903388

research-article2020
IJSXXX10.1177/1066896920903388International Journal of Surgical PathologyBarrett et al

Pitfalls in Pathology
International Journal of Surgical Pathology

Cystic Squamous Cell Carcinomas

1­–7
© The Author(s) 2020
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DOI: 10.1177/1066896920903388
https://doi.org/10.1177/1066896920903388

Histopathological Pitfalls journals.sagepub.com/home/ijs

Andrew W. Barrett, PhD, FDS, FRCPath1 , Montey Garg, MFDS, MRCS1,

Daniel Armstrong, MFDS1, Brian S. Bisase, FRCS, FDS1,
Lawrence Newman, FRCS, FDS1, Paul M. Norris, FRCS, FDS1,
Michael Shelley, FRCS, FDS1, John V. Tighe, FRCS, FDS1,
Nicholas C. Hyde, FRCS, FDS2, Nicola J. Chaston, FRCPath3,
and Aakshay Gulati, FRCS, FDS1

Abstract
Cystic squamous cell carcinomas (SCCs) of the jaws, including carcinoma cuniculatum, are rare, slow growing,
and relentlessly invasive. The aim of this article is to present 12 cases, 4 of which were designated as carcinoma
cuniculatum on the basis of deeply endophytic, anastomosing channels of cystic stratified squamous epithelium and
keratin microabscesses. The other 8 were also cystic, but more heterogeneous morphologically and were diagnosed
as well differentiated SCCs. Six patients were female, 6 were male (mean age = 74.0 years, range = 50-94 years). Six
tumors affected the mandible, 6 the maxillary alveolus with or without extension into the hard palate. All patients
underwent primary resection with neck dissection and were staged as T4a N0 M0. In 4 patients, diagnosis was delayed
as a result of superficial biopsies and/or confusing histopathology. Cystic SCCs of the jaws can be difficult to diagnose
and clinicoradiological correlation is essential. Long-term follow-up is mandatory.

Keywords
oral cavity, carcinoma cuniculatum, verrucous carcinoma

Introduction years ago. The epithet “cuniculate” was coined because

Squamous cell carcinoma (SCC) is the commonest
malignant neoplasm of the oral cavity.1 Histologically,
the typical features of oral SCC comprise a keratinizing
superficial component and a less well differentiated inva-
sion front. Thus, many are classified as “moderately dif-
ferentiated,” the histopathologist taking an “average”
between the 2 components. Uniformly well or poorly dif-
ferentiated SCCs are less common. In its latest classifica-
tion, the World Health Organization lists several specific
variants of oral SCC, including carcinoma cuniculatum
(CCu), verrucous SCC, and papillary SCC.1 All are well
differentiated, although the third may be keratinized or
nonkeratinized, and all are rare compared with “conven-
tional” oral SCC. CCu is characterized by irregular, laby-
rinthine, deeply burrowing anastomosing crypts lined by
stratified squamous epithelium showing varying degrees
of dysplasia. The crypts contain a mixture of keratin and
microabscesses. A recent review2 identified only 43 pre-
viously reported cases of oral CCu, even though CCu was
first described (in the foot) by Aird and coworkers3 >65
of the resemblance of the crypts to a rabbit warren.
Fliegar and Owanski4 were first to document a case in the
oral cavity, and the largest series of oral examples have
comprised 15 cases5 and 10 cases.6. Difficulties arise
with CCu when the apparently bland histopathology of a
superficial biopsy conflicts with a frankly malignant clin-
ical presentation. Furthermore, some oral SCCs may be
cystic but lack the arborizing pattern seen in CCu.7 The
aim of this article is to present a series of 12 SCCs, 4 of
which fulfilled the diagnostic histological criteria of
CCu. Although the other 8 resembled CCu in places, they
1
Queen Victoria Hospital NHSF Trust, East Grinstead, West Sussex,
UK
2
St. George’s University Hospitals NHSF Trust, London, UK
3
William Harvey Hospital, Ashford, Kent, UK
Corresponding Author:
Andrew W. Barrett, Department of Histopathology, Queen Victoria
Hospital NHSF Trust, Holtye Road, East Grinstead RH19 3DZ, UK.
Email: bill.barrett@nhs.net
2 International Journal of Surgical Pathology 00(0)

Table 1.  Clinical Details of 12 Patients With Cystic SCC.

