ARTICLE
Miescher's cheilitis granulomatosa is an idiopathic condition affecting
predominantly young adults. It occurs as a separate entity or, less often,
as one of the triad of signs comprising Melkersson-Rosenthal syndrome.
The complete triad of signs for Melkersson-Rosenthal syndrome consists
of recurrent orofacial swellling, one or more episodes of facial nerve
palsy, and lingua plicata [1, 2]. Most commonly involved sites are, in
order of frequency: upper lip, cheek, lower lip, nose, eyelids, and upper
alveolar process [3].
The cause of cheilitis granulomatosa is not known, however delayed-type
hypersensitivity to prosthetic materials [4], cobalt [5], food additives
[6], and focal and viral infections [4] have been discussed as initiating
factors.
We report a case of cheilitis granulomatosa associated with delayed
hypersensitivity to nickel and cobalt, chronic periodontitis and IgD myeloma.
The association of cheilitis granulomatosa with nickel hypersensitivity
and monoclonal protein has not been reported, and to our knowledge this
is also the first report of latent IgD myeloma.
Case report
A 58-year-old woman was referred to our department with a 2-year history
of an upper lip swelling that developed after dental work. At first it
partially subsided, but after recurrent attacks at irregular intervals
it became persistent.
She had had chronic nephritis about 40 years previously followed by
hypertension and intermittent proteinuria. She also had a 5-year history
of diabetes mellitus that has been well-controlled on diet, and urticaria
with no current urticarial wheals. Her family history was unremarkable.
The patient denied a history of facial nerve palsy or any minor signs
of Melkersson-Rosenthal syndrome, such as migraine-like headaches, tinnitus,
paroxysmal epiphora, rhinorrhea or visual disorders [7]. On examination,
there was diffuse, elastically soft swelling of the upper lip (Fig.
1) without accompanying enlargement of regional lymph nodes, and
there was no plicated tongue. Her general condition was good and, besides
the lip swelling, she had no other complaints.
Patch testing revealed nickel and cobalt hypersensitivity. However,
there were no clinical manifestations of nickel or cobalt contact dermatitis.
She was referred to a dentist and was treated for her chronic periodontitis
of the upper central incisor teeth.
Histological examination of a biopsy specimen from the upper lip revealed
mild acanthosis, focal mild exocytosis with lymphocytes in the tips of
the dermal papillae. From the subpapillary dermis extending to the deep
dermis there was marked edema and a patchy, perivascular, partially diffuse,
mild to moderate, dense infiltrate consisting predominantly of plasma
cells and lymphocytes (Fig. 2),
and also of mast cells (Giemsa stain), 20 per higher field. Serial sectioning
failed to disclose granulomatous infiltration. PAS and congo red stains
were negative and immunohistochemically, the plasma cells of the dermal
infiltrate were found to be polyclonal, consistent with a reactive process.
The diagnosis of cheilitis granulomatosa was
confirmed and the lip swelling resolved almost completely within about
six months under treatment with indomethacin, 100 mg a day.
Laboratory examinations showed a moderately increased ESR of 37 mm/h;
complete blood cell count, C-reactive protein, urea nitrogen, creatinine,
uric acid, electrolyte testing, including calcium, and liver function
tests, total protein and albumin were within normal limits.
Serum protein electrophoresis demonstrated a small spike of M-protein,
which was shown to be a monoclonal IgD with lambda light chains on immunoelectrophoresis.
Total IgD (normal < 8 mg/dl) was 403 mg/dl (February 1995) and after
an initial decrease to 355 mg/dl (April) showed a sustained increase to
448 mg/dl (August), followed by another decrease to the level of 413 mg/dl
(January 1996). IgG, IgM, IgA, CH50, C1-INH, C1q, C3 and C4, IgE, beta
2 microglobulin and IL-6 were normal. We found no circulating immune complexes,
rheumatoid factor or antinuclear antibodies. TPHA was negative. There
was cryoglobulinemia and proteinuria (mostly albumin). However, urine
immunoelectrophoresis and immunofixation were negative for Bence-Jones
protein.
The condition and laboratory findings of our patient remained stable
during the one-year follow-up at our department. Chest X-ray was within
normal limits and there were no bone lesions on a skeletal X-ray survey.
Abdominal CT showed bilateral renal cysts.
