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Keywords:

  • aggressive systemic mastocytosis;
  • indolent systemic mastocytosis;
  • urticaria pigmentosa;
  • epidemiology;
  • Denmark

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of mast cells. Systemic mastocytosis (SM), in which abnormal mast cells are present in tissues beyond the skin, is divided into seven subcategories with varying degrees of severity and prognosis. Very little is known about the epidemiology of SM and its subcategories. This retrospective cohort study of 548 adults with SM diagnosed 1997–2010 was constructed using linked Danish national health registries. The most common subtype of mastocytosis was indolent SM (including urticaria pigmentosa) (n = 450; 82%), followed by SM with subtype unknown (n = 61; 11%), SM with associated clonal haematological non-mast cell lineage disease (n = 24; 4%), aggressive SM (n = 8; 2%), and mast cell leukaemia (n = 5; 1%). The incidence rate for SM (all subtypes including urticaria pigmentosa) was 0·89 per 100 000 per year. Cumulative incidence was 12·46 per 100 000, and the 14-year limited-duration prevalence as of 1 January, 2011 was 9·59 per 100 000. This nationwide cohort from Denmark is the first population-based epidemiological study of mastocytosis. In this cohort of patients aged 15 years and older, SM was found to be overall relatively rare with notable variation by subtype for patient characteristics, survival and epidemiological measures.

Mastocytosis is a heterogeneous group of diseases characterized by an abnormal proliferation and accumulation of mast cells in one or more tissues. Mastocytosis is considered a myeloproliferative neoplasm according to the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues (Horny et al, 2008). Mastocytosis is divided into two major categories including cutaneous mastocytosis (CM), in which the accumulation of abnormal mast cells is limited to the skin, and systemic mastocytosis (SM), in which abnormal mast cells are present in tissue sites beyond the skin (Valent et al, 2007). According to the 2008 WHO diagnostic criteria (Horny et al, 2008), a diagnosis of SM requires the identification of morphological, immunophenotypic and/or mutational characteristics of the neoplastic mast cells in extracutaneous tissue, and almost always involves a bone marrow biopsy. A diagnosis of SM in childhood is rare (Uzzaman et al, 2009) whereas most adults with urticaria pigmentosa (UP) will show SM when fully investigated (Valent et al, 2007).

Clinically, patients with SM may experience skin lesions (UP) and symptoms related to mast cell mediator release, which can dramatically impact quality of life and are heterogeneous including wheals, flushing, gastrointestinal symptoms (abdominal pain, diarrhoea, peptic symptoms), headaches, lack of concentration, musculoskeletal pain and anaphylaxis. Triggers of mediator symptoms can include heat, cold, stress (physical or emotional), medications, insect stings and food, or it may be idiopathic.

SM is divided into seven subtypes according to the 2008 WHO criteria (Horny et al, 2008). Indolent SM (ISM) is by far the most frequent subtype among adults. In aggressive SM (ASM), symptoms arise from organ dysfunction due to infiltration of mast cells (e.g. cytopenia, ascites, malabsorption or osteolytic skeletal lesions). Other subtypes of SM include SM with an associated clonal haematological non-mast cell lineage disease (SM-AHNMD), in which another clonal haematological disease is found concomitant to SM, and mast cell leukaemia (MCL), which is very rare and follows a very rapid course with poor prognosis. While available therapies often provide relief from symptoms, there currently are no curative treatments for SM.

Mastocytosis is considered a relatively rare disease but is very likely underdiagnosed for several reasons, including that symptoms may be heterogeneous or have overlap with many other conditions; skin lesions may be inconspicuous; work-up demands special expertise on the part of treating physicians as well the investigating pathologist and laboratory; and, there is a generally low awareness of the disease among medical care providers. Very little information describing the epidemiology of mastocytosis is currently available. In this report, we define a cohort of adult Danish patients with SM using national health registries from Denmark and characterize patient demographics and comorbidities as well as provide estimates of the epidemiology of SM and its subtypes.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

A nationwide cohort study of patients with SM aged 15 years and older was conducted in Denmark, which has a population of approximately 4·5 million adults. In Denmark, a tax-supported healthcare plan guarantees universal medical care for all residents. A unique personal identifier [Civil Personal Registration (CPR) number] assigned to all Danish residents at birth or immigration allows the linkage of national data regarding hospital diagnoses, pathology reports and many other health registries under the auspices of the Danish government (Pedersen, 2011). The complete, systematic, national registry system in Denmark allowed for the assembly and tracking of a nationwide cohort study of patients diagnosed with SM in an unbiased fashion (Frank, 2000). The study period was chosen as 1 January, 1997 to 31 December, 2010 because the computerized medical records necessary to identify and follow patients with SM were available and complete in this time period. Analyses were restricted to adult patients (age 15 years and older) as children generally have cutaneous forms of mastocytosis that resolve by adulthood (Uzzaman et al, 2009).

