Diagnosis of periodontal

manifestations of systemic
diseases
Richard C. K. Jordan
Many systemic diseases may present or are mani-
fested in the gingiva, producing signs and symptoms
that resemble chronic gingivitis or periodontitis.
Although, by comparison, most of these conditions
are uncommon, their management is markedly dif-
ferent, hence the need for prompt and effective diag-
nosis. Moreover, the mechanism to establish the
diagnosis may differ from that used for chronic per-
iodontitis, relying more on histologic, immunohisto-
chemical and in some cases serologic testing.
Therefore, a high index of suspicion is often neces-
sary to identify specic signs and symptoms of these
systemic diseases and prompt the clinician to pursue
further investigations. This chapter will review a
number of systemic conditions that may mimic clini-
cally both gingivitis and chronic periodontitis, focus-
ing on the features that will assist in making the
diagnosis. The conditions are presented in order of
frequency from most to least common.
Systemic diseases that mimic
gingivitis
Lichen planus
The hallmark of lichen planus is reticulated, hyper-
keratotic lesions (60). However, when lichen planus
occurs on the gingiva it is frequently erythematous
with little evidence of reticulation and can be mis-
diagnosed as plaque-induced gingivitis (5). Figure 1
illustrates the gingival lesions arising in an otherwise
well patient. There are patchy erythematous lesions
but little evidence of hyperkeratosis. Biopsy of one
area of the gingiva showed features of lichen planus.
Lichenplanus is acommonchronicmucocutaneous
condition of unknown etiology. It affects between
0.22.0% of the population, with women slightly more
oftenaffectedthanmen(60). Withinthe mouth, lichen
planus presentsasbilateral, reticulated, hyperkeratotic
lesions that may be associated with erythema and
ulceration. On the gingiva, lichen planus is an impor-
tant cause of gingival inammation and pain (34).
The cause of lichen planus is not known; however,
many of the features suggest an immune-mediated
hypersensitivity reaction. The epithelium and under-
lying connective tissues are inltrated by T lympho-
cytes that express CD4 and CD8 antigens. In
addition, there is an increase in the number of intrae-
pithelial Langerhans cells, the antigen-presenting
cells of skin and mucosa (66). Inammation med-
iates basal epithelial cell damage that ultimately
results in hyperkeratinization. More marked inam-
mation can lead to more extensive epithelial break-
down and resultant oral ulceration (56).
Clinically, lichen planus affects middle-aged men
and women. It is rare in children. There is an asso-
ciation between lichen planus and hepatitis C infec-
tion but the proposed relationship between lichen
planus and diabetes mellitus or hypertension is more
likely due to a drug reaction than to the conditions
themselves (27, 67). The classical form of lichen pla-
nus has ne, white reticulations on the buccal
mucosa, tongue and gingiva with or without inam-
mation (Fig. 2). Often on the gingiva there is marked
inammation but with little discernible hyperkerato-
sis. The inammation is frequently patchy and dis-
tributed in all four quadrants, although focal disease
can also occur. The key to clinical diagnosis is the
identication of reticulated hyperkeratotic areas
either on the gingiva or at other intraoral sites. On
the gingiva, superimposed inammation and abun-
dant plaque will make this diagnosis more challen-
ging (34).
217
Periodontology 2000, Vol. 34, 2004, 217229 Copyright
#
Blackwell Munksgaard 2004
Printed in Denmark. All rights reserved
PERIODONTOLOGY 2000
The diagnosis of lichen planus is made by biopsy
showing a band-like inltrate of lymphocytes in the
supercial connective tissue and into the epithelium
that exhibits hyperkeratosis and degeneration of
basal keratinocytes (Fig. 3)(56). For equivocal cases,
direct immunouorescence can be helpful, showing
a band of brinogen deposited at the epithelial
mesenchymal interface (Fig. 4)(35).
Topical corticosteroids are the mainstay of treat-
ment for lichen planus. Occasionally systemic ster-
oids can be used for patients with severe disease,
prior to initiation of topical therapy (69). Other treat-
ments have included vitamin A analogues and anti-
fungal medications but these have proven less
effective than corticosteroid therapy (43). Topical
cyclosporin has also been used with promising
results although the medication costs are high in
comparison with corticosteroids (25).
Primary herpes simplex infection
Figure 5 shows the clinical presentation of an
11-year-old slightly febrile female patient with a 2-day
history of generalized, erythematous, painful gingiva.
Previously she had good oral hygiene and there was
minimal plaque. Questioning of the parent revealed
that she had been exposed to a relative with recurrent
Fig. 2. The hallmark of oral lichen planus is reticulated
hyperkeratotic lesions on the buccal mucosa. In this case
there is very little evidence of inammation and no ulcera-
tion.
Fig. 1. There is patchy inammation affecting the man-
dibular and maxillary marginal gingiva with little evidence
of hyperkeratosis. Biopsy showed features of oral lichen
planus.
Fig. 5. Primary herpetic gingivostomatitis typically has an
acute presentation with painful, diffusely erythematous
gingiva with or without areas of ulceration.
Fig. 3. Histology of oral lichenplanus shows hyperkeratosis
of the epithelium covering connective tissue containing a
band-like inltration of lymphocytes in the lamina propria.
Fig. 4. Immunouorescence studies of oral lichen planus
show deposits of brinogen (green) at the epithelial-
mesenchymal interface (courtesy of Dr. T. Daniels, UCSF).
Jordan
218
herpes labialis several days earlier. Based on the his-
tory and clinical ndings, a diagnosis of primary
herpetic gingivostomatitis was made.
Herpes simplex virus infections are common in the
mouth. Herpes simplex virus is a DNA virus and
member of the herpes family. There are two forms
of the disease: primary (systemic) infection and sec-
ondary (localized) disease. In immunocompetent
patients, both forms are self-limiting. Primary herpes
simplex virus produces generalized gingivitis termed
primary herpetic gingivostomatitis. Infection is
transmitted in aerosolized droplets or by direct con-
tact (65). Following an incubation period of several
days to 2 weeks a primary vesiculoulcerative eruption
develops on any oral mucosal surface including the
gingiva, which are red, slightly hyperplastic and ten-
der (Fig. 6). Primary herpes simplex virus most com-
monly affects children but adults who have not been
previously exposed or infected may also develop the
disease. Resolution of the primary infection can be
expected in 710 days, during which the virus
becomes latent in basal ganglia (64).
