Moderators: Dr. Antonio Cardesa and Dr. Bruce Wenig
Section 3 -
Reactive (Pseudoneoplastic) Epithelial Proliferations
John W. Eveson
This is characterised by inflammation of salivary gland tissue, typically in the palate and
clinically usually presents as a painless lump or indolent ulcer. Men are affected 3x more commonly than
women and the average age at diagnosis is 50. Microscopically there is necrosis of salivary acini and
regenerative hyperplasia of the surrounding ducts which form solid cords which simulate invasive tumor.
There may also be pseudoepitheliomatous hyperplasia of the overlying epithelium. Necrotising
sialometaplasia responds to conservative excision but will heal spontaneously, usually within one or two
Granular Cell Tumor (Myoblastoma)
This oddity was once considered a degenerative disease of muscle. However, on the basis of its
ultrastructural features and positive staining with a variety of markers including neurone-specific
enolase, S-100 protein, calretinin, inhibin alpha, PCP9.2and CD68, a Schwann or Schwann-precursor cell
origin seems likely. The dorsum of the tongue is the most frequent site and clinically the lesion
usually forms a small circumscribed lump or firm area just beneath the surface. If there is involvement
of the surface epithelium with Candida albicans, lesions can present as
white plaques. Occasionally, the lesion is large and clinically resembles a carcinoma. Rarely they may
develop in the midline of the tongue and may then be mistaken for cancer or median rhomboid glossitis.
Microscopically, the appearance is difficult to reconcile with a neural origin as the large granular
cells frequently appear to be in continuity with muscle fibers. The eosinophilic and PAS-positive
granules may be coarse, making the cells conspicuous, or so fine that the granular cells are difficult to
see. The cell membranes are typically well-defined. In about a third of cases, the overlying epithelium
undergoes striking pseudoepitheliomatous hyperplasia which may easily be mistaken for a carcinoma and
treated as such. Recurrence is uncommon but multifocal and rare malignant variants have both been
This rare but distinctive lesion forms most commonly in the oral cavity. There is no association with
HPV in the vast majority of cases. Verruciform xanthomas are seen at all ages but are most frequent in
the fifth to seventh decades. There is a roughly equal sex incidence. They usually present as solitary,
painless, discrete nodules that may be the colour of the surrounding mucosa, reddish or pink. They can
be sessile or pedunculated and the surface can be domed or flat, and can be keratotic or papilliferous.
They usually have sharply defined margins and are typically less than a centimeter in diameter. They do
not appear to be related to any local irritating factors and most cases are asymptomatic. The gingival
margin accounts for 85% of cases. Other common sites include the hard palate, tongue, buccal mucosa and
a variety of other intraoral locations. Microscopy typically shows corrugated, hyperplastic epithelium
with elongated, broad rete ridges which extend to a straight, well- defined lower border. There are deep
clefts within the epithelium that often contain keratinised plugs. The surface shows parakeratinsed
spikes which often stain a deep orange colour. There may be secondary candidal infestation of the
surface keratin layers. The characteristic feature is the presence of vacuolated, foamy xanthomatous
cells which fill the papillary corium. These xanthoma cells can occasionally extend into the overlying
epithelium or into the deeper corium. The xanthoma cells have been shown to be derived from cells of the
monocyte/ macrophage lineage.
The lesions are entirely benign and recurrence following even conservative surgery is very rare.
Focal Epithelial Hyperplasia (Heck Disease)
This is a rare disease predominantly but not exclusively of children and young adults and is caused by
HPV 13 and 32. It was originally described in Inuits and native Americans but since then cases have been
reported over a wide geographical distribution and in a variety of other ethnic groups. Occasional cases
have been reported in HIV+ individuals. The disease most commonly affects the buccal, labial and lingual
mucosa and forms multiple, painless, sessile swellings. These may have a domed or somewhat flattened and
have a slightly nodular, creamy coloured surface. Lesions may spontaneously resolve as new ones develop.
Microscopically the lesions form a sharply demarcated area of acanthosis with broad rete ridges that may
be confluent. The surface may be slightly corrugated but there are no epithelial projections of the type
seen in squamous papillomas. There is often chronic inflammation in the underlying corium. Koilocytes
may be present in the upper epithelial layers. Nuclei with coarse, clumped chromatin resembling mitotic
figures in the suprabasal layers ('mitosoid cell') are characteristic but not specific. There is usually
spontaneous resolution over a number of years and there is no malignant potential.