Patients with SM were identified from three primary health registries. The first was the Danish National Registry of Patients (NRP), which includes hospital admissions since 1977 and all outpatient and emergency room visits since 1995 (Lynge et al, 2011). The NRP includes dates of admissions and discharges, surgical procedures performed and up to 20 diagnoses classified according to the International Classification of Diseases, 8th revision (ICD-8) until the end of 1993 and 10th revision (ICD-10) thereafter. The second was the National Pathology Registry, which contains information on all pathological tests performed in Denmark since 1 January, 1997. Data on pathology procedures are reported by pathology departments in each region, including the CPR number, patient residence, referring department, performing department, date of the test, the pathological specimens and procedures, the site of the biopsy and the diagnoses assigned according to the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED) (the classification system used for pathological specimens in all Pathology Departments in Denmark). As most patients with SM undergo a bone marrow aspirate, small bowel or other biopsies during the course of the disease, SNOMED codes for mastocytosis had to be supplemented with a biopsy code in order for the patient to be included in our study from the National Pathology Registry. Finally, the Danish National Cancer Registry, which includes mandatory reporting of all incidental cases of cancer occurring in Denmark since 1987 (Storm et al, 1997), was used to identify patients with ASM (ICD10: C96.2) or MCL (ICD10: C94.3). The unique identifier assigned to each resident, the CPR number, is used by all registries in Denmark, thus preventing duplication of any SM patients identified through more than one of the three registries used in this study.

Cases of SM were classified according to subtypes as defined by the WHO (Horny et al, 2008). Subtypes were categorized using combinations of ICD-10 and SNOMED codes as shown in Table 1. For this analysis, patients were classified by the most severe disease found in either the pathology registry, cancer registry or NRP. Patients with a SNOMED code of M97411 (mastocytosis, not known if benign or malignant) in the National Pathology Registry but without any mastocytosis diagnoses in the NRP were classified as SM (subtype unknown). Several studies have shown that adults with UP in the skin will almost always be diagnosed with SM and not CM when fully investigated by bone marrow biopsy (Valent et al, 2007) and consequently, we have considered UP to be ‘probable ISM’ and thus have grouped UP and ISM together in the analyses. The prediagnostic term ‘mastocytosis in the skin’ has also been proposed for this group of patients with UP-skin lesions who have not undergone a bone marrow biopsy and hence are not strictly diagnosed in accordance with WHO criteria (Valent et al, 2007). Further, in order to not miss patients in the registries misclassified as mastocytomas that are in fact patients with SM, we included mastocytomas with bone marrow as the recorded site code in our analysis in the SM (subtype unknown) group. Finally, combined statistical analyses for patients with ISM (including UP), SM (subtype unknown), and ASM were additionally conducted because differentiating between the different forms of SM may be prone to error and has high potential for misclassification.

Table 1. Danish National Patient Registry and National Pathology Registry codes used to identify cohort of mastocytosis patients.
 Danish National Patient Registry codes (ICD-10)Pathology Registry SNOMED codesa
  1. ICD, International Classification of Diseases; SNOMED, Systematized Nomenclature of Medicine-Clinical Terms.

  2. a

    As most patients with systemic mastocytosis undergo a bone marrow aspirate, small bowel or other biopsies during the course of the disease, SNOMED codes for mastocytosis had to be supplemented with a biopsy code [Site code = T06 (bone marrow biopsy)].

  3. b

    Categorized as potential indolent systemic mastocytosis because site code=bone marrow

  4. c

    The Danish National Cancer Registry was also used to identify aggressive systemic mastocytosis (ICD10 code C96.2) and mast cell leukaemia (ICD-10 code C94.3).