The diagnosis is made based on history and clin-
ical ndings. In equivocal cases, serology demon-
strating a rising antibody titer can be useful in
establishing the diagnosis. In the immunocompe-
tent, treatment is palliative until resolution occurs
(8). Acyclovir can also be used either topically or
systemically early in the course of the disease.
Mucous membrane pemphigoid
Mucous membrane pemphigoid occurs commonly
on the gingiva and can frequently mimic plaque-
induced gingivitis (75). Indeed, when mucous mem-
brane pemphigoid occurs on the gingiva it is often
described under the clinical rubric desquamative gin-
givitis or gingivosis. Figure 7 illustrates a 56-year-old
female patient with persistent erythematous gingivi-
tis that was unresponsive to local plaque control
procedures. A biopsy was taken from the gingiva that
showed subepithelial separation consistent with
mucous membrane pemphigoid and the diagnosis
was conrmed by direct immunouorescence exam-
ination, showing deposits of IgG and complement at
the epithelialmesenchymal interface.
Mucous membrane pemphigoidis a chronic blister-
ing disorder that affects the oral and ocular mucosae.
Other sites can be affected include the oropharyngeal
mucosa and the skin. The condition is also known as
cicatricial pemphigoid, benign mucous membrane
pemphigoid, and ocular pemphigoid.
The etiology of mucous membrane pemphigoid is
unknown, although it is believed to be an autoim-
mune disease (75). Immunoglobulins and comple-
ment are frequently identied along the basement
membrane of oral epithelium and their presence, as
demonstrated using immunouorescence study, is
diagnostic. The target antigens are laminin 5 and a
180 kDa protein bullous pemphigoid antigen (6).
The clinical features of mucous membrane pem-
phigoid are variable. It typically affects adults and the
elderly, with women more often affected than men.
The condition is rare in children. Erythema is fol-
lowed by vesicle and bulla formation that rupture
to leave ulcerations (Fig. 8). On the gingiva, there is
band-like or patchy erythema that affects all four
quadrants. Usually there is supercial gingival
Fig. 7. Mucous membrane pemphigoid can present as dif-
fusely erythematous gingiva. Collapsed vesicles and bulla
may also be seen with careful inspection.
Fig. 6. Extensive involvement of the palatal gingiva is also
a common nding in primary herpetic gingivostomatitis.
219
Periodontal manifestations of systemic diseases
ulceration. Patient discomfort frequently results in
discontinuation of routine oral hygiene, leading to
a build-up of plaque and consequent worsening of
the condition (70). A key point in the diagnosis is the
identication of collapsed vesicles or bullae,
although it is rare to see these intact since trauma
commonly induces rupture.
Mucous membrane pemphigoid can also affect
other mucosal surfaces suchas the conjunctiva produ-
cing erythema and ulceration (Fig. 9). Conjunctival
scarring leads toinversionof the eyelashes (entropion)
that abrade the cornea, thereby compromising vision.
Other mucosal sites affected include the pharynx and
genital region. About 10% of patients with mucous
membrane pemphigoid also have skin lesions.
The diagnosis of mucous membrane pemphigoid
is established by biopsy showing separation of the
epithelium and connective tissue at the level of the
basement membrane (Fig. 10). Areas of ulceration
are not diagnostic and are not suitable for histologic
examination. Therefore, intact or collapsed vesicles
or an area adjacent to ulceration are preferable sites
to biopsy. Direct immunouorescence, showing lin-
ear deposits of IgG and complement along the base-
ment membrane region, is often necessary to
establish or conrm the diagnosis (Fig. 11). Indirect
immunouorescence studies of serum are usually
negative and are not often performed (19).
Mucous membrane pemphigoid is treated using
topical and systemic steroids often in combination.
Other medications that have been used to control the
disease include sulfapyridine, sulfones, antibiotics,
gold injections and nutritional supplements (70).
Linear IgA disease
Figure 12 shows a female patient presenting for
assessment of erythematous lesions affecting the
Fig. 8. A collapsed bulla is present on the attached gingiva
of this patient with mucous membrane pemphigoid.
Trauma frequently leads to rupture of the bulla contents.
Fig. 10. Biopsy of mucous membrane pemphigoid shows
characteristic separation of the epithelium from the
underlying connective tissue at the level of the basement
membrane.
Fig. 11. Immunofluorescence study of an oral lesion from
a patient with mucous membrane pemphigoid shows
deposits of IgG at the epithelial-mesenchymal interface
(yellow line) (courtesy of Dr. T. Daniels, UCSF).
Fig. 9. Patients with ocular involvement in mucous mem-
brane pemphigoid may show marked conjunctivitis. If left
untreated, there may be scarring of leading to inversion of
the eyelash and abrasion of the cornea.
220
Jordan
mucogingival junction of the maxillary tissues. Her
oral hygiene was good and she was otherwise well. A
biopsy was performed that showed separation of the
epithelium from the underlying connective tissue at
the level of the basement membrane and, by immu-
nouorescence examination, linear deposits of IgA at
the epithelialmesenchymal interface.
Linear IgA disease is a chronic mucocutaneous
disease of the skin that also affects the oral mucosa
and gingiva. Similar to dermatitis herpetiformis this
condition is also characterized by deposits of IgA in
the tissues but is not associated with gluten-sensitive
enteropathy (33). Linear IgA disease resembles
mucous membrane pemphigoid both clinically and
histologically. The oral lesions are erythematous and
ulcerative; when involving the gingiva, lesions are
seen in all four quadrants (14). Microscopically, there
is separation of the epithelium from the connective
tissue at the level of the basement membrane
(Fig. 13). By direct immunouorescence, linear
deposits of IgA are seen along the basement mem-
brane with the target a 120 kDa protein (11). Linear
IgA disease is treated in a manner similar to mucous
membrane pemphigoid using topical and systemic
steroids. Cyclosporine has also proven effective in
the management of the disease but, unlike dermatitis
herpetiformis, linear IgA disease usually shows a
poor response to dapsone (44, 76).
Pemphigus vulgaris
Pemphigus comprises a group of autoimmune, vesi-
culobullous disorders characterized by involvement
of the skin, mouth and other mucous membrane
sites. Four main types are recognized: pemphigus
vulgaris, pemphigus foliaceous, pemphigus erythe-
matosus and pemphigus vegetans. They differ in
the level of intraepithelial involvement. Pemphigus
vulgaris and pemphigus vegetans affect the supraba-
sal and prickle layers while pemphigus foliaceous
and pemphigus erythematosus affect the upper
prickle cell and keratin layers. Only pemphigus vul-
garis and pemphigus vegetans involve the oral
mucosa (74). Pemphigus vegetans is very rare and
is generally considered a variant of pemphigus vul-
garis. All forms of pemphigus arise because patients
have circulating immunoglobulin directed against
desmosomes of skin and mucous membranes. The
target antigen is desmoglein 3, a protein in the des-
mosome-tonolament complex (29). The antibody
binding to these sites activates complement and
plasminogen activator, resulting in acantholysis,
vesicle formation, erosion and ulceration.
The clinical features of pemphigus vulgaris are
nonspecic with areas of erosion at any mucosal site,
although nonkeratinized sites appear to be affected
most often. When the lesions involve the gingiva,
there is erythema, vesiculation and ulceration
(Fig. 14)(20). Skin lesions may or may not be present.
Pemphigus vulgaris is usually a disease of older peo-
ple, with women being more affected than men. The
oral mucosa is involved initially in about 50% of
cases of pemphigus vulgaris and, indeed, oral invol-
vement often precedes involvement at other sites.
Because the condition is life threatening without
treatment, it is important to conrm clinical suspi-
cion of the disease by histologic and immunologic
investigations at an early stage (74).
The diagnosis is made by biopsy of an intact or
recently ruptured vesicle or bulla (Fig. 15). Tissue
Fig. 12. Linear IgA disease often has a clinical presenta-
tion similar to mucous membrane pemphigoid. Here there
is bilateral, band-like inflammation of the maxillary
gingiva and alveolar mucosa.
Fig. 13. Biopsy of linear IgA disease shows separation of
the epithelium from the underlying connective tissue at
the level of the basement membrane. There is inflamma-
tion in the connective tissues with inflammatory cells and
extravasated red blood cells present in the cleft.
221
Periodontal manifestations of systemic diseases
should be sent for both routine histopathology and
direct immunouorescence. A blood sample should
be sent for indirect immunouorescence, which will
demonstrate circulating autoantibody (IgG) (19). The
titer of circulating antibody is important since it
reects the degree of disease activity and can be used
to monitor the effectiveness of immunosuppression
therapy.
Pemphigus vulgaris is managed with systemic cor-
ticosteroids, often taken for prolonged periods. Topi-
cal corticosteroids are also used for oral lesions in
conjunction with systemic therapy since they often
show poor response to the systemic route (58). Once
control is achieved and no new lesions develop, then
the dose of steroids is reduced to a maintenance
level. Drugs such as azathioprine or cyclophospha-
mide have an important role in management as they
allow the dose of steroid to be reduced (61). Because
pemphigus is a lifelong disease, corticosteroid ther-
apy can be reduced but usually never discontinued.
Occasionally, complications of long-term steroid
therapy, such as cataracts, diabetes and duodenal
ulcers, can develop and these need appropriate
investigation and treatment.
Leukemia
Figure 16 shows the clinical presentation of a patient
with diffusely hyperplastic and erythematous gingiva
that bled easily. She had been unwell prior to pre-
sentation suffering lethargy and fatigue. Biopsy of the
gingiva showed sheets of atypical myeloid cells con-
sistent with a diagnosis of chronic myeloid leukemia.
This diagnosis was conrmed by bone marrow
biopsy showing similar features.
Leukemias encompass a group of disorders char-
acterized by neoplastic proliferation of bone marrow
lymphocyte or myeloid precursors that replace the
marrow and can be identied in the peripheral
blood. Neoplastic cells can also inltrate other
organs such as the liver, spleen, lymph nodes and
other tissues (50). A number of different causes have
been attributed to the development of specic forms
of leukemia, including genetic factors, specic chro-
mosome translocations in chronic myeloid leukemia
and environmental agents such as benzene, ionizing
radiation and viruses such as HTLV1 in adult T-cell
leukemia (12, 15, 46).
Leukemias are classied based on the type of pro-
genitor cell (myeloid or lymphoid lineage) and the
clinical presentation (acute or chronic). Acute leuke-
mias are characterized by the presence of immature
cells and a fulminant clinical course and chronic
Fig. 14. Pemphigus vulgaris often presents first in the
mouth. Here there is a collapsed bulla affecting the upper
labial mucosa. It is uncommon to see intact vesicles or
bullae in pemphigus vulgaris.
Fig. 16. Markedly and diffusely hyperplastic gingiva in a
patient who was shown to have chronic myelogenous
leukemia.
Fig. 15. Biopsy of a gingival lesion from a patient with
pemphigus vulgaris shows separation within the epithe-
lium (acantholysis) with free-floating epithelial cells in the
cleft.
222
Jordan
leukemias are characterized by the presence of better
differentiated, mature cells and a more indolent clin-
ical course. Chronic leukemias of the myeloid lineage
are the most common form to inltrate the gingiva
causing edema and erythema. The gingivae are red,
boggy, edematous, and bleed easily. Sometimes this
may be the initial presenting feature of chronic mye-
loid leukemia. The gingival appearance is due to
inltration by neoplastic myeloid cells and is initially
out of proportion to the amount plaque that is pre-
sent.
The diagnosis of leukemia is made by biopsy show-
ing sheets of neoplastic, immature myeloid cells
(Fig. 17). Histochemistry showing chloroacetate
esterase expression and immunohistochemistry to
demonstrate myeloid lineage will assist making the
diagnosis. Bone marrow biopsy will conrm the diag-
nosis and is used to type the disease (28, 37).
Chemotherapy is used to manage all forms of leu-
kemia (30). Some acute leukemias show good
response to treatment and cures can be expected
while others such as chronic lymphocytic leukemia
are essentially incurable but characterized by a pro-
tracted clinical course (23).
Wegener's granulomatosis
Wegener's granulomatosis is an inammatory con-
dition of unknown etiology. The classical clinical
triad consists of necrotizing granulomatous vasculitis
in the upper respiratory tract, lung and kidney; how-
ever, most often patients present with only two of the
three sites of involvement. Patients with Wegener's
granulomatosis present with sinusitis, rhinitis, nasal
stufness, epistaxis, hemoptysis, and hematuria (10).
Ulceration of the maxilla is common, as is perfora-
tion of the hard palate in the midline (36). The
gingivae appear hyperplastic, red and granular with
a generalized, uniform distribution (Fig. 18). This
appearance has been likened to a ``strawberry stuck
on the gums'' (49).
The diagnosis of Wegener's granulomatosis is
made by biopsy showing necrotizing vasculitis and
granulomatous inammation. Serologic demonstra-
tion of antineutrophil cytoplasmic antibodies is posi-
tive in over 90% of patients with active disease and
helpful to establish the diagnosis. This assay is also
used to monitor disease response to therapy (9). Prior
to the introduction of chemotherapy Wegener's
granulomatosis had a uniformly poor prognosis.
Wegener's granulomatosis is now managed with
the cytotoxic agent cyclophosphamide supplemen-
ted with prednisone. Remission can be expected in
about 75% of cases (1, 51).
Systemic diseases that mimic
periodontitis
Tuberculosis
Tuberculosis is caused by the aerobic bacillus Myco-
bacterium tuberculosis. Tuberculosis is one of the
most common infectious diseases and is particularly
common in the developing world. Spread of the
infection is favored by poor living conditions, low
socioeconomic status, low native resistance, and
compromised immunity.
Tuberculosis is spread by infected aerosol droplets
to the lungs where the organism is engulfed by
macrophages, leading to a characteristic granuloma-
tous reaction. The infection may lay dormant in the
lungs or spread to regional lymph nodes. Clinically,
the lesions occur mainly in the lung, usually in the
Fig. 17. Gingival biopsy of a patient with chronic myelo-
genous leukemia shows a diffuse infiltrate of immature
myeloid cells.
Fig. 18. The oral presentation of Wegener's granulomatosis
shows hyperplastic, erythematous gingivaethat bleedeasily.
223
Periodontal manifestations of systemic diseases
upper lobes. Lesions can occur in other sites by
implantation of infected sputum (47). Within the
mouth, any mucosal site may be involved, including
the gingiva. Here, the appearance is nonspecic,
showing ulceration and bone destruction (3, 42).
The diagnosis of tuberculosis is established by
biopsy since the clinical features are nonspecic,
resemblingother ulcerativeconditions suchas neopla-
sia. On histology, there are well-formed granulomata,
necrosis and Langhans-type giant cells (Fig. 19). His-
tochemical staining will demonstrate acid-fast bacilli
contained within the granulomata (13).
Tuberculosis is managed with an antibiotic regi-
men consisting of combinations of isoniazid, rifam-
pin, streptomycin and ethambutol with treatment
times typically prolonged amounting to several
months or a year (2).
Deep fungal infections
Figure 20 shows a male patient who presented with a
painless gingival ulceration of several weeks' dura-
tion. It had been unresponsive to local plaque control
procedures. He also had a cough and recent weight
loss. Gingival biopsy showed granulomatous inam-
mation and giant cells containing organisms consis-
tent with histoplasmosis.
Deep fungal infections are caused by a group of
organisms that typically infect the lungs but may also
produce secondary lesions elsewhere including the
gingiva. This group includes the diseases histoplas-
mosis, coccidiodomycosis, blastomycosis and cryp-
tococcosis. Histoplasmosis is endemic in the Eastern
United States and acquired by inhalation of dried
pigeon droppings (22). Coccidiodomycosis is also
endemic in the Western United States, particularly
the San Joaquin Valley of California, where it
is known locally as ``valley fever''. Blastomycosis is
also seen in North America particularly in the Ohio-
Mississippi river basin (63). Cryptococcosis has a
widespread distribution and is acquired by inhala-
tion of avian excrement.
The initial lesions of these deep fungal infections
occur in the lungs. Symptoms include cough, fever,
night sweats, weight loss, and chest pain. Oral infec-
tions typically follow implantation of infected spu-
tum from the lung. On the gingiva there are
ulcerative, indurated, and frequently painful bone-
destroying lesions that can be single or multiple.
Diagnosis is established by biopsy showing granulo-
matous inammation and demonstration of the
organism using histochemical stains (Fig. 21). Cul-
ture and serologic testing do not play a signicant
role in the diagnosis of these diseases (22, 63).
Treatment consists of the antifungal medication
uconazole, ketoconazole or amphotericin B. The
Fig. 20. A solitary ulcer causing bone loss around a
mandibular tooth in this patient with biopsy-proven
histoplasmosis.
Fig. 19. Biopsy of a patient with oral tuberculosis lesions
shows caseating granulomas with Langhans-type giant
cells.
Fig. 21. A silver stained (GMS) biopsy of histoplasmosis
show small round organisms (black) surrounded by
inflammatory cells (green).
224
Jordan
choice depends on the clinical setting, severity of
infection and prior antifungal use.
Metastatic carcinoma
Figure 22 shows a gingival mass from a patient
known to have esophageal carcinoma. The mass
was not painful and had been growing for several
weeks. Biopsy showed carcinoma consistent with
an esophageal primary.
In terms of frequency, the most common malig-
nancy of the skeleton is metastatic carcinoma.
Approximately 1% of all malignancies metastasize
to the jaws with 80% of these to the mandible, about
15% to the maxilla and 5% to both jaws (77). Meta-
static tumors can also metastasize to the gingiva,
producing a gingival mass, or it may mimic period-
ontal disease. In adults the most common metastatic
malignancies to the jaws are breast carcinoma in
women and lung carcinoma in men (53). In children,
neuroblastoma and osteosarcoma are the most com-
mon tumors to metastasize to the jaws (21). In about
30% of cases a jaw metastasis will be the rst sign of
the primary malignancy.
The most common sites in the jaws for metastatic
tumors are the premolarmolar areas and the angle
and body of the mandible. Bone pain, loosening of
the teeth, paresthesia, swelling and gingival mass are
the most common presenting features (26). Radio-
graphically, there is a poorly demarcated, irregular,
expansile radiolucency with a moth-eaten periphery.
However, some tumors such as prostatic and thyroid
carcinomas are often osteoblastic.
The diagnosis is established by biopsy showing
metastatic tumor. If the primary is not recogniz-
able by histology alone, immunohistochemistry is
often necessary to establish the diagnosis. Solitary
metastatic deposits are managed with surgery and
or chemoradiotherapy. Jaw deposits that represent
generalized metastases are managed with palliation.
Overall, metastasis is a poor prognostic sign asso-
ciated with a 10% 5-year survival rate (53).
Langerhans cell disease
Figure 23 shows a female patient who presented with
hyperplastic gingiva and periodontal bone loss of
several weeks' duration. The condition was unre-
sponsive to local plaque control procedures. A
panoramic radiograph showed extensive bone loss
around the roots of the teeth, prompting biopsy,
which showed sheets of Langerhans cells mixed with
eosinophils consistent with a diagnosis of Langer-
hans cell disease. A skeletal survey failed to identify
any other lesions and she was then treated with local
radiotherapy.
Langerhans cell disease, formerly known as histio-
cytosis X, represents a proliferation of antigen- pre-
senting Langerhans cells. There is spectrum of
behavior from localized, relatively indolent, intra-
osseous disease to widespread, fulminant disease of
theskinandorgans resemblingneoplasia. The etiology
of Langerhans cell disease is unknown. The acute dis-
seminated form may represent overt neoplasia but
less disseminated forms may represent an immune
response to an unknown antigenic challenge (40).
Classically, there are three distinct types of Langer-
hans cell disease. Chronic localized Langerhans cell
disease, or eosinophilic granuloma, produces single
or multiple bone lesions only. Chronic disseminated,
or HandSchullerChristian, disease consists of a clas-
sical triad of lytic bone lesions, exophthalmos, and
diabetes insipidus. Acute disseminated Langerhans
cell disease, or LettererSiwe disease, is characterized
Fig. 22. Esophageal carcinoma metastatic to the mandib-
ular gingiva.
Fig. 23. The clinical presentation of a patient with
Langerhans cell disease showing hyperplastic and erythe-
matous gingiva.
225
Periodontal manifestations of systemic diseases
by a fulminant, rapidly progressive usually fatal
course with widespread inltration of the skin, bones
and organs. Typically, neonates and infants are
aficted (38).
In general, Langerhans cell disease is a disease of
children and young adults. Males are slightly more
often affected than females. Any bone can be
involved including the skull, mandible, maxilla, ribs,
vertebrae and the long bones (55). Involvement of the
jaws consists of single or multiple radiolucencies
with sharply dened borders producing a punched-
out appearance. Most often lesions are located at the
apices of teeth, producing the appearance of teeth
``oating in air'' (Fig. 24)(16). Teeth become loose in
the affected area and there may be pain, tenderness
and swelling. The gingival tissue is frequently
inamed, hyperplastic and ulcerated.
Diagnosis is made by biopsy showing sheets of
Langerhans cells intermixed with eosinophils. Imm-
unohistochemical staining will show expression of
CD1a and S100 antigens by the Langerhans cells (32).
Treatment varies depending on the extent of the
disease and site. For small, well localized chronic
Langerhans cell disease surgical excision may be an
option but, more commonly, low-dose radiation
therapy is used. Chemotherapy is reserved for more
extensive disease or for those with acute dissemi-
nated forms. Cure rates vary and depend on the
extent and type of Langerhans cell disease (39).
Papillon-Lefevre syndrome
Papillon-Lefevre syndrome is a hereditary disorder
transmitted in an autosomal recessive manner. The
predominant clinical manifestations are palmar and
plantar keratosis coupled with rapid periodontal dis-
ease (57). Patients show an immunologic decit
related to altered or impaired neutrophil function
that is the result of mutation in the cathepsin C gene
located on chromosome 11q14 (68). The prevalence
of Papillon-Lefevre syndrome is about 14 per mil-
lion in the general population.
The dermatologic manifestations consisting of pal-
mar and plantar keratosis appear in the rst 3 years
of life. Other sites that can be involved include the
legs, thigh, toes, and ngers. Dramatic, advanced
periodontitis affecting both the primary and perma-
nent dentition is also characteristic. The gingiva
appear hemorrhagic and hyperplastic with loss of
bone and tooth exfoliation (7). The diagnosis of
Papillon-Lefevre syndrome is made by history and
clinical ndings. Biopsy of gingival tissues is nonspe-
cic, showing acute and chronic inammation with
granulation tissue.
Retinoids are used to treat the skin lesions (45).
Treatment of the periodontal disease is often dif-
cult, with poor success. Most patients with Papillon-
Lefevre syndrome show rapidly progressing period-
ontal disease and eventually lose their teeth (24).
Scrupulous oral hygiene coupled with topical anti-
septic mouthrinses and antibiotic prophylaxis for
Actinobacillus actinomycetemcomitans can slow the
pace of periodontal destruction but it may not be a
cure (73).
Hypophosphastasia
Hypophosphastasia is a rare, hereditary condition
transmitted in an autosomal recessive manner that
produces a deciency of tissue-nonspecic alkaline
phosphatase. Over 60 different mutations of the alka-
line phosphatase gene have been described in associ-
ation with this disease (31, 48). Alkaline phosphatase
is thought to play a role in the production of bone but
its mechanism of action is unknown (71).
Four types of hypophosphatasia are recognized,
depending on the time of onset and severity of symp-
toms (62). The perinatal form is congenital and
invariably fatal due to respiratory failure. The infan-
tile form appears within 6 months of life and is asso-
ciated with 50% morbidity. Infants so affected show
vomiting and hypotonia. Skeletal manifestations that
resemble rickets are common, as are nephrocalcino-
sis and nephrolithiasis. If these infants survive, there
is premature shedding of the primary teeth. The
childhood form is detected within 624 months of
age and has a range of severity. The most consistent
feature is premature loss of the primary teeth, which
have enlarged dental pulps. The cementum is hypo-
plastic or aplastic and there is frequently hypoplasia
Fig. 24. Radiographic changes in a patient with Langer-
hans cell disease showing punched-out radiolucencies
surrounding the roots of the mandibular teeth. Biopsy of
one of these lesions confirmed the diagnosis.
