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Regression of Urticaria Pigmentosa in Adult Patients With Systemic Mastocytosis
Correlation With Clinical Patterns of Disease
Knut Brockow, MD;
Linda M. Scott, MS, CRNP;
Alexandra S. Worobec, MD;
Arnold Kirshenbaum, MD;
Cem Akin, MD, PhD;
Mary M. Huber, RN;
Dean D. Metcalfe, MD
Arch Dermatol. 2002;138:785-790.
ABSTRACT
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Objective To determine clinical correlates of urticaria pigmentosa (UP) regression
in adult patients with systemic mastocytosis (SM).
Design Cohort study of the natural history of mastocytosis.
Setting National Institutes of Health Clinical Center.
Patients In a study of adult patients referred to the National Institutes of
Health after 1980 and observed for a minimum of 10 years, 12 of 106 adult
patients experienced clearance or fading of UP.
Main Outcome Measures Data from each patient's history and results of physical examination,
laboratory evaluation, and organ biopsy at presentation to the National Institutes
of Health were compared with findings at the patient's most recent visit.
Results In the patients in whom clearance of (n = 5) or a decrease in skin lesions
(n = 7) was noted, UP had persisted from 4 to 34 years (median, 17 years).
Older age was a prognostic feature for regression of UP. Despite improvement
of UP, the 2 patients with SM with an associated hematologic disorder experienced
a deterioration in clinical condition. In the 10 patients with indolent SM,
severity and frequency of symptoms decreased as the UP regressed. However,
bone marrow changes consistent with SM remained.
Conclusions Urticaria pigmentosa regresses in approximately 10% of the older patients
who have SM. In patients with an associated hematologic disorder such as myelodysplasia,
this regression may be accompanied by disease progression. In contrast, regression
of UP in patients with indolent SM parallels a decrease in disease intensity,
although bone marrow findings of indolent SM remain.
INTRODUCTION
URTICARIA pigmentosa (UP), characterized as hyperpigmented red-brown
macular or papular skin lesions, is the most common form of cutaneous mastocytosis.1 Urticaria pigmentosa may be associated with systemic
disease without or with an associated hematologic disorder, in which the disease
is termed indolent systemic mastocytosis (ISM) or systemic mastocytosis with an associated hematologic disorder (SMAHD), respectively.2 Although UP
in adults may persist indefinitely, it has been reported that from 7% to 19%
of adults may experience fading or resolution of their UP.3-5
The literature, however, is not clear on the clinical significance of the
fading or resolution of these dermal lesions. Horan and Austen5
reported that in patients with ISM, the fading or resolution of UP was not
accompanied by remission of systemic symptoms. Others, in writing of mastocytosis
in reviews,2 have stated that the resolution
of UP is a poor prognostic sign and that progressive bone marrow disease develops
in some of these patients.
To determine the significance of regression or resolution of UP, we
reviewed the records of 106 patients with adult-onset UP who had been followed
up at the National Institutes of Health (NIH), Bethesda, Md. We identified
12 patients within this group who had experienced regression or resolution
of UP. These events were then correlated with changes in symptoms and evolution
of bone marrow pathologic changes. As will be shown, changes in the intensity
of UP have a very different meaning in patients with ISM, compared with patients
with SM and an evolving myelodysplastic or myeloproliferative bone marrow
picture.
PATIENTS AND METHODS
PATIENTS
In a group of 106 patients with adult-onset UP followed up at the NIH
from January 1, 1980, through December 31, 2000, on an informed consent protocol,
we observed 12 patients (aged 47-72 years; median age, 65.5 years) in whom
total clearance or fading of skin lesions was noted over time. All 12 patients
had been followed up for at least 10 years or, in 2 cases, had died 7 or 2
years after the initial evaluation. The diagnosis of SM had been confirmed
by results of bone marrow biopsy in all cases.