Age at
Case Diagnosis Primary Site of TNM Outcomes (Time Intervals Specify Period
Number (Years) Sex Tumor Diagnosis Staging After Diagnosis of SCC)
Case 1 78 Male Mandible-alveolus CCu T4aN0M0 Alive 10 years on
Case 2 71 Male Maxilla-hard palate CCu T4aN0M0 Died of bronchopneumonia after 50 months
Case 3 78 Female Mandible-alveolus WDSCC T4aN0M0 Died after 55 months
Case 4 50 Male Maxilla-hard palate WDSCC T4aN0M0 Died after 57 months
Case 5 73 Female Mandible-alveolus WDSCC T4aN0M0 Alive 7 years on
Case 6 76 Female Maxilla-hard palate WDSCC T4aN0M0 Died after 6 months
Case 7 55 Male Maxilla-hard palate WDSCC T4aN0M0 Alive 7 years on
Case 8 81 Male Mandible-alveolus WDSCC T4aN0M0 Alive 3 years on
Case 9 94 Female Mandible-alveolus CCu T4aN0M0 Alive 2 years on
Case 10 69 Male Mandible-alveolus CCu T4aN0M0 Alive 18 months on
Case 11 87 Female Maxilla-hard palate WDSCC T4aN0M0 Alive 10 months on
Case 12 75 Female Maxilla-hard palate WDSCC T4aN0M0 Alive 9 months on

Abbreviations: SCC, squamous cell carcinoma; TNM, tumor, node, and metastasis; CCu, carcinoma cuniculatum; WDSCC, well differentiated SCC.

Figure 1.  (a) Clinical presentation of case 3: an ulcerated mass overlying the left mandibular alveolus and mucosa of the cheek; (b)
panoral tomogram of case 9 showing bony destruction of the left mandible (arrow).

were more morphologically heterogeneous and reported
as well differentiated SCC.
Materials and Methods
Histopathological data on 12 patients treated between
2008 and 2019 with unusual, cystic SCC of the jaws were
retrieved from the departmental archive. Ten had been
treated locally, the other 2 cases were referrals for histo-
logical review. Clinical and radiological data were
reviewed from the patients’ hospital notes and picture
archiving and communications systems.
Results
Six women and 6 men were affected (Table 1). The mean
age at diagnosis was 74.0 years (range = 50-94 years).
Six tumors affected the mandible, 6 the maxillary alveo-
lus with or without extension into the hard palate. In the
11-year time period, 526 local patients underwent a
resection for a primary SCC of the oral cavity; thus, the
10 local cases comprised 1.9% of the total. However, the
6 mandibular tumors were 3.7% of the 161 patients who
underwent a mandibulectomy for SCC, and the 6 maxil-
lary tumors were 11.5% of the 52 who underwent a max-
illectomy for SCC. Clinical presentation varied, ranging
from relatively innocuous-looking ulceration to a grossly
ulcerated mass (Figure 1a), with radiological evidence of
bony destruction in all cases (Figure 1b). Five patients
were nonsmokers, 2 had stopped smoking many years
prior to diagnosis, but both had been heavy smokers. The
smoking histories of the other 5 patients were unknown.
Five admitted to consuming alcohol, though none to
more than 28 units per week. All underwent primary
resection and synchronous neck dissection. All tumors
demonstrated histopathological evidence of invasion
through the bony cortex of the involved jaw and were
thus categorized as T4a. No patient had any evidence of
cervical lymph node or distant metastasis. None devel-
oped any notable postoperative complications, but 4
Barrett et al 3