Urticaria pigmentosaQ82.2Not applicable
MastocytomabNot applicableM97401 Mastocytoma
Systemic MastocytosisNot applicableM97411 (Mastocytosis, not known if benign or malignant)
Indolent systemic mastocytosis (confirmed)D47.0M97411 (Mastocytosis, not known if benign or malignant)
Aggressive systemic mastocytosiscC96.2M97411 (Mastocytosis, not known if benign or malignant)
Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseaseC96.2 (Aggressive systemic mastocytosis) and one of the following:
  1. Myeloid leukaemia (ICD-10: C92)
  2. Myelodysplastic syndrome (ICD-10: D46)
  3. Plasma cell myeloma (ICD-10: C90)
  4. Unclassifiable myelogenous malignancy
M97413 (Malignant mastocytosis, SM-AHNMD)
Mast cell LeukaemiacC94.3 (Mast cell leukaemia)M97423 (Mast cell leukaemia)

Co-morbidities occurring among SM patients were also characterized. Occurrences of the 19 conditions included in the Charlson co-morbidity index, the most widely used comorbidity index (Charlson et al, 1987; Thygesen et al, 2011), were obtained for all SM patients. The conditions were counted and then categorized according to the total number of co-morbid conditions occurring in each patient (0, 1, 2 or 3+). The ICD8 and ICD10 codes for each of the 19 conditions are listed in Appendix Appendix.

Statistical analyses

Descriptive analyses of the cohort, including tabulations of demographic characteristics and comorbidities, are presented. Incidence rates, the average rate of disease during the study period, for mastocytosis by subtype were calculated for 1997–2010. Cumulative incidence, or the number of new cases occurring during the study period, was calculated based on the mean population in Denmark (aged 15 years and older) from 1997 to 2010. The 14-year limited-duration prevalence was calculated as of 1 January, 2011 because the contributing data sources went back only to 1997. Survival was estimated using the Kaplan–Meier estimator with overall survival being defined as the time between diagnosis and death (from any cause) or end of follow-up (censored). As vital status information was available up to 2011, the end of follow-up for the survival analyses was 31 December, 2011.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Mastocytosis cohort

A total of 548 patients age 15 years and older with potential SM were identified via the NRP, National Pathology Registry and National Cancer Registry between 1997 and 2010. The distribution of subtypes was ISM (including UP (n = 276; 50%) and confirmed cases of ISM (n = 174; 32%) combined) (n = 450; 82%), SM with subtype unknown (n = 61; 11%), SM-AHNMD (n = 24; 4%), ASM (n = 8; 2%) and MCL (n = 5; 1%).

Over 40% of the patients with SM-AHNMD had only a SNOMED code of M97413 (n = 10) with no specific clonal diseases identified in the NRP. Of the 14 SM-AHNMD patients with at least one clonal disease found in the NRP, the most common were plasma cell myeloma (ICD10 code C90; n = 9), myelodysplastic syndromes (ICD10 code D46; n = 4), and myeloid leukaemia (ICD10 code C92; n = 3).

Characteristics of these patients by subtype are shown in Table 2. For most subtypes of SM, diagnosis occurred in middle-age. The average age at diagnosis of mast cell leukaemia was higher (mean age = 75·4 years) than for other subtypes (mean age range = 46–61 years). ISM was present in more females (62%) than males (38%) whereas MCL was more common in males (80% vs. 20%). Slightly more women than men were affected by the remaining subtypes.

Table 2. Characteristics of mastocytosis patients by subtype, 1997–2010.
CharacteristicUPISMSM (unk)ASMSM-AHNMDMCLTotal
  1. UP, urticaria pigmentosa; ISM, indolent systemic mastocytosis; SM (unk), systemic mastocytosis, subtype unknown; ASM, aggressive systemic mastocytosis; SM-AHNMD, systemic mastocytosis with associated clonal haematological non-mast cell lineage disease; MCL, mast cell leukaemia; SD, standard deviation.

Total (%)276 (50·4)174 (31·8)61 (11·1)8 (1·5)24 (4·4)5 (0·9)548 (100·0)
Year diagnosed
1997–2000 (%)71 (25·7)87 (50·0)12 (19·7)3 (37·5)1 (4·2)1 (20·0)175 (31·9)
2001–2006 (%)100 (36·2)65 (37·4)29 (47·5)2 (25·0)13 (54·2)1 (20·0)210 (38·3)
2007–2010 (%)105 (38·0)22 (12·6)20 (32·8)3 (37·5)10 (41·7)3 (60·0)163 (29·7)
Age
Mean (SD)45·5 (15·3)50·9 (18·6)65·9 (13·6)60·3 (19·2)59·0 (11·5)75·4 (8·4)49·6 (16·9)
Min–Max16–8716–8923–8832–8938–8563–8616–89
15–44 (%)124 (44·9)69 (39·7)11 (18·0)2 (25·0)3 (12·5)0 (0·0)209 (38·1)
45–64 (%)117 (42·4)62 (35·6)33 (54·1)2 (25·0)15 (62·5)1 (20·0)230 (42·0)
65+ (%)35 (12·7)43 (24·7)17 (27·9)4 (50·0)6 (25·0)4 (80·0)109 (19·9)
Gender
Male (%)94 (34·1)78 (44·8)30 (49·2)3 (37·5)11 (45·8)4 (80·0)220 (40·2)
Female (%)182 (65·9)96 (55·2)31 (50·8)5 (62·5)13 (54·2)1 (20·0)328 (59·9)
Status at end of 2010
Alive (%)248 (89·9)128 (73·6)44 (72·1)4 (50·0)14 (58·3)0 (0·0)438 (79·9)
Dead (%)25 (9·1)43 (24·7)17 (27·9)4 (50·0)9 (37·5)5 (100·0)103 (18·8)
Emigrated (%)3 (1·1)3 (1·7)0 (0·0)0 (0·0)1 (4·2)0 (0·0)7 (1·3)

On average, patients had less than one co-morbidity, with the most common co-morbidity being any tumour (10%), followed by chronic pulmonary disease (4%), connective tissue disease (4%) and ulcer disease (n = 4%). Patients with ASM (average co-morbidities = 1·6) and MCL (average co-morbidities = 3·2) had more co-morbidities compared to patients with other subtypes (average co-morbidities ranged from 0·4 to 0·7) (Table 3).

Table 3. Selected co-morbidities among mastocytosis patients by subtype, 1997–2010.
Co-morbidityISM (including UP) (n = 450)SM (unk) (n = 61)ASM (n = 8)SM-AHNMD (n = 24)MCL (n = 5)Total (n = 548)
  1. ISM, indolent systemic mastocytosis; UP, urticaria pigmentosa; SM (unk), systemic mastocytosis, subtype unknown; ASM, aggressive systemic mastocytosis; SM-AHNMD, systemic mastocytosis with associated clonal haematological non-mast cell lineage disease; MCL, mast cell leukaemia; AIDS, acquired immunodeficiency syndrome; SD, standard deviation.

Myocardial infarction (%)5 (1)3 (5)1 (13)0 (0)0 (0)9 (2)
Congestive heart failure (%)9 (2)2 (2)1 (13)0 (0)0 (0)12 (2)
Peripheral vascular disease (%)8 (2)1 (2)1 (13)2 (8)0 (0)12 (2)
Cerebrovascular disease (%)9 (2)3 (5)1 (13)0 (0)0 (0)13 (2)
Dementia (%)2 (0)0 (0)0 (0)0 (0)0 (0)2 (0)
Chronic pulmonary disease (%)18 (4)4 (7)0 (0)1 (4)0 (0)23 (4)
Connective tissue disease (%)19 (4)1 (2)0 (0)0 (0)0 (0)20 (4)
Ulcer disease (%)12 (3)10 (16)1 (13)0 (0)0 (0)23 (4)
Mild liver disease (%)6 (1)3 (5)0 (0)0 (0)0 (0)9 (2)
Diabetes (type I and II) (%)12 (3)0 (0)0 (0)0 (0)0 (0)12 (2)
Hemiplegia (%)2 (0)0 (0)0 (0)0 (0)0 (0)2 (0)
Moderate to severe renal disease (%)4 (1)1 (2)0 (0)0 (0)1 (20)6 (1)
Diabetes with end organ damage (%)1 (0)0 (0)0 (0)0 (0)0 (0)1 (0)
Any tumour (%)50 (11)3 (5)2 (25)0 (0)2 (40)57 (10)
Moderate to severe liver disease (%)2 (0)0 (0)0 (0)1 (4)0 (0)3 (1)
Metastatic solid tumour (%)15 (3)0 (0)1 (13)0 (0)2 (40)18 (3)
AIDS (%)3 (1)0 (0)0 (0)0 (0)0 (0)3 (1)
Number of co-morbidities
Mean (SD)0·7 (1·5)0·6 (1·1)1·6 (2·4)0·3 (0·7)3·2 (3·0)0·7 (1·5)
Min–Max0–90–70–60–30–60–9
0 (%)325 (72·2)40 (65·6)5 (62·5)20 (83·3)2 (40·0)392 (71·5)
1 (%)56 (12·4)13 (21·3)0 (0·0)3 (12·5)0 (0·0)72 (13·1)
2 (%)35 (7·8)6 (9·8)0 (0·0)0 (0·0)0 (0·0)41 (7·5)
3+ (%)34 (7·6)2 (3·3)3 (37·5)1 (4·2)3 (60·0)43 (7·9)

Follow-up time from diagnosis to death or end of follow-up ranged from 0 to 15 years with a median follow-up time of 6·1 years. Kaplan–Meier survival estimates varied greatly across subtypes of SM (Fig 1). At the end of follow-up, more than half of the patients with ISM (including UP) and SM (subtype unknown) were still alive while median survival was 6·7 years for ASM, 4·4 years for SM-AHNMD and 0·8 years for MCL. For comparison, the survival estimates for a sample of the general population of Denmark age- and sex-matched to the SM cohort are also shown in Fig 1.

image

Figure 1. Kaplan–Meier survival curves for systemic mastocytosis patients by subtype. ISM, indolent systemic mastocytosis; UP, urticaria pigmentosa.

Download figure to PowerPoint

It can be difficult to distinguish between subtypes of SM, particularly in registry data, and therefore, combined analyses of the patients classified as ISM (including UP), SM (subtype unknown), and ASM were conducted. Mean age at diagnosis among this group was 48·9 years at diagnosis, 61% were female, and an average 0·4 co-morbidities was observed.

Epidemiology of systemic mastocytosis

SM had an average incidence rate (IR) for all subtypes combined of 0·89 per 100 000 per year over the 1997–2010 study period (Table 4). IRs were higher for ISM (including UP) (IR = 0·73 per 100 000 per year) than other conditions. Cumulative incidence, the number of new cases of all SM subtypes combined occurring between 1997 and 2010 in the Danish population aged 15 years or older, was 12·46 per 100 000. The 14-year limited-duration prevalence as of 1 January, 2011 was 9·59 cases of any type of SM per 100 000. In the combined group of ISM (including UP), SM (subtype unknown) and ASM, the IR was 0·84 per 100 000 per year and the prevalence was 9·29 per 100 000.

Table 4. Incidence rate (1997–2010), cumulative incidence (1997–2010) and prevalence (1 January, 2011) of mastocytosis by subtype.
SubtypeIncidence rate per 100 000 (95% CI)Cumulative incidence per 100 000 (95% CI)aPrevalence per 100 000 (95% CI)b
  1. ISM, indolent systemic mastocytosis; UP, urticaria pigmentosa; SM (unk), systemic mastocytosis, subtype unknown; ASM, aggressive systemic mastocytosis; SM-AHNMD, systemic mastocytosis with associated clonal haematological non-mast cell lineage disease; MCL, mast cell leukaemia; 95% CI, 95% confidence interval.

  2. a

    Mean population (15 years and older) in Denmark from 1997 to 2011 was 4 397 709·21.

  3. b

    Population in Denmark (15 years and older) on 1 January 2011 was 4 565 541.

ISM (including UP)0·73 (0·67–0·80)10·23 (9·32–11·21)8·24 (7·44–9·10)
SM (unk)0·10 (0·08–0·13)1·39 (1·07–1·77)0·96 (0·71–1·28)
ASM0·01 (0·006–0·03)0·18 (0·09–0·34)0·09 (0·03–0·21)
SM-AHNMD0·04 (0·03–0·06)0·55 (0·36–0·80)0·31 (0·18–0·50)
MCL0·01 (0·003–0·02)0·11 (0·04–0·25)0·00
Total0·89 (0·82–0·97)12·46 (11·45–13·54)9·59 (8·73–10·52)

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

In this cohort study of patients aged 15 years and older with SM as identified from Danish health registries over a 15-year period, the incidence and prevalence of all subtypes of SM were found to be quite rare. Survival estimates were found to vary greatly by subtype in this cohort with the highest survival among those with the ISM subtype and the worst survival among those with MCL.

Very few studies have reported on the incidence or prevalence measures of SM. A recent analysis in the Groningen region in the Netherlands estimated the prevalence of ISM to be 13 per 100 000 on 1 January, 2011 (van Doormaal et al, 2013). This study included both ISM patients and presumed ISM patients in the calculation of prevalence. Inclusion of potential ISM in our population (including UP as well as SM with unknown subtype) resulted in a prevalence of 9·2 per 100 000, which is comparable to the Dutch estimate.

Regarding survival by subtype of SM, again, very few studies have provided survival estimates and small numbers have limited precision. In general, ISM is regarded as having a favourable prognosis with a life expectancy not different from the background population, whereas ASM, SM-AHNMD and MCL carry lower survival, as shown in a retrospective study of 342 consecutive SM patients seen at the Mayo Clinic in the United States between 1976 and 2007 (Lim et al, 2009).

Survival patterns in our Danish cohort were similar to those observed in the Mayo study, with the highest survival among patients in the ISM group followed by ASM, SM-AHNMD and finally MCL, which had the lowest survival among the subtypes in the present study. At approximately 14 years of follow-up (the longest available in our Danish cohort), survival estimates were higher for each subtype in the Danish cohort to the Mayo Clinic cohort. Although the median age for each subtype in our study was similar to the Mayo Clinic study and the proportion of male patients with ISM and ASM was similar in both studies, there were many more males with SM-AHNMD in the Mayo Clinic study (70% males) than in our study (46%). Additionally, the Mayo Clinic study was a hospital-based case series rather than a population-based cohort, which may have led to the ascertainment of sicker patients at the Mayo Clinic. The finding of a favourable survival profile for patients with the ISM subtype was also observed in the Spanish Network on Mastocytosis study of 145 patients with ISM (Escribano et al, 2009). We did observe slightly lower survival in the ISM group compared to the general population of Denmark and this was in contrast to the findings from the Mayo Clinic study (Lim et al, 2009), which found similar survival among the ISM patients and the general population. The most probable explanation for this finding is the risk of misclassification of patients with an aggressive variant (ASM, SM-AHNMD, MCL) wrongly coded as ISM in this register-based study. However, some studies, including a follow up of the Mayo Clinic study (Pardanani et al, 2009) have suggested that even though no firm prognostic markers have been identified, ISM may have a more heterogeneous survival profile than previously thought. This heterogeneity may be due to a small proportion of patients having a less favourable prognosis, including those with the provisional subvariant of ISM called smouldering SM (SSM), characterized by a higher mast cell burden, which could not be separated from ISM in our study.

Regarding subtype distribution, we found differences in SM subtypes between the Mayo Clinic study (Lim et al, 2009) and our study. In our cohort ISM was by far more common (82% vs. 46%) whereas SM-AHNMD (4% vs. 40%) and ASM (2% vs. 12%) were much rarer in our study and MCL was very rare in both studies (1%). The data are however not completely comparable, as our study included a group (11%) that could not be classified into a specific subtype of SM (SM unknown). Further, as opposed to the Mayo Clinic study and other hospital-based series, our study included patients with UP in the ISM group based on the aforementioned evidence that this group of ‘mastocytosis in the skin’ patients will show ISM when fully investigated. These are the main explanations for the higher proportion of ISM patients in our cohort.

The distribution of clonal diseases most commonly associated with the SM-AHNMD subtype in this cohort (38% with plasma cell myeloma and 12·5% with myeloid leukaemia) was not consistent with previous reports showing that myeloid neoplasms are the most common AHNMD with chronic lymphocytic leukaemia/small lymphocytic lymphoma or plasma cell myeloma being much less common (Stoecker & Wang, 2012). Due to the rare nature of the disease and the SM-AHNMD subtype in particular, it seems likely that variation due to small sample sizes and/or misclassification in the coding of clonal diseases may explain these discrepancies.

This study has several strengths including being the first population-based presentation of descriptive epidemiological measures for SM and its subtypes. Also, this study included a relatively long follow-up of up to 15 years. Additional strengths are related to the registry-based cohort study design in which the nationalized health care system in Denmark provides an extensive collection of health data with uniform coding and the ability to link multiple registries with no duplication of patients.

The registry-based cohort design is also a limitation of the study, as a heterogeneous and rarely-encountered disease like SM is prone to misclassification via coding in the registries, especially concerning the categorization of the rarest subtypes, such as ASM and SM-AHNMD. As a further limitation, it is likely that SM cases were under-reported in this study as it is thought that the disease is underdiagnosed for several reasons. First, many patients with CM may actually have SM that has gone undiagnosed because they have not undergone the necessary bone marrow procedures to diagnose systemic involvement; this limitation, however, may be somewhat ameliorated in this analysis as we included patients with UP to address this limitation. Further, the symptoms of SM can be subtle or even absent, and the disease may thus go entirely undetected in some individuals. Finally, there is a low awareness of mastocytosis on the part of physicians in general: our experiences at the Mastocytosis Centre in Odense, a Centre of Excellence in the European competence network for mastocytosis, indicate that the awareness of mastocytosis in Denmark is overall low, but comparable to most other European and industrialized countries. As a correct diagnosis demands experience both on the clinical and pathological sides, SM may be easily missed or misdiagnosed. The collective result of these limitations is that the epidemiology measures reported here are probably lower limits of the true burden of disease. A further limitation is that diagnosis was limited to ICD and SNOMED codes. Finally, it should be noted that the number of patients with certain subtypes of SM, such as ASM and MCL, were very small, leading to imprecision in estimates of epidemiological measures.

In conclusion, using national data from health registries in Denmark, SM was found to be a relatively rare disease in individuals aged 15 years and older. Subtypes of SM show significant differences in patient characteristics and survival.

Acknowledgements

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

All authors and acknowledged contributors have read and approved the manuscript. The EpidStat Institute acknowledges and appreciates the scientific inputs of Erica Evans, PhD, and Christopher B. Franco, PhD of Blueprint Medicines, Cambridge, MA, USA.

SC designed the study, interpreted data and wrote the manuscript. SS collected data, analysed and interpreted data and revised the manuscript critically. JF designed the study, interpreted data and wrote the manuscript. SBO designed the study, interpreted data and wrote the manuscript. HV, TK, MM and CBJ interpreted data and revised the manuscript critically.

Odense University Hospital received no financial or otherwise support for this project. The EpidStat Institute received financial support for performing the data analysis from Blueprint Medicines, Cambridge, MA, USA. The Department of Clinical Epidemiology, Aarhus University, was supported by the EpidStat Institute.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
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Appendix

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

The 19 chronic diseases included in the Charlson co-morbidity Index according to International Classification of Diseases, 8th revision (ICD-8) and 10th revision (ICD-10) codes.

DiseaseICD8ICD10
Myocardial infarction410I21;I22;I23
Congestive heart failure427·09; 427·10; 427·11; 427·19; 428·99; 782·49I50; I11.0; I13.0; I13.2
Peripheral vascular disease440; 441; 442; 443; 444; 445I70; I71; I72; I73; I74; I77
Cerebrovascular disease430–438I60–I69; G45; G46
Dementia290·09–290·19; 293·09F00–F03; F05.1; G30
Chronic pulmonary disease490–493; 515–518J40–J47; J60–J67; J68.4; J70.1; J70.3; J84.1; J92.0; J96.1; J98.2; J98.3
Connective tissue disease712; 716; 734; 446; 135·99M05; M06; M08; M09; M30; M31; M32; M33; M34; M35; M36; D86
Ulcer disease530·91; 530·98; 531–534K22.1; K25–K28
Mild liver disease571; 573·01; 573·04B18; K70.0–K70.3; K70.9; K71; K73; K74; K76.0
Diabetes
Type I249·00; 249·06; 249·07; 249·09E10.0, E10.1; E10.9
Type II250·00; 250·06; 250·07; 250·09E11.0; E11.1; E11.9
Hemiplegia344G81; G82
Moderate to severe renal disease403; 404; 580–583; 584; 590·09; 593·19; 753·10–753·19; 792I12; I13; N00–N05; N07; N11; N14; N17–N19; Q61
Diabetes with end organ damage
Type I249·01–249·05; 249·08E10.2–E10.8
Type II250·01–250·05; 250·08E11.2–E11.8
Any tumour140–194C00–C75
Leukaemia204–207C91–C95
Lymphoma200–203; 275·59C81–C85; C88; C90; C96
Moderate to severe liver disease070·00; 070·02; 070·04; 070·06; 070·08; 573·00; 456·00–456·09B15.0; B16.0; B16.2; B19.0; K70.4; K72; K76.6; I85
Metastatic solid tumour195–198; 199C76–C80
Acquired immunodeficiency syndrome079·83B21–B24