METHODS
Clinical variables used to assess the disease activity included an evaluation
of findings on physical examination and of biopsies of bone marrow and skin
specimens. A history was obtained and a physical examination was performed
at every follow-up visit. Bone marrow biopsies (range, 2-8 per patient; median,
4) and other diagnostic studies were performed as medically indicated and
after informed consent was obtained, or as specified in the protocol. The
period from the first to the last bone marrow biopsy in a given patient ranged
from 1 to 16 years, with a median of 10 years. Bone marrow involvement consistent
with mastocytosis was defined as discrete foci or diffuse collections of mast
cells in the bone marrow specimen.2, 6
We compared the initial and the final extent of skin involvement and intensity
of erythema and papulation using the results of serial physical examinations
and evaluation of photographs. Total tryptase values in plasma were determined
by means of enzyme-linked immunosorbent assay. Ten patients underwent screening
for the presence of the activating Asp816Val mutation in Kit (the receptor
for stem cell factor) in peripheral blood mononuclear cells (PBMCs) by means
of analysis of the HinfI digestion products as described.
This mutation is known to correlate with the severity of adult-onset sporadic
mastocytosis.7
Symptomatic follow-up treatment for mastocytosis consisted of antihistamines
to block H1 and H2 receptors, nonsteroidal anti-inflammatory
drugs, aspirin, cromolyn sodium, and omeprazole. In 5 patients, oral prednisone
was given for treatment of malabsorption; 1 of these also required prednisone
concomitantly for treatment of rheumatoid arthritis. In 1 patient, interferon
alfa-2b therapy was started but discontinued after 17 months because of lack
of a beneficial effect.8
RESULTS
DEMOGRAPHICS
Twelve adult patients (7 women and 5 men) were identified who had experienced
regression or resolution of UP (Table 1). Ten patients had ISM, which excluded associated hematologic abnormalities,
aggressive mastocytosis, and mast cell leukemia.2, 9
Two patients (patients 11 and 12) had SMAHD. None of the patients had isolated
cutaneous involvement. The median age of onset of UP was 41.5 years. The duration
of UP at the initial presentation ranged from 1 to 19 years (median, 8 years)
in patients with ISM and was 1 or 2 years in patients with SMAHD.
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Table 1. Demographics of Patients With Mastocytosis Experiencing Regression
or Resolution of UP*
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INITIAL VISIT
Symptoms of mastocytosis at initial presentation are listed in Table 2. All patients presented with numerous
symmetrically distributed oval or round red-brown macules or slightly elevated
papules (Figure 1A). In 4 patients,
UP lesions were present over the entire body, sparing only the acral regions
and the face. In 8 patients, the UP lesions were variably present on the trunk,
thighs, and extremities. Lesions were macular in 9 patients and maculopapular
in 3. Individual lesions typically ranged from 2 to 5 mm in diameter, and
sometimes reached confluence. Mast cell infiltrates in the dermis, as determined
by skin biopsy findings, were located predominantly in a perivascular pattern
consistent with mastocytosis. There was no clinical difference in UP between
patients with ISM compared with those with SMAHD.
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Table 2. Comparison of Clinical Characteristics, Including Extent of
UP at the Initial and Most Recent Evaluations*
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Figure 1. Regression of urticaria pigmentosa
in a patient with indolent systemic mastocytosis (patient 1). Early in the
disease course, multiple disseminated round and oval red-brown macules are
present (A). After 12 years, lesions are less numerous and have faded in all
areas (B).
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At initial presentation to the NIH, patients variously reported symptoms
typical of systemic disease, including pruritus, headache, flushing, abdominal
pain, and fatigue (Table 2). Intermittent
pruritus, flushing, headache, diarrhea, abdominal pain, and nausea constituted
the most frequent complaints in ISM. Fatigue and weight loss were most prominent
in patients with SMAHD.
Abnormalities of hematologic and/or routine laboratory findings were
noted in 2 patients (patients 2 and 8) with ISM. The first (patient 2) had
moderately elevated levels of serum phosphorus, urea nitrogen, alkaline phosphatase,
and serum IgG. These laboratory findings remained stable during the follow-up
visits. In the second patient (patient 8), neutropenia was recorded, which
persisted for 6 years. One patient (patient 11) with SMAHD had a persistent
elevation in IgG and IgM levels and transient increased alkaline phosphatase
levels, whereas another patient (patient 12) had persistent findings consistent
with chronic myelomonocytic leukemia, ie, an elevated white blood cell count,
absolute monocytosis, decreased platelet count, anemia, and elevated alkaline
phosphatase and transaminase levels.
The classic focal aggregates of mast cells, lymphocytes, and eosinophils
were present in the findings of the initial bone marrow biopsy in 11 patients6 (Figure 2).
