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).
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 ×100).
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Brockow K, Scott LM, Worobec AS, et al. Regression of Urticaria Pigmentosa in Adult Patients With Systemic Mastocytosis: Correlation With Clinical Patterns of Disease. Arch Dermatol. 2002;138(6):785–790. doi:10.1001/archderm.138.6.785
Copyright 2002 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2002
To determine clinical correlates of urticaria pigmentosa (UP) regression in adult patients with systemic mastocytosis (SM).
Cohort study of the natural history of mastocytosis.
National Institutes of Health Clinical Center.
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.
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.
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.
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.
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.
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
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.
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.
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.
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 α form (the β 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 α-tryptase values for the 2 patients with SMAHD. Thus, comparing the mean calculated α-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.
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.
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.
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.
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: email@example.com).
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