Figure 2.  Carcinoma cuniculatum: low-power views of case 10 (a) and case 9 (b and c). The surface epithelium is flat or verrucous
and gives rise to endophytic, anastomosing channels lined by cytologically bland stratified squamous epithelium. There is heavy
chronic inflammation in case 9 (b and c), and the intraepithelial edema and papilloverrucous epithelium prompted a differential
diagnosis of focal acantholytic mucositis, warty dyskeratoma, and pemphigus vulgaris. (d) Keratinous abscesses seen at higher power
in case 1. (e) An axial slice of the resection specimen case 9 shows diffuse invasion of the mandible, the tumor extending close to
the mesial margin (short arrow; long arrow = mental nerve on lateral aspect).

patients died (Table 1). In 4 patients, the final diagnosis
was CCu, in 5 others, CCu had been considered at the
time of initial diagnosis but, as with the remaining 3, the
final diagnosis was well differentiated SCC.
Carcinoma cuniculatum (cases 1, 2, 9, and 10;
Table 1)
3 men and 1 woman were affected (mean age = 78.0 years,
range = 69-94 years). The mandible was the primary site
of the tumor in 3 patients, the maxillary alveolus/hard pal-
ate in the other. Microscopy showed oral mucosa covered
by stratified squamous epithelium, which was either flat or
had a papilloverrucous surface morphology, with underly-
ing, endophytic, invaginated cystic channels containing
keratinous microabscesses (Figure 2a-e). Case 2 was a
man aged 71 years when he underwent a left maxillec-
tomy, but he had had numerous papilloverrucous severe
epithelial dysplasias removed from various sites in the left
side of his oral cavity in the preceding 5 years, and in the
ensuing 4 before he died, consistent with a retrospective
diagnosis of proliferative verrucous leukoplakia. This
patient’s CCu has been illustrated in a previous article.8
Histological diagnosis required only one biopsy in all
patients except case 9, a woman of 94 years who required
2; the first incisional biopsy produced a differential diag-
nosis of focal acantholytic mucositis, warty dyskeratoma,
and pemphigus vulgaris (Figure 2b and c). The epithelial
hyperplasia was interpreted as pseudocarcinomatous, and
it was only after several discussions by the multidisci-
plinary team that verrucous carcinoma, “conventional”
SCC and, finally, CCu were considered, the relatively
innocent histopathological features at odds with the
aggressive clinicoradiological scenario. Definitive treat-
ment was further delayed, while second opinions were
sought, and definitive surgery was finally undertaken 4
months after initial biopsy. Examination of the resection
specimen revealed neoplastic cysts extending close to the
excision margin (Figure 2e).
Cystic, well differentiated SCCs (cases 3-8, 11,
and 12; Table 1)
5 women and 3 men had a mean age of 71.9 years (range
50-87 years). Three cases involved the mandible, 5 the
maxillary alveolus/hard palate. In case 3, the tumor
extended from the mandibular alveolus into the soft tis-
sues of the mucosa of the cheek and had a papillary cystic
4 International Journal of Surgical Pathology 00(0)

Figure 3.  Cystic squamous cell carcinoma (SCC): (a) low-power view of case 3 showing papillary cystic invasion of the mandibular
alveolus (long arrow) and mucosa of the cheek (short arrow). Deeply invaginated cystic SCC of the maxillary alveolus in cases 4
(b) and 12 (c). In case 6 (d), the tumor had the appearances of a verrucous carcinoma in places (arrow), but elsewhere appeared
extensively cystic.

microscopic appearance (Figure 3a). In cases 4 and 12,
the tumors in question were second primary oral SCC; a
year previous to his maxillary SCC, case 4 had an exten-
sive “conventional” moderately differentiated SCC,
which required resection of the floor of mouth and para-
symphyseal mandible. Case 12 had had a SCC of the
mandibular alveolus (also a year before her maxillary
neoplasm) which, although it had been classified as well
differentiated, was not cystic. Both patients had deeply
endophytic maxillary SCC (Figure 3b and c), the burrow-
ing nature of which was also reminiscent of CCu without
fulfilling its other histological criteria. In fact, a diagno-
sis of CCu was considered in 5 of the 8 neoplasms (cases
3, 5-8) but finally discarded in favor of well differenti-
ated SCC on the basis that the features did not strictly
fulfil the histological criteria for CCu. In several areas,
the features of case 6 were typical of verrucous carci-
noma, but elsewhere, the tumor appeared cystic (Figure
3d). In 5 of the 8 patients, the diagnosis of malignancy
was made after one incisional biopsy, but case 5 required
4, and cases 7 and 9 required 2 each. Case 5 presented
with nonhealing sockets following the extraction of the
left mandibular incisors. The first biopsy was nonspe-
cific, the second showed epithelial atypia of the overly-
ing oral mucosa, which was continuous with a cystic
invagination lined by papilloverrucous, hyperkeratinized
epithelium with a prominently palisaded basal layer and
reversed nuclear polarity, which suggested an odonto-
genic origin. Symptoms persisted for a further 2 months,
and on fourth biopsy, a diagnosis of CCu was considered.
However, although the tumor was cystic (Figure 4a), the
deeply burrowing, infiltrative pattern and keratin micro-
abscesses characteristic of CCu were absent and a final
diagnosis of well differentiated SCC was made. Features
of odontogenic epithelium were again present (Figure
4b), and it remained unclear as to whether the tumor had
an origin from the surface epithelium, rests of odonto-
genic epithelium in the periodontal ligament or indeed a
preexisting odontogenic cyst, since in several areas, the
appearances were reminiscent of an odontogenic kerato-
cyst (Figure 4c). Case 7 underwent 7 biopsies in all, 5 of
which were the result of 3 recurrences on an almost
annual basis in the years following his initial resection.
The surface epithelium showed papilloverrucous hyper-
plasia associated with an endophytic, cystic tumor typical
of CCu (Figure 4d). However, there was also convention-
ally invasive well differentiated SCC and a focus of baso-
philic, basaloid tumor, which was absent in all but the
resection specimen (Figure 4d). Immunohistochemistry
for p16 was negative. Case 11, a woman aged 87 years,
Barrett et al 5

Figure 4.  (a) Cystic neoplastic epithelium infiltrating the lamina propria in case 5: at high-power view, the epithelium in the
boxed area is dyskeratotic, with a prominently palisaded basal layer and reversed nuclear polarity (b) conferring an odontogenic
appearance. (c) In places the invaginated epithelium resembled an odontogenic keratocyst, the origin of the tumor may have been
from the surface epithelium or odontogenic epithelial rests in the periodontal ligament (arrow = root of mandibular incisor tooth).
(d) Cysts containing keratinous abscesses reminiscent of carcinoma cuniculatum were present in case 7, but elsewhere, there was
conventionally invasive well differentiated squamous cell carcinoma and (e) a focus of basophilic, basaloid tumor. (f) Case 11: low-
power view showing perforation of the bone of the hard palate by a cystic invagination lined by bland epithelium.

had widespread field change of the palatal mucosa, but
while her first 2 biopsies showed severe epithelial dyspla-
sia, there was no unequivocal invasive SCC despite bony
destruction radiologically and obvious malignancy clini-
cally. Following discussion by the multidisciplinary
team, it was concluded that the severely dysplastic epi-
thelium represented the lining of a cystic, well differenti-
ated SCC, and the patient underwent maxillectomy and
neck dissection. In fact, microscopic examination of the
resection specimen showed that, where the tumor
punched through the palatal bone (Figure 4f), the epithe-
lium was cytologically bland. There was possible con-
ventional SCC close by, but this could also have been
carcinoma in situ extending along the duct of a minor
salivary gland.
Discussion
Cystic SCCs are not a recognized subset of SCC of the
oral cavity and there is no literature specifically describ-
ing them. By contrast, CCu are well documented and are
probably one of the “family” of papilloverrucous dyspla-
sias and carcinomas that affect the oral cavity, albeit one
with specific histopathological features. Patients with
CCu are usually aged >60 years, but the mean age in the
present series is higher than that reported in a recent
review,2 which also found a slight female preponderance
(55.8%). There are 2 reported instances of CCu in chil-
dren younger than 10 years.4,9 The question arises as to
whether CCu is biologically distinct, and a further prob-
lem lies in the consistency with which the diagnostic cri-
teria are applied. Other than the 4 cases in this report,
which we were satisfied met the histological require-
ments for CCu, we considered the diagnosis in 5 others
but decided, on review, the features were not “pure”
enough. Farag et al2 cite at least one case report10 in
which the histological evidence for CCu is dubious.
Although bona fide cases of CCu affecting the tongue
have been reported,11,12 in the series of 15 oral CCu
described by Sun and coworkers5 (and included in the
review by Farag and coworkers2), there are, suspiciously,
8 lingual examples and the one illustrated is entirely exo-
phytic with no apparent burrowing, endophytic compo-
nent. The vast majority of the other reported cases suggest
that the jaws, and particularly the mandibular alveolus, is
the most common site of oral CCu. While local
6 International Journal of Surgical Pathology 00(0)
destruction is a common feature, metastasis is unusual,
and as 3 of the 4 metastases stated to have occurred by
Farag et al2 were reported by Sun et al,5 this figure is also
unreliable. The etiology is uncertain; >30% of patients
are tobacco smokers or heavy consumers of alcohol, or
both.2 Human papilloma virus would appear to have no
role.11,12
The main dilemma posed by some cystic SCC, includ-
ing CCu, for the histopathologist are the findings of rather
bland microscopic features in the face of an anxious clini-
cian certain that he or she is dealing with malignancy.
Without evidence of bony invasion or infiltrative growth,
histologically a superficial biopsy of a cystic SCC or CCu
may appear misleadingly innocent or interpreted as pseu-
docarcinomatous hyperplasia.2,5,12,13 Misdiagnosis may
occur in one-third of cases.14 Although diagnosis was rea-
sonably straightforward in 8 of the 12 cases reported here,
it proved particularly problematical in cases 5, 7, 9, and 11.
Where diagnosis was delayed, the incisional biopsies were
superficial, and in case 9 produced a differential diagnosis
indicative of the reporting histopathologist’s desperation.
Immunohistochemistry for proliferation markers and p53
is of no help,11,12,14-16 and while radiology is helpful to
demonstrate the unequivocally invasive nature of the
tumor, these cases demonstrate the importance of good
communication between surgeons and histopathologists to
correct diagnosis and treatment.
All the tumors reported in this series can be confused
with verrucous SCC clinically and histologically, and in
the past, the 2 terms have been used interchangeably.13,17
Both are locally aggressive, well differentiated forms of
SCCs, which may have exophytic, as well as endophytic,
components, and while the interconnecting network of
invaginated channels typical of CCu are typically absent in
verrucous carcinoma, which is characterized by a cohe-
sive, broad “pushing” invasion front, Kubik and Rhatigan13
described the presence of “sinuses” in verrucous carci-
noma which may bring CCu to mind; this may have been
the case in patient 6 (Figure 3d). The pattern of cystic
change in the 12 cystic SCCs described here is different to
the comedo necrosis seen in human papilloma virus–asso-
ciated basaloid SCC of the oropharynx. Although it is
assumed that 11 tumors arose from the stratified squamous
epithelium lining the oral mucosa, the possibility of an
intraosseous odontogenic origin in some cystic tumors of
the jaws was highlighted in case 5, which particularly
resembled odontogenic keratocyst in 2 biopsies, a resem-
blance previously noted.14,18
In conclusion, cystic, well differentiated SCCs of
the jaws are rare, but diagnosis can be difficult and
require multiple biopsies along with correlation with
clinical and radiological features. Surgical resection is
the mainstay of treatment, and long-term follow-up is
mandatory.
Acknowledgments
The invaluable librarial assistance of Patricia Rey, Karen
Clements and Kat Maclennan at Queen Victoria Hospital NHS
Foundation Trust is gratefully acknowledged.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Ethical Approval
Not applicable, because this article does not contain any studies
with human or animal subjects.
Informed Consent
Not applicable, because this article does not contain any studies
with human or animal subjects.
Trial Registration
Not applicable, because this article does not contain any clinical
trials.
ORCID iD
Andrew W. Barrett https://orcid.org/0000-0003-4442-6081
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