226
Jordan
of the enamel. There is alveolar bone loss, especially
in the anterior mandible and maxilla. Long bones
also show inadequate mineralization and suffer
stress fractures. The adult form is rare, occurring in
late adolescence and adulthood, and has a mild pre-
sentation. There is premature loss of the primary or
permanent teeth. Stress fractures are also common,
particularly following relatively minor trauma (54).
The diagnosis of hypophosphatasia is made based
on the clinical ndings coupled with the demonstra-
tion of reduced levels of serum alkaline phosphatase
and increased levels of phosphoethanolamine in the
urine and blood (72). Since there is no therapeutic
means to replace the alkaline phosphatase, treat-
ment is essentially symptomatic. The prognosis var-
ies by the onset of symptoms and type of the disease.
Patients with both childhood and adult forms have a
normal life span.
Cyclic neutropenia
Neutropenia is dened as an absolute reduction in
circulating neutrophils. Prolonged or persistent neu-
tropenia is associated with leukemia, certain blood
dyscrasias, many drugs and radiation or chemother-
apy. Cyclic neutropenia is a rare disorder character-
ized by a severe, cyclical depression of neutrophils
from the blood and bone marrow. Mean periodicity
is about 21 days (17). Recent genetic, molecular, and
cellular studies have shown that autosomal-dominant
cyclic neutropenia and sporadic cases are due to a
mutation in the gene for neutrophil elastase (ELA2),
located at chromosome 19p13.3. This enzyme is
synthesized in neutrophil precursors early in the pro-
cess of primary granule formation (4, 18).
During episodes of cyclic neutropenia there is
fever, malaise, cervical lymphadenopathy, infections,
and oral ulcers. Mouth ulcerations are common on
nonkeratinized surfaces and may appear as single or
multiple discrete lesions. Patients are often prone to
severe periodontal disease (52).
The diagnosis is established by examination of the
peripheral blood differential showing a reduction in
circulating neutrophils during episodes of oral
ulceration. Usually, it is necessary to sample the
blood sequentially over several days to document a
drop in circulating neutrophils. The neutrophil count
should be less than 500/mm
3
for 35 days during
each of three successive cycles to establish the diag-
nosis (17).
There is no specic management for the condition.
Medical investigations may be needed to rule out
other causes of neutropenia (41). During episodes
of neutropenia, antibiotics may be given to prevent
oral infection. Scrupulous oral hygiene is needed to
minimize periodontal disease (59).
Summary
Many systemic diseases can mimic periodontitis or
gingivitis. These include many immunologic, infec-
tious, neoplastic and metabolic disorders. In com-
parison with periodontitis and gingivitis, these
disorders are considerably less common. However,
since their diagnosis and management differ, a high
index of suspicion is frequently needed when con-
fronted a patient presenting with gingival or period-
ontal disease. This chapter has reviewed a number
of systemic conditions that may mimic clinically
both gingivitis and chronic periodontitis and has
focused on the features that may assist the clinician
in making the diagnosis and providing specic thera-
pies.
References
1. Aasard K, Iversen BM, Hammerstrm J, Bostad L, Vatten L,
Jrstad S. Wegener's granulomatosis: clinical course in 108
patients with renal involvement. Nephrol Dial Transplant
2000: 15: 611618.
2. Agrawal S, Thomas NS, Dhanikula AB, Kaul CL, Panchagnu-
la R. Antituberculosis drugs and new drug development.
Curr Opin Pulm Med 2001: 7: 142147.
3. de Aguiar MC, Arrais MJ, Mato MJ, de Araujo VC. Tubercu-
losis of the oral cavity: a case report. Quintessence Int 1997:
28: 745747.
4. Aprikyan AAG, Dale DC. Mutations in the neutrophil elas-
tase gene in cyclic and congenital neutropenia. Curr Opin
Immunol 2001: 13: 535538.
5. Bagan-Sebastian JV, Milian-Masanet MA, Penarrocha-Diago
M, Jimenez Y. A clinical study of 205 patients with oral
lichen planus. J Oral Maxillofac Surg 1992: 50: 116118.
6. Bernard P, Prost C, Durepaire N, Basset-Seguin N, Didier-
jean L, Saurat J-H. The major cicatricial pemphigoid antigen
is a 180-kD protein that shows immunologic cross-reactiv-
ities with the bullous pemphigoid antigen. J Invest Dermatol
1992: 99: 174179.
7. Bimstein E, Lustmann J, Sela MN, Neriah ZB, Soskolne WA.
Periodontitis associated with Papillon-Lefevre syndrome.
J Periodontol 1990: 61: 373377.
8. Birt D, From L, Main J. Oral manifestations of herpes sim-
plex virus infections. Laryngoscope 1977: 87: 872878.
9. Borges A, Fink J, Villablanca P, Eversole R, Lufkin R. Midline
destructive lesions of the sinonasal tract: simplified termi-
nology based on histopathologic criteria. Am J Neuroradiol
2000: 21: 331336.
10. Burlacoff SG, Wong FSH. Wegener's granulomatosis. The
great masquerade: a clinical presentation and literature re-
view. J Otolaryngol 1993: 22: 94105.
227
Periodontal manifestations of systemic diseases
11. Chan LS, Regezi JA, Cooper KD. Oral manifestations of
linear IgA disease. J Am Acad Dermatol 1990: 22: 362365.
12. Clarkson BD, Strife A, Wisniewski D, Lambek C, Carpino N.
New understanding of the pathogenesis of CML: a prototype
of early neoplasia. Leukemia 1997: 11: 14041428.
13. Cleary KR, Batsakis JG. Mycobacterial disease of the head
and neck: current perspective. Ann Otol Rhinol Laryngol
1995: 104: 830833.
14. Cohen DM, Bhattacharyya I, Zunt SL, Tomich CE. Linear
IgA disease histopathologically and clinically masquerading
as lichen planus. Oral Surg Oral Med Oral Pathol Oral Radi-
ol Endod 1999: 88: 196201.
15. Cremin P, Flattery M, McCann SR, Daly PA. Myelodysplasia
and acute myeloid leukaemia following adjuvant che-
motherapy for breast cancer using mitoxantrone and meth-
otrexate with or without mitomycin. Ann Oncol 1996: 7:
745746.
16. Dagenais M, Pharoah MJ, Sikorski PA. The radiographic
characteristics of histiocytosis X. A study of 29 cases that
involve the jaws. Oral Surg Oral Med Oral Pathol 1992: 74:
230236.
17. Dale DC, Hammond WP. Cyclic neutropenia: a clinical re-
view. Blood Rev 1988: 2: 178185.
18. Dale DC, Bolyard AA, Aprikyan A. Cyclic neutropenia. Semin
Hematol 2002: 39: 8994.
19. Daniels TE, Quadra-White C. Direct immunofluorescence in
oral mucosal disease: a diagnostic analysis of 130 cases. Oral
Surg Oral Med Oral Pathol 1981: 51: 3847.
20. Davenport S, Chen SY, Miller AS. Pemphigus vulgaris: clin-
icopathologic review of 33 cases in the oral cavity. Int J
Periodontics Restorative Dent 2001: 21: 8590.
21. DeLeon EL, Finney RA, Ruth A, Sullivan JE. Neuroblastoma
with metastasis to maxilla and mandible: review of literature
and report of case. J Oral Surg 1970: 28: 773780.
22. Dobleman TJ, Scher N, Goldman M, Doot S. Invasive his-
toplasmosis of the mandible. Head Neck 1989: 11: 8184.
23. Druker BJ. Current treatment approaches for chronic mye-
logenous leukemia. Cancer J 2001: 7 (Suppl 1): S14S18.
24. Eickholz P, Kugel B, Pohl S, Naher H, Staehle HJ. Combined
mechanical and antibiotic periodontal therapy in a case of
Papillon-Lefevre syndrome. J Periodontol 2001: 72: 542549.
25. Eisen D, Ellis CN, Duell EA, Griffiths CEM, Voorhees JJ.
Effect of topical cyclosporine rinse on oral lichen planus.
A double-blind analysis. N Engl J Med 1990: 323: 290294.
26. Ellis GL, Jensen JL, Reingold IM, Barr RJ. Malignant neo-
plasms metastatic to gingivae. Oral Surg Oral Med Oral
Pathol 1977: 44: 238245.
27. Gandolfo S, Carbone M, Carrozzo M, Gallo V. Oral lichen
planus and hepatitis C virus (HCV) infection: is there a
relationship? A report of 10 cases. J Oral Pathol Med 1994:
23: 119122.
28. Glassman AB. Cytogenetics, in situ hybridization and mo-
lecular approaches in the diagnosis of cancer. Ann Clin Lab
Sci 1998: 28: 324330.
29. Hashimoto T, Ogawa MM, Konohana A, Nishikawa T. De-
tection of pemphigus vulgaris and pemphigus foliaceus
antigens by immunoblot analysis using different antigen
sources. J Invest Dermatol 1990: 94: 327331.
30. Hehlmann R, Hochhaus A, Berger U, Reiter A. Current
trends in the management of chronic myelogenous leuke-
mia. Ann Hematol 2000: 79: 345354.
31. Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte
MP. Different missense mutations at the tissue-nonspecific
alkaline phosphatase gene locus in autosomal recessively
inherited forms of mild and severe hypophosphatasia. Proc
Natl Acad Sci USA 1992: 89: 99249928.
32. Herzog KM, Tubbs RR. Langerhans cell histiocytosis. Adv
Anat Pathol 1998: 5: 347358.
33. Hietanen J, Reunala T. IgA deposits in the oral mucosa of
patients with dermatitis herpetiformis and linear IgA dis-
ease. Scand J Dent Res 1984: 92: 230234.
34. Holmstrup P, Schiotz AW, Westergaard J. Effect of dental
plaque control on gingival lichen planus. Oral Surg Oral
Med Oral Pathol 1990: 69: 585590.
35. Jordan RC, Daniels TE, Greenspan JS, Regezi JA. Advanced
diagnostic methods in oral and maxillofacial pathology. Part
II: Immunohistochemical and immunofluorescent meth-
ods. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2002: 93: 5674.
36. Knecht K, Mishriki YY. More than a mouth ulcer. Oral ulcer
due to Wegener's granulomatosis. Postgrad Med 1999: 105
(May 1): 200, 203.
37. Kornblau SM, Goodacre A, Cabanillas F. Chromosomal ab-
normalities in adult non-endemic Burkitt's lymphoma and
leukemia: 22 new reports and a review of 148 cases from the
literature. Hematol Oncol 1991: 9: 6378.
38. Ladisch S. Langerhans cell histiocytosis. Curr Opin Hematol
1998: 5: 5458.
39. Ladisch S, Gadner H. Treatment of Langerhans cell histio-
cytosis evolution and current approaches. Br J Cancer
1994: 70 (Suppl XXIII): S41S46.
40. Lam K-Y. Langerhans cell histiocytosis (histiocytosis X).
Postgrad Med J 1997: 73: 391394.
41. Lange RD, Jones JB. Cyclic neutropenia. Review of clinical
manifestations and management. Am J Pediatr Hematol
Oncol 1981: 3: 363367.
42. Laskaris G. Oral manifestations of infectious diseases. Dent
Clin North Am 1996: 40: 395423.
43. Laurberg G, Geiger J-M, Hjorth N, Holm P, Hou-Jensen K,
Jacobsen KU, Nielsen AO, Pichard J, Serup J, Sparre-Jorgen-
sen A, Sorensen D, Thestrup-Pedersen K, Thomsen K, Unna
P, Urup J. Treatment of lichen planus with acitretin. A dou-
ble-blind, placebo-controlled study in 65 patients. J Am
Acad Dermatol 1991: 24: 434437.
44. Leonard JN, Haffenden GP, Ring NP, McMinn RMH, Sidg-
wick A, Mowbray JF, Unsworth DJ, Holborow EJ, Blenkin-
sopp WK, Swain AF, Fry L. Linear IgA disease in adults. Br J
Dermatol 1982: 107: 301316.
45. Lundgren T, Crossner C-G, Twetman S, Ullbro C. Systemic
retinoid medication and periodontal health in patients with
Papillon-Lefevre syndrome. J Clin Periodontol 1996: 23:
176179.