The other patient (patient 5) had no evidence of systemic disease in the findings
of the initial bone marrow biopsy. Two patients had SMAHD diagnosed on the
initial visit: patient 11 with myelofibrosis and patient 12 with myelodysplastic
syndrome.
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Figure 2. Persistence of paratrabecular
mast cell lesions in a fibrotic matrix in the bone marrow in a patient with
indolent systemic mastocytosis (patient 1) on the findings of the initial
biopsy (A) and 13 years later (B), consistent with systemic disease (hematoxylin-eosin,
original magnification x100).
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COURSE OF DISEASE
In patients with ISM, the mean duration of follow-up from the initial
NIH visit ranged from 12 to 20 years (median follow-up, 15 years). Patients
made from 9 to 56 follow-up visits (median, 17 visits) during that period.
The 2 patients with SMAHD died after a period of follow-up. Patient 11 died
due to complications of surgery for aortic stenosis, performed elsewhere,
after a 7-year follow-up. Patient 12 died of sepsis, 2 years after the initial
NIH visit, at another institution.
The course of UP varied among patients. In 6 patients, initial worsening
was followed by a stable phase (median, 1 year), then a slow decrease in lesion
numbers and extent for 2 to 9 years (median, 3.5 years) that continued through
the most recent visit. Of these 6 patients, 1 had experienced total clearance
of the lesions by the last visit. In the other group of patients, lesions
were initially stable or faded with total resolution in 4. This improvement
paralleled a decrease in the severity of elevation, erythema, and hyperpigmentation
of skin lesions (Figure 1). In the
5 patients in whom UP cleared during follow-up, UP disappeared completely
in 3. In 1 patient (patient 2), pruritus persisted, and UP-like lesions were
visible only after hot showers and exercise. The final patient (patient 6)
had UP for 6 years, followed by fading and a UP-free period of 4 years with
total absence of pruritus and skin lesions. The UP lesions in this patient
then returned on the axilla and thighs, with lesions visible on the abdomen
and legs after alcohol consumption or exercise.
In patients with ISM, symptoms of mast cell mediator release and constitutional
and abdominal symptoms increased in some patients after the initial evaluation,
but later decreased in severity in all patients. In parallel with the fading
of skin lesions, an overall improvement in the patients' well-being was noted.
Some patients' symptoms resolved totally. In contrast, patients with SMAHD
experienced a slowly progressive increase in hepatomegaly, ascites, and constitutional
symptoms, despite prednisone therapy with or without interferon alfa-2b.8
It remains unproven that total mast cell serum tryptase levels measured
in healthy subjects or in patients with mastocytosis during quiescent periods
between flushing attacks, when most tryptase is of the  form (the 
form is released in anaphylaxis), reflect the total body burden of mast cells.10 Total serum tryptase values before UP began to regress
and after UP lesions were no longer identifiable or had reached a plateau
were available for 1 patient with ISM and 2 patients with SMAHD. For the patient
with ISM, the tryptase value in 1991 before regression of lesions was 6 ng/mL.
Seven years later, after regression of lesions, this value had risen to 31
ng/mL. From 1998 to 2000, the patient experienced new UP lesions, but the
plasma tryptase level remained essentially unchanged at 30 ng/mL. In the 2
patients with SMAHD, the mean tryptase values before compared with after regression
of lesions remained essentially unchanged or appeared to increase (141 [n
= 1] vs 243 [n = 1] ng/mL; 55 [n = 3] vs 66 [n = 2] ng/mL). Data were sufficient
to calculate -tryptase values for the 2 patients with SMAHD. Thus,
comparing the mean calculated -tryptase values before and after regression
of UP yielded a similar conclusion (140 [n = 1] vs 242 [n = 1] ng/mL; 54 [n
= 3] vs 64 [n = 2] ng/mL).
Findings of the final bone marrow biopsy did not differ significantly
from the initial findings in the patients undergoing the procedure (Table 3 and Figure 2), with the exception of patient 5, who showed no focal
mast cell lesions initially, but in whom mast cell lesions were demonstrated
in results of subsequent bone marrow biopsies.
