ARTICLE
Necrobiotic xanthogranuloma (NXG) with paraproteinemia was first described
as a distinct clinical entity in 1980 by Kossard and Winkelmann [1]. Before
that, cases of atypical multicentric reticulohistiocytosis with paraproteinemia
[2], atypical xanthoma disseminatum [3] or atypical forms of necrobiosis
lipoidica diabeticorum [4], could be possible cases of NXG. Approximately
60 cases of NXG have been reported since then, most associated with Ig
G monoclonal gammopathy but with an unclear causal relationship.
Cutaneous lesions are typically yellow-red to violaceous nodules and
plaques, characteristically involving the periorbital area, face, trunk
and extremities.
We report a case of a patient with a long standing disease without extracutaneous
involvement, that responded positively to low-dose chlorambucil.
Case report
Disease presentation
A 51 year-old male white farmer had a 6-year history of multiple firm
violaceous papulonodules on the trunk and arms. The patient was otherwise
asymptomatic. Dermatological examination revealed about 20 red to violaceous
plaques (Fig. 1) in an asymmetric distribution, on the neck and
trunk (the biggest one at the right supraclavicular area, 12 cm long).
The smallest lesions were red-brown nodules on the limbs. Some plaques
showed a central yellow-red colour, with telangiectasias and xanthomatization.
A 0.8 cm diameter nodule was noted on the left inferior eyelid. Xanthelasma
on the eyelids and periferical nerve enlargement were also observed. The
rest of the physical examination was normal.
Cutaneous histopathological findings
Three cutaneous biopsies of different lesions were performed. A prominent
feature in all biopsy specimens was the presence of a histiocytic infiltrate
and aggregated epithelioid cells from the middle dermis through subcutis.
There were numerous multinucleated giant cells, which were frequently
of the Touton type, foam cells and atypical foreign body giant cells (Fig.
2). Two specimens contained focal areas of cholesterol clefts and
hyaline necrobiosis marginated from the surrounding granuloma (Fig.
3).
Laboratory findings
Laboratory examination revealed elevated sedimentation rate (119 mm/hr,
normal < 10 mm/hr) and B2 microglobulin (3,438 ng/ml, normal < 1,900
ng/ml); platelets and total white blood cell counts were below normal
(platelets = 123 x 103/µl; WCC = 3.30 x 103/µl;
differential count: 36.3% lymphocytes, 49% neutrophils); haemoglobin was
normal (14.1 g/dl); protein electrophoresis showed a monoclonal gammopathy
of the Ig G lambda type (Ig G = 3,160 mg/dl, normal 793-1,590 mg/dl).
Bence-Jones proteins were not recovered in urine. Iliac crest bone marrow
aspirate revealed a normocellular marrow with 4% plasma cells (76% of
which showed an abnormal imunophenotype: CD38+, CD 138+,
CD56+, CD19-) and bone marrow biopsy showed 5 to
10% lambda monoclonal plasma cells. Serum lipids (triglycerides = 112
mg/dl, normal 40-160 mg/dl; total cholesterol = 125 mg/dl, normal <
200 mg/dl), liver tests, creatinine and glucose tolerance test were normal.
There was cryoglobulinemia (372 mcg/ml, normal < 40 mcg/ml) Ig A, Ig
G and Ig M type, without monoclonality or rheumatoid factor activity.
The complement profile revealed subnormal levels of C1q (1 mg/dl, normal
12.4-19 mg/dl), C4 (3 mg/dl, normal 12-42 mg/dl) and CH50 (classic pathway
8.0 U/ml, normal >19.2 U/ml; alternative pathway 1.4 U/ml, normal >
2.8 U/ml), but elevation of C3d (1.140 mg/dl, normal < 0.55 mg/dl).
Levels of C3 (139 mg/dl, normal 81-167 mg/dl) and esterase inhibitor C1
(36.9 mg/dl, normal 31.9-38.5 mg/dl) were normal.
Extracutaneous disease study
Chest and skeletal x-ray films were normal; chest-abdominal-pelvic CT
scan showed homogeneous splenomegaly (150 mm), without other alterations.
