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Inflammatory Pseudotumor and Related Lesions of the Oral and

Maxillofacial Region: A critical reappraisal based on recent
information
Introduction
So-called pseudotumor is a generic term used to de-
scribe a benign space-occupying lesion of disputed no-
sology and commonly applied to inflammatory pseudotu-
mor (IPT) (1). The unifying histologic feature of IPT is
that of a locally destructive proliferation of myofibro-
blasts / fibroblasts with a characteristic inflammatory ap-
pearance (2-4). Since plasma cells can constitute the ma-
jor cellular population in many cases, the term plasma
cell granuloma (PCG) has been used interchangeably (2,
3). On the other hand, some authors view all IPTs as be-
nign neoplasms of myofibroblasts and recommend renam-
ing the IPT inflammatory myofibroblastic tumor (IMT)
(2, 4, 5).
The lung may be the single most common site of
IPT, but extrapulmonary lesions can occur in virtually all
anatomic sites involving the oral and maxillofacial region
(2-5). Once designation of extrapulmonary IPT came to be
widely accepted, subsequent case studies began to ex-
pand its spectrum continuously. Their reports resulted in
a plethora of designations and have challenged the con-
cept that ITP is simply a single nosologic entity. More-
over, there is no consensus whether IPT represents a
purely postinflammatory response or a true neoplastic
process (3).
This article attempts to present an overview of IPT
and related lesions in the oral and maxillofacial region,
with emphasis on morphological heterogeneity. We also
explore unanswered questions about the nature of IPT
based on data from our own series.
1. So-called pseudotumors of the oral and maxillo-
facial region
IPT and other lesions that may be part of the spec-
trum of IPT in the oral and maxillofacial region are listed
in Table 1. The detail of these lesions is discussed in sub-
sequent sections.
Fumio Ide
1, 2)
,Tetsuo Shimoyama
1)
, Takao Kato
1)
, Norio Horie
1)
and Kaoru Kusama
2)
1) Department of Oral Surgery, Saitama Medical Center, Saitama Medical School, Kawagoe, Japan 2) Department of Oral Pathology,
Meikai University School of Dentistry, Sakado, Japan
Ide F, Shimoyama T, Kato T, Horie N and Kusama K: Inflammatory pseudotumor and related
lesions of the oral and maxillofacial region: A critical reappraisal based on recent information.
Oral Med Pathol: 2000; 5: 41~47. ISSN 1342-0984.
The term pseudotumor is used for a broad category of tumorous proliferations that are consid-
ered to be reactive rather than neoplastic and that can simulate malignant tumors. Presently,
its nosologic position in the pathological diagnosis is still largely elusive and disputable. In this
report, we present a comprehensive review of so-called inflammatory pseudotumor and its re-
lated lesions in the oral and maxillofacial region with different diagnostic considerations. The
spectrum of these pseudotumors undoubtedly encompasses a diverse group of inflammatory fi-
brohistiocytic / myofibroblastic lesions with different causes, pathogeneses, and clinical and
pathological implications.
Key words: differential diagnosis, fibrohistiocytic lesion, inflammatory pseudotumor, myofi-
broblastic lesion, oral and maxillofacial region, review
Correspondence: Fumio Ide, Department of Oral Surgery, Saitama Medical Center, Saitama Medical
School, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan
Table 1: So-called pseudotumors in the oral and maxillofacial
region
Classic inflammatory pseudotumor
Inflammatory myofibroblastic tumor
Plasma cell granuloma
Post-traumatic spindle cell nodule
Focal myositis
Tumefactive fibroinflammatory lesion
Calcifying fibrous pseudotumor
Extranodal Rosai-Dorfman disease
2. Clinicopathologic features of classic IPT as re-
ported in the literature
The limitations in our current state of knowledge of
IPT are due to the fact that the lesion itself is uncommon
and occurs sporadically. To our knowledge, 28 convincing
cases have been documented in the oral and maxillofacial
region (6-22).
1). Reported sites
Locations of published IPT are shown in Table 2.
Reported cases of IPT associated with periapical lesions
in the jawbones, orbital IPT involving the sinus and PCG
were not listed (22, 23). We also excluded several ambigu-
ous cases without histologic verification (24, 25).
2). Clinical presentation
As shown in Table 2, IPT is reported to occur at any
age, ranging from 19 months (6) to 87 years (10), but it
seems that there is predilection for middle-aged or older
individuals. The lesions are almost equally distributed
between the sexes. IPT appears as a solitary soft tissue
mass and does not produce significant systemic symp-
toms. Routine laboratory examinations are normal, and
microbiological culture results are usually negative (20,
22). There is no tumor-related regional lymphadenopathy
in the majority of cases. Its rapid growth, persistency and
local invasiveness may mimic a malignant tumor. No ap-
parent history of preceeding trauma or infection was re-
corded except for a few cases (20, 22). Of incidental inter-
est, one patient had a past medical history significant for
retroperitoneal fibrosis (15). Reviewing the literature, we
noted another case of idiopathic multifocal sclerosis in
the submandibular gland and retroperitoneum (26).