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Table 3. Bone Marrow Findings in Patients With Mastocytosis
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PRESENCE OF THE Asp816Val MUTATION IN PBMCs
Analysis of the Asp816Val mutation (Table 1) using established techniques showed the mutation in the
PBMCs of 4 patients during remission (patient 12) or after clearance of UP
(patients 2, 6, and 11), including the 2 patients (patients 11 and 12) who
died during the follow-up.7 The mutation was
not detected in PBMCs in 6 patients after clearance (patient 8) or during
improvement of UP (patients 1, 3, 5, 7, 8, and 10), consistent with a previous
report.7 Thus, no correlation was found between
the presence of the mutation in PBMCs and the course of UP.
COMMENT
Urticaria pigmentosa commonly precedes the diagnosis of SM and is prominent
in most adult patients with this disease.5, 11
The analysis presented herein shows that regression of UP occurs in a subset
of patients with ISM or SMAHD. In all patients, reduction of the extent and
number of lesions (Table 2) was
paralleled by a concomitant reduction of erythema, hyperpigmentation, and
elevation of skin lesions (Figure 1).
In general, after an initial progression of UP, the increase in the number
of lesions appeared to reach a plateau phase, which was followed by a partial
or complete regression. However, even after regression of skin symptoms, the
overall bone marrow biopsy findings (Figure
2) remained essentially unchanged (Table 3).
In this study, remission of UP could not be predicted on the basis of
the extent and distribution of UP, the extent of organ involvement; the severity
and frequency of symptoms of mast cell mediator release, abdominal pain, or
constitutional symptoms; or the plasma tryptase levels. The absence or presence
of the Asp816Val mutation in PBMCs also did not predict the course of UP.7 The inability to detect the Asp816Val mutation in
PBMCs does not mean that these patients do not have cells that bear this mutation,
only that the mutated clone has not expanded to a sufficient extent to be
detectable in peripheral blood.12 The single
prognostic factor identified was the age of the patient, as regression of
UP was seen in the older patients. Mast cell densities in normal skin have
been reported to decrease with age.13 The median
age of patients in our study was 65.5 years at the end of the follow-up. No
improvement of skin lesions was seen in patients younger than 40 years, consistent
with an inverse correlation among UP number and density with age. A second
possibility for the decrease of skin lesions observed could relate to a change
in homing receptors to the skin expressed by the abnormal mast cell population
over time.
Regression of UP in adult-onset SM has been said to be associated with
a poor prognosis.2 The data presented herein
suggest that resolution of UP does not necessarily signal a worsening of disease,
but that when UP fades in a patient with ISM, the bone marrow does not improve
or present evidence of a more aggressive disease pattern. However, in patients
with SMAHD, the associated hematologic disorder persisted and progressed during
regression of UP. One conclusion is that disease progression in a patient
with SMAHD is better monitored with bone marrow biopsy findings than with
changes in the number, distribution, and intensity of skin lesions. Although
the bone marrow biopsy findings in patients with ISM persisted during regression
of resolution of UP, constitutional symptoms improved. This suggests that,
in part, the dermal mast cell burden with mediator release contributes to
or is associated with symptoms in the skin and internal organs. In contrast,
patients with SMAHD did not experience a decrease in constitutional symptoms,
including fatigue, which thus may be more related to the myeloplastic disease
than to the total body burden of mastocytosis.
CONCLUSIONS
In patients with SMAHD, regression of UP may occur even as the bone
marrow pathologic changes become more severe. In patients with ISM, improvement
or clearance of skin involvement appears to parallel improvement of patients'
symptoms over time. However, even after regression of UP, mast cell lesions
in the bone marrow of these patients with ISM persist.
AUTHOR INFORMATION
Accepted for publication August 3, 2001.
Corresponding author and reprints: Dean D. Metcalfe, MD, National
Institutes of Health/National Institute of Allergy and Infectious Diseases/LAD,
Bldg 10, Room 11C213, 10 Center Dr MSC 1881, Bethesda, MD 20892-1881 (e-mail: dmetcalfe{at}niaid.nih.gov).
From the Laboratory of Allergic Diseases, National Institute of Allergy
and Infectious Diseases (Drs Brockow, Worobec, Kirshenbaum, Akin, and Metcalfe
and Mss Scott and Huber), and Clinical Center Nursing Department (Ms Huber),
National Institutes of Health, Bethesda, Md.
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