Electrocardiogram and echocardiogram were normal. Clinical ophthalmological
examination did not reveal abnormalities.
Nerve biopsy showed a demyelinating neuropathy, without acid-fast bacilli
or granulomas.
Treatment
The patient was treated with low dose chlorambucil (2 mg/day) for 7
months, resulting in progressive flattening of the lesions (Fig. 4),
with eventual disappearance of all skin lesions. The paraprotein spike
has persisted unmodified during all the treatment and follow-up of the
patient. There was no complication with treatment, and no recurrence in
9 months of follow-up.
Discussion
Necrobiotic xanthogranuloma is characterized by peculiar clinical and
histopathological findings (Table I). It appears to have no sex
predilection and the average age of appearance is 56 years (range 17 to
85 years) [5]. Skin lesions usually occur on the head (frequently the
periorbital region), trunk and extremities. Early lesions are indurated
red to violaceous papules or nodules, that enlarge to plaques with a xanthomatous
color. Infiltrated plaques may show telangiectasias and central clearing
or atrophy, with ulceration [5]. The clinical appearance of the lesions
observed in our patient was very typical, but ulceration was not observed.
Typical history consists of a granulomatous dermal and subcutaneous
infiltrate with histiocytes, foam cells, Touton and foreign body giant
cells; a hyaline necrobiosis and cholesterol clefts [6]. All of these
findings were present in our case. In spite of typical histopathologic
features of NXG, Mehregan and Winkelmann recommend three biopsy specimens
from separate lesions in different locations [5].
Various reports have documented the association with extracutaneous
involvement including the eye (conjunctivitis, keratitis, scleritis, episcleritis,
iritis, uveitis, glaucoma, ptosis, ectropion, cataracts), upper respiratory
tract (presenting hoarseness or painful nodules), granulomatous infiltration
of the lung, skeletal muscle, kidney, hepatic and splenic granulomas,
necrobiotic lesions of the intestine, pelvic and retroperitoneal xanthogranuloma
lesions [5, 7]. Some authors have advised cardiac evaluation because of
the presence of myocardial NXG lesions in autopsies [7]. There was no
extracutaneous involvement in our case.
According to Mehregan and Winkelmann, 80% of patients with NXG tested
with protein electrophoresis were found to have paraproteinemia [5], 10%
of which had multiple myeloma [1], without an obvious correlation between
the severity of the hematological disease and the skin lesions [8]. Our
patient had paraproteinemia but did not have evidence of myeloma.
The demyelinating neuropathy documented by nerve biopsy was probably
also related to paraproteinemia.
Other associated laboratory abnormalities (Table I) have included:
elevated sedimentation rate, anaemia, leukopenia, abnormal glucose tolerance
test, cryoglobulinemia and hypocomplementemia (reduced CH50, C1q, C2,
C4 and C1 inhibitor). Lipids may be elevated, normal or reduced. Many
of these laboratory abnormalities were seen in our case.
The etiopathogenesis of NXG is unknown. Lipoprotein profile described
in the literature of NXG are quite distinct and their relationship to
XNG aetiology is not known. Our patient is normolipemic. Circulating immunoglobulins
may be complexed with lipids and deposit in the skin and produce a foreign-body
granulomatous reaction [9]. Complement abnormalities may contribute to
immune-complex formation [10]. More recently a new possible pathogenesis
of NXG was postulated: the activation of monocytes in vivo may
contribute to the intracellular accumulation of lipoprotein-derived lipids
and marked hypocholesterolemia [11].
Although there is no definitive specific therapy for NXG, alkylating
agents (such as chlorambucil or melphalan) with or without glucocorticoids
have been reported to induce remission of skin lesions. Resistant patients
or those with severe side effects from this treatment may be subjected
to other approaches [1] like plasmapheresis [12] or recombinant interferon
alfa 2 b [13] (Table I). Treatment with chlorambucil in our case
led to total remission of the skin lesions but his paraproteinemia remained
unmodified.
Article accepted on 26/3/01
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