Excision of tumor mass is the treatment of choice.
The benefit of chemotherapy and radiation therapy may
yet be unproven, but high-dose steroid therapy was effec-
tive in some cases (11, 18). The general tendency is to
spontaneous regression after simple excision (6, 13, 22).
Local recurrence has not , to our knowledge, been re-
ported.
3). Histopathological findings
The histological appearances are extremely varied,
although there are several consistently shared features.
The reliable histologic feature is that of a benign, nonen-
capsulated mass composed of an admixture of spindle
and round cells, and plasma cells. The ratio of three types
of lesional cells differed from case to case. The spindle
cells constituted the major cellular population in most
cases and exhibit a fascicular growth pattern ( Fig. 1) .
They lack atypical features but some degree of invasive
growth can be observed (Fig. 2). Round or oval cells with
clear or foamy cytoplasm merge with spindle cells and ag-
gregate focally. Chronic inflammatory cells , especially
plasma cells are usually seen. In addition, fibrosclerotic
features are noted in many lesions (16).
As shown in Table 3, most spindle cells show posi-
tive reactivity for both vimentin and -smooth muscle ac-
tin (10, 13, 16, 17, 19, 21, 22) and have the immunohisto-
chemical profile of myofibroblasts . These cells usually
lack of the expression of desmin and cytokeratin (10, 13,
16, 22). Round cells, some with foamy features, are posi-
tive for CD 68, lysozyme, 1-antichymotrypsin and Mac
387 (10, 16, 17, 19, 22), giving evidence of a histiocytic
lineage. However, S-100 protein has not proven to be
positive ( 10, 13, 16, 17, 19, 22 ) . Immunostaining of
Table 2: Clinical features of classic IPT
Location No. of cases Age Sex Reference
Maxillary sinus 7 13y-83y* M3, F4 9, 12, 20**
Parotid gland 6 46y-87y M3, F3 10
Cheek 6 19mo-77y M2, F4 6, 16, 17, 21
Submandibular region 3 53y-63y M2, F1 14, 18, 19
Gingiva 2 43y, 44y M1, F1 13, 22
Parapharyngeal space 2 3y, 36y M1, F1 8, 11
Tonsil 1 62y F 15
Pterygomaxillary space 1 55y M 7
*Range. **Published cases in Japanese. Abbreviations: M, male; F, female.
Fig. 1: IPT in the buccal mucosa (21) ( H & E, 200).
Fig. 2: IPT in the gingiva (22) (H & E, 100).
42 Ide et al Oral pseudotumor
plasma cells confirms a polyclonal population (15, 16, 19).
Stated simply, IPT consists of a highly variable mixture
of three main cell types: myofibroblasts/ fibroblasts, his-
tiocytes and plasma cells.
3. Some cases of IPT, particularly those of the skin,
are caused by localized fibrosing vasculitis
The cause and pathogenesis of IPT are mostly un-
known (2-4). It is widely recognized that the majority of
the classic IPT represent postinflammatory or postin-
fective reactive response (3). Recently, Carlson and Le-
Boit (27) suggested that some IPT in the skin, and per-
haps of other sites, could be the result of localized chronic
fibrosing vasculitis. Since previously reported cases of cu-
taneous and oral IPTs showed fibrosis but no vasculitis (6
-22, 28, 29), this theory fails to explain satisfactorily the
cause of IPT.
4. The term IMT should be applied only for a genu-
ine neoplasm of myofibroblasts
The appellation IMT was initially proposed by Pet-
tinato et al . (30) in 1990, in their clinicopathologic study
of pulmonary IPT. The idea of a possible neoplastic na-
ture is not new. In 1984, Spencer (31) had already dis-
cussed the concept of pulmonary plasma cell-
histiocytoma complex, suggesting that two cases in his
series merge into a neoplastic transformation. Subse-
quently, Coffin et al . (4, 5) regarded all extrapulmonary
IPTs as bona fide neoplasms . Since recent molecular
studies pointed to clonal cytogenetic aberrations in some
cases of IPT (32), it appears that an unknown proportion
of IPT represents legitimately true neoplasms (33, 34).