Papillary Hyperplasia of the Palate
This is a papillary overgrowth of the palatal epithelium and consists clinically of soft nodular
hyperplasia of the mucosa of the vault of the palate, typically in a strip 10-15 mm wide along the
midline. Very rarely, similar appearances are seen on the dorsum of the tongue. The nodules are often
red and made more swollen by inflammation under a denture. Though it is commonly assumed that papillary
hyperplasia is caused by dentures, it does not resolve if the denture is removed, and is sometimes seen
in patients who do not wear dentures. Microscopy shows multiple papillary projections of hyperplastic
epithelium, each with a vascular connective tissue core. The epithelium may sometimes show
pseudoepitheliomatous hyperplasia. There is usually a chronic inflammatory cellular infiltrate in the
corium as a result of superimposed infection.
Discoid Lupus Erythematosus (DLE)
DLE may clinically resemble lichen planes; there is a pattern of red areas or superficial ulceration
associated with a suggestion of striae. However, the lesions tend to be less well-defined than those of
lichen planes, are often unilateral and are frequently seen on the hard palate, a site rarely affected by
lichen planes. Histological, oral discoid lupus erythematosus shows a variety of appearances and the
epithelial changes range from atrophy to irregular hyperplasia. One unusual and sometimes characteristic
feature is an exceptionally irregular pattern of acanthosis in which the deep profile of the epithelium
is flame-like or has exceedingly long, straggly downgrowths. Rarely, epithelial proliferation may be
justifiably termed pseudoepitheliomatous. A newly described possible variant called lichenoid and granulomatous stomatitis will be discussed.
Median Rhomboid Glossitis
Median rhomboid glossitis was thought to be a developmental abnormality caused by persistence of the
tuberculum impar which is normally overgrown by the lateral lingual tubercles during embryogenesis.
However, doubt has been cast on this hypothesis as the condition appears to be very rare in children.
The average frequency in the general population is in the region of 0.2%. The lesion is usually
asymptomatic or may cause slight soreness or a burning sensation. It forms a lozenge-shaped area devoid
of papillae immediately anterior to the sulcus terminalis. The surface may be flat or slightly raised
and is occasionally fissured or lobulated. Many cases of median rhomboid glossitis are associated with
Candida albicans infection and may be a localised form of chronic hyperplastic candidosis. Microscopy
shows absence of lingual papillae and parakeratosis of the epithelium, which may be extensive. There is
acanthosis with downward growth of the rete ridges which may divide and anastomose. The suprapapillary
epithelium may be thinned. Neutrophils are often seen in the superficial epithelial layers and candidal
hyphae may be present. The underlying corium is usually very vascular and infiltrated by variable
numbers of chronic inflammatory cells. Although on occasions the epithelium may be dysplastic, the
dorsal surface of the tongue is an exceedingly rare site for squamous cell carcinomas to develop. This
area can occasionally be the site of a granular cell tumour causing additional diagnostic confusion.
HIV Associated (Koilocytic) Dysplasia
This is a recently characterised type of dysplasia that is usually associated with human
papillomavirus. Clinically the lesions present as white patches. These may be flat, raised or
papillary, and typically involve the buccal, labial or lingual mucosa. The lesions may be small and
discrete, or fuse to form confluent plaques. There is a marked male predominance with an average age of
39 years, and the large majority of patients are HIV positive or have AIDS. Microscopically, the early
lesions show typical features of an epithelial viral infection. There is acanthosis, basal cell
hyperplasia and hyperchromatic keratinocyte nuclei, some with perinuclear halos. There may be occasional
multinucleated keratinocytes. At this stage there is no cytological atypia. More advanced lesions show
striking dysplastic features. There is usually parakeratosis and suprapapillary atrophy, together with
either broad acanthosis or irregular hyperplasia of the rete ridges. There is hyperchromatism of the
cells in the middle of the stratum spinosum where the cells become somewhat spindle shaped and
distorted. There may be binucleated or multinucleated epithelial cells. There is a loss of cellular
cohesion and normal stratification. The basal cell layer may be almost normal or can be involved in the
dysplastic process. Apoptotic bodies and dyskeratotic cells are frequently seen. Paradoxically, mitoses
are not usually common and there may be 'mitosoid' nuclear degenerations, particularly in lesions showing
papillomatous or condylomatous architecture. The typical basal cell budding or drop-shaped rete ridge
configurations seen in conventional oral epithelial dysplasia are not present. HPV can be demonstrated
by in situ hybridisation in about 80% of patients. Whether this represents
viral induction or carriage is not known. The clinical significance, and any malignant potential of
these lesions, has not been established.