Bone marrow examination revealed plasmacytosis, 12.2% with significant
atypia (variable size of nuclei, increased N/C ratio, perinuclear clear
zones, 2-3 nucleoli in some cells and clear nucleoli with fine chromatin
in some cells). Immunohistochemical studies showed light chain restriction
(lambda > kappa) as well as heavy chain restriction (IgD >> IgA
>> IgG > IgM) and therefore evidence of a clonal plasma cell
population.
The diagnosis of IgD myeloma, latent type, was made and we referred
the patient to the department of internal medicine for further careful
monitoring and eventual initiation of therapy should overt, clinically
manifested myeloma develop.
Discussion
IgD myeloma is rare with an incidence of 1% and is usually of the lambda
type. The outstanding features are a high rate of renal involvement and
Bence-Jones proteinuria, and extraosseous manifestations are more frequent
than in other forms of myeloma [8, 9].
It usually follows a more aggressive course, but IgD myeloma is often
not diagnosed until later in its course [9]. M-protein level is frequently
low and there might be a very small or no spike on the serum electrophoresis
[10]. The detection of an IgD M-protein in the serum is generally indicative
of a malignant plasma cell proliferative disorder [11] and only about
two cases of IgD benign monoclonal gammopathy have so far been reported
[11, 12].
To our knowledge, this is the first report of IgD myeloma, which was
diagnosed in its asymptomatic, latent form.
The European diagnostic criteria for multiple myeloma include two or
more of the following: monoclonal serum immunoglobulin, lytic bone lesions,
and a clonal population of plasma cells in the bone marrow [13]. Patients
with latent myeloma satisfy M-protein and bone marrow criteria for multiple
myeloma [14]. Their "M" component is stable [8] and they may remain stable
for years without treatment. How-ever, their condition must be carefully
followed up for early detection of progression to overt myeloma [14].
Cheilitis granulomatosa arises as episodes of
recurrent angioedema eventually leading to permanent marked enlargement
of the lips [15]. Regional lymph nodes are enlarged in about 50% of cases
[16]. Histologically, we can see tuberculoid or sarcoid-like granulomas
or a lymphoid-plasma-cellular infiltrate [17], and as granulomatous changes
are not always present, their absence does not rule out the diagnosis
[1].
The differential diagnoses involving a swollen lip include angioedema,
hemangioma, lymphangioma, cheilitis granulomatosa, neurofibroma, hematoma,
dentoalveolar abscess, Ascher's syndrome, Anderson-Fabry disease, sarcoidosis,
Crohn's disease, granulomatous infection and leukemic infiltrate [18].
Cheilitis granulomatosa is difficult to treat and therapeutic efforts
are often unrewarded. In the initial stage and in severe cases systemic
corticosteroids are recommended, and in cases of longer duration of the
disease and permanent residual swelling, oral clofazimine can be tried
[16]. Intralesional triamcinolone injections are used either as a monotherapy
or as a prevention of recurrence after surgical cheiloplasty, and successful
treatment with acetylsalicylic acid, indomethacin, phenylbutazone, dapsone,
sulfasalazine, hydroxychloroquine, antimicrobial and immunosuppressive
drugs has been described [16].
The cause of the disease remains unknown. It has been postulated that
a vasomotor disturbance of both the vasa nervorum and the small arterioles
of the subcutaneous tissue occurs after a nonspecific stimulus producing
edema of the face and nerve [19].
It is considered to be a polyetiologic syndrome
under the influence of genetic factors, anatomical and functional vegetative
dysregulations as well as inflammatory, possibly infectious-allergic mechanisms
[4].
The association of monoclonal immunoglobulin and cheilitis granulomatosa
has not been reported and we conclude that the presence of M-protein may
have predisposed the patient to the development of edema by some unknown
mechanism.
It has been reported by Sussman et al. [20] that 9 of their 16
patients developed cheilitis granulomatosa after extensive dental work,
however, no consistent procedure or component was identified.
We suggest that the combination of focal odontogenic infection, namely
chronic periodontitis, with nickel and cobalt hypersensitivity may have
played a role in the pathogenesis of cheilitis granulomatosa in our patient,
as nickel-plated instruments are used in dental procedures and may become
a cause of allergic contact dermatitis and cheilitis in sensitive individuals
[21]. Moreover, there was both nickel and cobalt in her dentures, although
those which were in the direct contact with the upper lip had not been
present there until almost two years after the development of cheilitis
granulomatosa.
CONCLUSION
Acknowledgements
The authors are grateful to Dr. Kenji Miyake from the Second Department
of Pathology, Okayama University Medical School, for his helpful suggestions
and for performing the immunohistochemical studies.
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