46. Metayer C, Lynch CF, Clarke EA, Glimelius B, Storm H,
Pukkala E, Joensuu T, van Leeuwen FE, van't Veer MB,
Curtis RE, Holowaty EJ, Andersson M, Wiklund T, Gospo-
darowicz M, Travis LB. Second cancers among long-term
survivors of Hodgkin's disease diagnosed in childhood and
adolescence. J Clin Oncol 2000: 18: 24352443.
47. Milburn HJ. Primary tuberculosis. Curr Opin Pulm Med
2001: 7: 133141.
48. Mornet E. Hypophosphatasia: The mutations in the tissue-
nonspecific alkaline phosphatase gene. Hum Mutat 2000:
15: 309315.
49. Napier SS, Allen JA, Irwin CR, McCluskey DR. 'Strawberry
gums' a case of Wegener's granulomatosis. Br Dent J 1993:
175: 327329.
228
Jordan
50. Neiman RS, Barcos M, Berard C, Bonner H, Mann R, Rydell
RE, Bennett JM. Granulocytic sarcoma: A clinicopathologic
study of 61 biopsied cases. Cancer 1981: 48: 14261437.
51. Novack SN, Pearson CM. Cyclophosphamide therapy
in Wegener's granulomatosis. N Engl J Med 1971: 284:
938942.
52. Okada M, Kobayashi M, Hino T, Kurihara H, Miura K. Clin-
ical periodontal findings and microflora profiles in children
with chronic neutropenia under supervised oral hygiene.
J Periodontol 2001: 72: 945952.
53. Piattelli A, Fioroni M, Rubini C. Gingival metastasis from a
prostate adenocarcinoma: report of a case. J Periodontol
1999: 70: 441444.
54. Plagmann H-C, Kocher T, Kuhrau N, Caliebe A. Periodontal
manifestation of hypophosphatasia. A family case report.
J Clin Periodontol 1994: 21: 710716.
55. Rapidis AD, Langdon JD, Harvey PW, Patel MF. Histiocyto-
sis X. An analysis of 50 cases. Int J Oral Surg 1978: 7: 7684.
56. Regezi JA, Deegan MJ, Hayward JR. Lichen planus: immu-
nologic and morphologic identification of the submucosal
infiltrate. Oral Surg Oral Med Oral Pathol 1978: 46: 4452.
57. Reyes VO, King-Ismael D, Abad-Venida L. Papillon-Lefevre
syndrome. Int J Dermatol 1998: 37: 268270.
58. Robinson JC, Lozada-Nur F, Frieden I. Oral pemphigus vul-
garis: a review of the literature and a report on the manage-
ment of 12 cases. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1997: 84: 349355.
59. Rylander H, Ericsson I. Manifestations and treatment of
periodontal disease in a patient suffering from cyclic neu-
tropenia. J Clin Periodontol 1981: 8: 7787.
60. Scully C, El Kom M. Lichen planus: review and update on
pathogenesis. J Oral Pathol 1985: 14: 431458.
61. Scully C, Paes De Almeida O, Porter SR, Gilkes JJH. Pem-
phigus vulgaris: the manifestations and long-term manage-
ment of 55 patients with oral lesions. Br J Dermatol 1999:
140: 8489.
62. Silve C. Hereditary hypophosphatasia and hyperphospha-
tasia. Curr Opin Rheumatol 1994: 6: 336339.
63. Sposto MR, Scully C, de Almeida OP, Jorge J, Graner E,
Bozzo L. Oral paracoccidioidomycosis. A study of 36 South
American patients. Oral Surg Oral Med Oral Pathol 1993: 75:
461465.
64. Steiner I. Human herpes viruses latent infection in the ner-
vous system. Immunol Rev 1996: 152: 157173.
65. Straus SE, Rooney JF, Sever JL, Seidlin M, Nusinoff-Lehrman
S, Cremer K. Herpes simplex virus infection: Biology, treat-
ment, and prevention. Ann Intern Med 1985: 103: 404419.
66. Sugerman PB, Rollason PA, Savage NW, Seymour GJ. Sup-
pressor cell function in oral lichen planus. J Dent Res 1992:
71: 19161919.
67. Sugerman PB, Savage NW, Walsh LJ, Seymour GJ. Disease
mechanisms in oral lichen planus. A possible role for auto-
immunity. Australasian J Dermatol 1993: 34: 6369.
68. Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench
N, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham
A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein
IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ,
Thakker NS. Loss-of-function mutations in the cathepsin
C gene result in periodontal disease and palmoplantar ker-
atosis. Nat Genet 1999: 23: 421424.
69. Vincent SD, Fotos PG, Baker KA, Williams TP. Oral lichen
planus: the clinical, historical, and therapeutic features of
100 cases. Oral Surg Oral Med Oral Pathol 1990: 70: 165171.
70. Vincent SD, Lilly GE, Baker KA. Clinical, historic, and ther-
apeutic features of cicatricial pemphigoid. A literature re-
view and open therapeutic trial with corticosteroids. Oral
Surg Oral Med Oral Pathol 1993: 76: 453459.
71. Whyte MP. Hypophosphatasia and the role of alkaline phos-
phatase in skeletal mineralization. Endocr Rev 1994: 15:
439461.
72. Whyte MP, Teitelbaum SL, Murphy WA, Bergfeld MA, Avioli
LV. Adult hypophosphatasia. Clinical, laboratory, and ge-
netic investigation of a large kindred with review of the
literature. Medicine 1979: 58: 329347.
73. Wiebe CB, Hakkinen L, Putnins EE, Walsh P, Larjava HS.
Successful periodontal maintenance of a case with Papillon-
Lefevre syndrome: 12-year follow-up and review of the lit-
erature. J Periodontol 2001: 72: 824830.
74. Williams DM. Vesiculobullous mucocutaneous disease:
pemphigus vulgaris. J Oral Pathol Med 1989: 18: 544553.
75. Williams DM. Vesiculo-bullous mucocutaneous disease: be-
nign mucous membrane and bullous pemphigoid. J Oral
Pathol Med 1990: 19: 1623.
76. Young HS, Coulson IH. Linear IgA disease: successful treat-
ment with cyclosporin. Br J Dermatol 2000: 143: 204205.
77. Zachariades N. Neoplasms metastatic to the mouth, jaws
and surrounding tissues. J Craniomaxillofac Surg 1989: 17:
283290.
229
Periodontal manifestations of systemic diseases