Once the myofibroblast had come to be recognized
as a principal cellular constituent of IPT ( 33, 34) , ex-
trapulmonary IMT eventually joined the list of soft tissue
tumor (35). To our knowledge, there have been only two
cases of IMT in the oral and maxillofacial region : one in
the maxillary sinus (2) and one the tonsil (36). We stud-
ied the first case of the tongue (37) (Fig. 3). Both immuno-
histochemical and ultrastructural observations showed
that the myofibroblast has a central role in the develop-
ment of our IMT. Recently, Donner et al . (38) reported an
interesting case of IMT of the arm that recurred five
times, progressed into sarcoma, and metastasized to the
lungs, causing the patients death. In this respect, the
term IMT should be used strictly for tumors with a neo-
plastic myofibroblastic character. Of course, there is no
definitive pathological criteria for differentiating between
tumors and pseudotumors at present (1). Another conun-
drum is the relationship between IMT and inflammatory
fibrosarcoma, which will probably be resolved in future
studies (5, 39, 40).
5. Pure PCG should not be called an IPT
PCG is a benign mass-forming lesion of polyclonal
plasma cells. This term was introduced by Bhadori and
Liebow (41) in 1973 for IPT of the lung with prominent
plasma cell component. The oral and maxillofacial region
is an exceedingly uncommon location, with only 7 previ-
ously documented cases (42). We have encountered PCG
Table 3: Immunohistochemistry of classic IPT
Authors
Common markers
Vim SMA Des CK S-100 CD 68
Williams et al . (10)
Foo & Poh (12) NT NT NT NT
Earl et al . (13) NT
Shek et al . (17) NT NT
Monteil et al . (19)
Ide et al . (21, 22)
Abbreviations: Vim, vimentin; SMA, smooth muscle actin; Des, desmin; CK, cytokeratin; S-100, S-100 pro-
tein; NT, not tested. Lesional cells were also positive for muscle specific actin (10), Mac 387 (19), or 1-
antichymotrypsin (22).
Fig. 3: IMT in the tongue (37) (H & E, 200). Fig. 4: PCG in the buccal mucosa (42) (H & E, 100).
Oral Med Pathol 5(2000) 43
of the oral mucosa with angiokeratomatous features (42)
(Fig. 4). This is the first case of oral mucosal analogue of
cutaneous angioplasmocellular hyperplasia. On the other
hand, exaggerated plasma cell infiltration in the gingiva
was described in the literature under the term PCG (43-
45). However, the gingival location of PCG is usually the
representation of plasma cell gingivitis (46).
By contrast to PCG, a diffuse mucosal swelling com-
posed of an aggregate of polytypic plasma cells in the up-
per aerodigestive tract was also reported under a variety
of descriptive terms, including mucous membrane plas-
macytosis (47) or plasma cell mucositis (48). Unlike PCG,
this condition might occasionally evoke a hypersensitiv-
ity response to the environmental antigens (48).
As already mentioned, in the past literature the
term PCG has been known equally well, if not better, as
IPT ( 3) . In the oral and maxillofacial region, it seems
more appropriate that the term PCG be restricted to ex-
tragingival tumorous polyclonal plasma cell lesions with
no or minimal myofibroblastic spindle cell proliferation
(22, 42, 49). Since granulomatous reaction is not a feature
of PCG, Ballesteros et al. (49) recommended the new term
plasma cell pseudotumor.
6. Post-traumatic spindle cell nodule ( PTSN) is
closely related to nodular fasciitis
PTSN, originally described as postoperative spindle
cell nodules in the genitourinary tract, has received scant
attention in the dental literature (50). This is a reactive
exuberant proliferation of myofibroblasts often histologi-
cally misdiagnosed as sarcoma. We encountered the third
case of PTSN in the oral mucosa shortly after minor
trauma (50) (Fig. 5). Overall architecture is closely simi-
lar, if not identical to nodular fasciitis. Moreover, our
case showed qualitatively the same immunophenotypes
with nodular fasciitis (51, 52). Oral fasciitis is a sponta-
neously occurring lesion unrelated to trauma (50) ; how-
ever, remote or undetected ( inflammatory) injury may
still be an etiologic possibility. Since these two entities
appear to have many overlapping clinical and histological
features, the dividing line is difficult to draw (51).
7. Focal myositis (FM) should not be confused with
IPT
FM is an uncommon pseudotumor whose clinical
presentation is an ill-defined mass in the head and neck
region (53). The lesion is often rapidly enlarging and on
clinical evaluation may be misdiagnosed as a malignant
neoplasm. Our review of the literature has revealed 8
cases of FM involving the oral cavity (54-59). Microscopi-
cally, there are marked myopathic changes with a focal
collections of inflammatory cells. Thus, it looks nothing
like IPT. Despite its clinical resemblance, FM is a miscel-
laneous fibroinflammatory process unrelated to IPT.