Several rare cases of pseudoepitheliomatous hyperplasia have been associated with oral Spitz nevi,
particularly lesions involving the tongue. A junctional component is associated with a spindle cell
melanocytic proliferation, together with an epithelioid component. Although there may be moderate
atypia, mitoses are scanty and melanin may be sparse or absent. In addition there is striking
pseudoepitheliomatous squamous proliferation.
A rare but almost pathognomonic oral presentation of Wegener granulomatosis is the presence of a
proliferative gingivitis which has a purple and red, granular, mottled surface and is know as
'strawberry gums'. The proliferations may be focal or widespread. Microscopically there is a heavy
mixed inflammatory infiltrate with dense focal aggregates of neutrophils and polymorphs forming
microabscesses. There are vascular lakes with evidence of recent and old hemorrhage. Characteristic
multinucleated giant cells may be scantily distributed and many sections may need to be examined to
identify them. Vasculitis is uncommon in these gingival lesions. The overlying epithelium shows
irregular epithelial hyperplasia which has been described as 'pseudoepitheliomatous' but there is rarely
any true confusion with malignancy.
- Brannon RB, Fowler CB, Hartman
KS . Necrotizing sialometaplasia. A clinicopathologic study of sixty-nine cases and review of the
literature. Oral Surg Oral Med Oral Pathol 1991;72:317-25.
- Carlos R, Sedano HO. Multifocal
papilloma virus epithelial hyperplasia. Oral Surg Oral Med Oral Pathol 1994;77:631-5.
- Dorji T,
Cavazza A, Nappi O et al Spitz nevus of the tongue with pseudoepitheliomatous hyperplasia: report of
three cases of a pseudomalignant condition. Am J Surg Pathol 2002; 26:774-7.
- Fornatora M, Jones AC, Kerpel S et al Human papillomavirus-associated oral epithelial dysplasia
(koilocytic dysplasia): an entity of unknown biologic potential. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1996;82:47-56.
- Gorsky M, Raviv M, Taicher S. Squamous cell carcinoma mimicking median rhomboid glossitis region:
report of a case. J Oral Maxillofac Surg 1993;51:798-800.
- Harris AM, van Wyk CW. Heck's
disease (focal epithelial hyperplasia): a longitudinal study. Community Dent Oral Epidemiol
- Karjalainen TK, Tomich CE. A histopathologic study of oral mucosal lupus erythematosus. Oral Surg
Oral Med Oral Pathol 1989; 67:547-54.
- Khansur T, Balducci L, Tavassoli M . Granular cell tumor. Clinical spectrum of the benign and
malignant entity. Cancer 1987; 60: 220-2.
- Le BH, Boyer PJ, Lewis JE et al Granular cell tumor: immunohistochemical assessment of inhibin-alpha,
protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation.
Arch Pathol Lab Med 2004;128:771-5.
- Manchanda Y, Tejasvi T, Handa R et al Strawberry gingiva:
a distinctive sign in Wegener's granulomatosis. J Am Acad Dermatol 2003;49:335-7.
- Ogus HD, Bennett MH Carcinoma of the dorsum of tongue: a rarity or misdiagnosis. Brit J Surg 1978;
- Philipsen HP, Reichart PA, Takata T et al Verruciform xanthoma--biological profile of 282 oral
lesions based on a literature survey with nine new cases from Japan. Oral Oncol 2003; 39:325-36.
- Praetorius F. HPV-associated diseases of oral mucosa. Clin Dermatol 1997;15:399-413.
- Reichart PA, Schmidt-Westhausen A, Samaranayake LP, Philipsen HP. Candida-associated palatal papillary
hyperplasia in HIV infection. J Oral Pathol Med 1994;23:403-5.
- Robinson CM, Oxley JD et al
Lichenoid and granulomatous stomatitis: an entity or a non-specific inflammatory process? J Oral Pathol
- Schiodt M. Oral discoid lupus erythematosus. III. A histopathologic study of sixty-six patients.
Oral Surg Oral Med Oral Pathol 1984;57:281-93.
- Schiodt M, Halberg P, Hentzer B. A clinical study of 32 patients with oral discoid lupus
erythematosus. Int J Oral Surg 1978;7:85-94.
- Tucker KM, Heget HS. The incidence of inflammatory papillary hyperplasia. J Am Dent Assoc
- Wright BA Median rhomboid glossitis: not a misnomer. Oral Surg Oral Med Oral Pathol 1978; 46: