPTED MANUSCRIPT A keratocystic odontogenic tumor (odontogenic keratocyst) or even carcinoma that arose within an odontogenic cyst, that perforates the cortical plate may appear similar to a carcinoma cuniculatum with bone invasion, but in such a case, the epicenter of the lesion is within the jawbone as opposed to being in the overlying mucosal
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tumor.17,20 Because the vast majority (over 85%) of carcinoma cuniculatum arise on the gingival or palatal mucosa, erosion and infiltration of the underlying bone by such tumors must be differentiated from central odontogenic lesions that perforate the
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Less than 40 cases of oral carcinoma cuniculatum have been reported.14,17,18 The
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majority of cases have an indolent course with a relatively good prognosis with only five cases (13%) with recurrences reported in the literature, similar to verrucous carcinoma. They may be successfully managed with surgical resection alone.14,16-18,20 Regional lymph node involvement and distant metastasis are infrequent with five cases (13%) exhibiting regional nodal involvement and only two cases (5%) with distant
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metastasis.14,17,18 In this case, 47 lymph nodes were histologically negative for nodal metastasis and these were FDG-avid level IIA, IIB and V nodes on PET-CT. They most likely represent reactive lymphadenitis, which is a common occurrence in the head and
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neck and may lead to false positive findings on PET-CT.21 Because the tumor was staged as pT3N0M0 (stage III) and she had tumor at the posterior margin, she received
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adjuvant radiation therapy.22
ACCEPTED MANUSCRIPT CONCLUSIONS This is a case of the rare carcinoma cuniculatum, a low-grade variant of SCCa. Carcinoma cuniculatum should be considered within the differential diagnosis of a mass with a relatively smooth surface especially if there is expression of keratin-like material
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from surface pits and tracts. The endophytic architecture with multiple keratin filled crypts and interconnecting burrows is classic for carcinoma cuniculatum. Clinicopathologic correlation is important to differentiate this tumor from verrucous
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(odontogenic keratocyst).
ACCEPTED MANUSCRIPT FIGURE LEGENDS Fig. 1A. There was a 3.0 x 2.5 cm mass involving almost the entire right hard palatal mucosa with overlying pebbly, nodular areas, 0.2-0.3 cm surface yellow papules (arrow) and deep pits and fissures (first visit).
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Fig. 1B. One of many deep pits measuring at least 0.6 cm in depth (second visit). Fig. 2A. CT image revealed a 3.4 x 1.4 cm soft-tissue attenuating mass of the right hard palatal mucosa without involvement of the pterygopalatine fossa, masticator space,
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orbit, or intracranial space.
Fig. 2B. CT image revealed complete opacification of the right maxillary sinus with
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mucoperiosteal thickening.
Fig. 3A. Squamous cell carcinoma with a complex endophytic architecture and keratinfilled cysts within the lamina propria. (x20) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03807.
Fig. 3B. Thinly parakeratinized surface epithelium exhibits the usually pattern of
keratin. (x100)
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maturation; large and small tumor islands are present with abscesses and abundant
Fig. 3C. Multiple keratin filled cysts lined by atypical epithelium with a mild lymphocytic
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Fig. 3D. Tumor cells exhibit marked atypia characterized by basal cell hyperplasia,
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pleomorphism and nuclear hyperchromasia. (x400) Fig. 4. PET-CT scan revealed a 4.2 x 2.0 cm FDG-avid mass of the right hard palatal mucosa with extension into the hard palate. Fig. 5A. The excision specimen consists of a carcinoma cuniculatum similar to the original biopsy with keratin-filled cystic islands of tumor cells, arising from dysplastic epithelium. (x40) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03808.
ACCEPTED MANUSCRIPT Fig. 5B. Cystic tumor islands exhibit basal cell hyperplasia, pleomorphism, and hyperchromasia; there is stromal infiltration present and a mild lymphocytic infiltrate. (x200) Fig. 5C. Tumor islands are present within bone. (x100)
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Fig. 5D. The overlying epithelium showed dysplasia with large, bulbous rete ridges exhibiting basal cell hyperplasia, pleomorphism, dyskeratosis and keratin pearl
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formation. (x200)
ACCEPTED MANUSCRIPT Table 1. Clinical and histopathologic features of carcinoma cuniculatum, verrucous carcinoma and well-differentiated papillary squamous cell carcinoma 14,17,19,23-25
Verrucous carcinoma
•
white exophytic verrucous/warty mass keratin-filled crypts in between exophytic papillary fronds
•
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white/red exophytic papillary mass
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Welldifferentiated papillary squamous cell carcinoma
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•
Histopathologic features • parakeratin, orthokeratin or both • variable papillary morphology with endophytic squamous proliferation forming thin trabecular and ribbon-like proliferation of atypical squamous epithelium lining deep ramifying keratinfilled cystic spaces that are connected to the surface • blunt pushing margin but may also see conventional infiltration • variable cytologic atypia • parakeratin • papillary exophytic and endophytic squamous proliferation • bulbous frond-like rete ridges with parakeratin plugging within crypts • bluntly-invasive, broad pushing tumor front without conventional infiltration • minimal cytologic atypia and low mitotic rate • parakeratin, orthokeratin or both • papillary exophytic and endophytic squamous proliferation • microabscesses at tips of rete ridges are often present • bluntly-invasive, broad pushing tumor front or invades as single cells or small islands of tumor cells • substantial cytologic atypia present
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Clinical features • poorly demarcated mass with a pebbly surface • yellow cheesy material may be expressed from surface pits and sinuses
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Carcinoma type Carcinoma cuniculatum
ACCEPTED MANUSCRIPT REFERENCES 1.
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carcinoma of the palate: A rare case report. J Indian Soc Periodontol. 2016;20:203-6. Elhakim MT, Breinholt H, Godballe C, Andersen LJ, Primdahl H, Kristensen CA, et
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al. Polymorphous low-grade adenocarcinoma: A Danish national study. Oral Oncol. 2016;55:6-10.
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literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121:210-4. Lin EM, Sparano A, Spalding A, Eisbruch A, Worden FP, Heth J, et al. Sinonasal
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outcomes and prognostic factors, including human papillomavirus, for sinonasal undifferentiated carcinoma: a retrospective review. Head Neck. 2015;37:366-74.
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Chen YK, Huang HC, Lin LM, Lin CC. Primary oral squamous cell carcinoma: an
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McKee PH, Wilkinson JD, Black MM, Whimster IW. Carcinoma (epithelioma)
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carcinoma cuniculatum: a variant of oral squamous cell carcinoma. J Oral Pathol Med. 2012;41:303-8. 15.
Padilla RJ, Murrah VA. Carcinoma cuniculatum of the oral mucosa: a potentially
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Bouquot, J.E., Slootweg, P.J. Carcinoma cuniculatum. In: Barnes L, Eveson, JW, Reichart, P.,
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Fitzpatrick SG, Neuman AN, Cohen DM, Bhattacharyya I. Papillary variant of
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ACCEPTED MANUSCRIPT Table 1. Clinical and histopathologic features of carcinoma cuniculatum, verrucous carcinoma and well-differentiated papillary squamous cell carcinoma 14,17,19,23-25
Verrucous carcinoma
•
white exophytic verrucous/warty mass keratin-filled crypts in between exophytic papillary fronds
•
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white/red exophytic papillary mass
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Welldifferentiated papillary squamous cell carcinoma
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•
Histopathologic features • parakeratin, orthokeratin or both • variable papillary morphology with endophytic squamous proliferation forming thin trabecular and ribbon-like proliferation of atypical squamous epithelium lining deep ramifying keratinfilled cystic spaces that are connected to the surface • blunt pushing margin but may also see conventional infiltration • variable cytologic atypia • parakeratin • papillary exophytic and endophytic squamous proliferation • bulbous frond-like rete ridges with parakeratin plugging within crypts • bluntly-invasive, broad pushing tumor front without conventional infiltration • minimal cytologic atypia and low mitotic rate • parakeratin, orthokeratin or both • papillary exophytic and endophytic squamous proliferation • microabscesses at tips of rete ridges are often present • bluntly-invasive, broad pushing tumor front or invades as single cells or small islands of tumor cells • substantial cytologic atypia present
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Clinical features • poorly demarcated mass with a pebbly surface • yellow cheesy material may be expressed from surface pits and sinuses
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Carcinoma type Carcinoma cuniculatum
ACCEPTED MANUSCRIPT FIGURE LEGENDS Fig. 1A. There was a 3.0 x 2.5 cm mass involving almost the entire right hard palatal mucosa with overlying pebbly, nodular areas, 0.2-0.3 cm surface yellow papules (arrow) and deep pits and fissures (first visit).
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Fig. 1B. One of many deep pits measuring at least 0.6 cm in depth (second visit). Fig. 2A. CT image revealed a 3.4 x 1.4 cm soft-tissue attenuating mass of the right hard palatal mucosa without involvement of the pterygopalatine fossa, masticator space,
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orbit, or intracranial space.
Fig. 2B. CT image revealed complete opacification of the right maxillary sinus with
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mucoperiosteal thickening.
Fig. 3A. Squamous cell carcinoma with a complex endophytic architecture and keratinfilled cysts within the lamina propria. (x20) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03807.
Fig. 3B. Thinly parakeratinized surface epithelium exhibits the usually pattern of
keratin. (x100)
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maturation; large and small tumor islands are present with abscesses and abundant
Fig. 3C. Multiple keratin filled cysts lined by atypical epithelium with a mild lymphocytic
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infiltrate. (x100)
Fig. 3D. Tumor cells exhibit marked atypia characterized by basal cell hyperplasia,
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pleomorphism and nuclear hyperchromasia. (x400) Fig. 4. PET-CT scan revealed a 4.2 x 2.0 cm FDG-avid mass of the right hard palatal mucosa with extension into the hard palate. Fig. 5A. The excision specimen consists of a carcinoma cuniculatum similar to the original biopsy with keratin-filled cystic islands of tumor cells, arising from dysplastic epithelium. (x40) A high-resolution version of this slide for use with the Virtual Microscope is available as eSlide: VM03808.
ACCEPTED MANUSCRIPT Fig. 5B. Cystic tumor islands exhibit basal cell hyperplasia, pleomorphism, and hyperchromasia; there is stromal infiltration present and a mild lymphocytic infiltrate. (x200) Fig. 5C. Tumor islands are present within bone. (x100)
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Fig. 5D. The overlying epithelium showed dysplasia with large, bulbous rete ridges exhibiting basal cell hyperplasia, pleomorphism, dyskeratosis and keratin pearl
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