8. Tumefactive fibroinflammatory lesion ( TFIL )
constitutes a distinctive category
TFIL of the head and neck was initially proposed by
Wold and Weiland (60). This is an idiopathic, histologi-
cally benign, mass-forming lesion that clinically simu-
lates a malignant tumor. More than 25 reported cases of
TFIL, including one case in the tongue, have appeared in
the literature (60-67). Although it is considered synony-
mous with IPT in the current World Health Organization
of Tumours of the Upper Respiratory Tract and Ear (68),
most authors believe that TFIL is not a single nosologic
entity, and that it includes a variety of unrelated inflam-
matory fibrosclerosing lesions (53). We also consider that
TFIL constitutes heterogeneous syndromic conditions
and is a distinct diffuse process that is more aggressive
than IPT (37).
9. Is calcifying fibrous pseudotumor (CFPT) a late
sclerosing stage of IPT?
In 1993, Fetsch et al . (69) reported a series of soft
tissue pseudotumors with distinctive pathological fea-
tures under the term CFPT. Recently, Van Dorpe et al .
(70) reported a unique case of combined features of CFPT
and IPT. Since the multiple ileocecal masses showed his-
tologic transition, the authors concluded that CFPT is a
cell-poor-end-stage of IPT. Unfortunately, no references
to an identical lesion in the oral and maxillofacial region
have been published to date (37).
10. Is extranodal Rosai-Dorfman disease (RDD) his-
togenetically related to IPT?
Extranodal RDD is characterized histologically by a
benign proliferation of large pale histiocytes which show
striking emperipolesis and immunoreactivity for S-100
protein (71). Govender and Chetty (72) reported an inter-
esting case of a chest wall mass showing combined fea-
tures of RDD and IPT. They concluded that there may be
a continuum spectrum between two lesions, with RDD
representing the early histiocytic lesion and IPT the later
myofibroblastic / fibroblastic lesion. Subsequently, a simi-
lar soft tissue lesion has been documented (73). Although
the head and neck is one of major principal sites of extra-
nodal RDD (74), only one case involved the third molar
area of the mandible (75). Due to the paucity of informa-
Fig. 5: PTSN in the buccal mucosa (H & E, 100).
44 Ide et al Oral pseudotumor
tion on both lesions in the oral and maxillofacial region,
we consider lumping of the two together premature.
11. Inflammatory type of follicular dendritic cell
tumor (FDCT) in the oral cavity should not be-
long to IPT
Extranodal FDCT is an extremely rare tumor of fol-
licular dendritic cells (76, 77). According to a recent re-
view (78), only six cases have been described in the oral
cavity; 4 in the tonsil and 2 in the palate. Chan (3) em-
phasized that some cases of IPT, particularly those of the
liver and spleen, represent Epstein-Barr virus-positive
inflammatory FDCT . However , it is recognized that
FDCTs are to be regarded as low-grade malignant tumors
with local recurrences and occasional distant metastases
(76, 77). At least, inflammatory type of FDCT in the oral
cavity is histogenetically unrelated to IPT and presents a
completely different entity. Moreover, it is as yet unclear
whether Epstein-Barr virus may have some role in the
cause of oral FDCT as well as IPT.
12. Recurrent IPTs are similar in some respects to
atypical histiocytic granuloma (AHG)
In recurrent cases of IPT, the spindle cell appear-
ance of the initial lesions was replaced by a population of
atypical histiocytic cells (79). These lesions bear some re-
semblance to AHG (6). AHG is a benign ulceroprolifera-
tive lesion of histiocytic origin affecting the oral mucosa
(80-83). This tumefactive ulceration may be mistaken on
clinical evaluation for a malignant tumor. Unlike IPT, no
myofibroblastic proliferation was ascertained in AHG
(80). It has come to be recognized that AHG is an entity
subsumed within one of pseudolymphomas (84) and prob-
ably shares a kinship with eosinophilic ulcer (85).
Conclusion
As a final note, the designation of IPT has been in-
discriminately applied to heterogeneous inflammatory fi-
brohistiocytic / myofibroblastic lesions with divergent be-
haviors. As shown in Table 4 it is at times tentatively
concluded that so-called IPTs are better divided into two
clinicopathologic entities : postinflammatory reparative
lesions (classic IPT) and true neoplasms (IMT). Unfor-
tunately, the potential dilenma and diagnostic pitfall of
IPT and the other category of pseudotumors such as
PTSN and PCG still exist . Moreover , it is unclear
whether pure histiocytic cell type of IPT really exists. To
define IPT and related lesions more precisely, further
study is required.
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Addendum: Since the submission of this manuscript, Car-
bone et al . (Ann Otol Rhinol Laryngol 1999; 108: 1095) re-
ported a review of RDD of the head and neck.
(Accepted for publication March 3, 2000)
Oral Med Pathol 5(2000) 47