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Systemic mastocytosis: Determining the subtype of disease

Systemic mastocytosis: Determining the subtype of disease
Authors:
Cem Akin, MD, PhD
Jason Gotlib, MD, MS
Section Editor:
Sarbjit Saini, MD
Deputy Editors:
Anna M Feldweg, MD
Alan G Rosmarin, MD
Literature review current through: Jul 2022. | This topic last updated: May 10, 2021.

INTRODUCTION — Mastocytosis describes a group of disorders in which pathologic mast cells accumulate in tissues. In the 2016 revisions of the World Health Organization's classification of tumors of the hematopoietic and lymphoid tissues, "mastocytosis" was removed as one of the subtypes under the major category of "myeloproliferative neoplasms" and is classified as its own major category [1]. In systemic mastocytosis (SM), mast cells infiltrate extracutaneous tissues. Once the diagnosis of SM has been reached, the subtype (variant) of disease must be determined, as treatment and prognosis differ for each disorder.

Topics related to other aspects of mastocytosis are found separately:

(See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

(See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis".)

(See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

(See "Advanced systemic mastocytosis: Management and prognosis".)  

(See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

SUBTYPES OF SYSTEMIC MASTOCYTOSIS — The World Health Organization's classification system defines five subtypes of systemic mastocytosis (SM) (table 1) [1,2]:

Indolent systemic mastocytosis (ISM)

Smoldering systemic mastocytosis (SSM)

Aggressive systemic mastocytosis (ASM)

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN)

Mast cell leukemia (MCL)

Each subtype of SM is distinguished by various features. (See 'Determining the subtype' below.)

EVALUATION

Basic evaluation — The basic evaluation of all patients with systemic mastocytosis (SM) should include the following:

Laboratory studies, including a complete blood count with differential, chemistries with liver and renal function, albumin, calcium, lactate dehydrogenase, serum tryptase level, and beta-2 microglobulin.

Bone marrow aspirate and biopsy should be sent for pathologic review, immunophenotyping by immunohistochemistry (for CD25, tryptase, and the receptor for stem cell factor, KIT [also known as CD117]) and/or flow cytometry (for CD117, CD25, and CD2), and KIT mutational analysis (preferably on bone marrow aspirate cells). If well-differentiated SM is suspected, CD30 staining is helpful, as mast cells in this variant do not express CD25. The KIT D816V mutation should be assessed by a sensitive technique, such as polymerase chain reaction employing mutation-specific primers, before concluding that it is negative [3]. Metaphase cytogenetics should be performed in patients with suspected coexistent hematologic disease [4].

Fluorescence in situ hybridization for cysteine-rich hydrophobic domain 2 deletion should be performed to detect Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) fusion gene in patients with a suspected chronic myeloid neoplasm with eosinophilia (chronic eosinophilic leukemia)/myeloproliferative hypereosinophilic syndrome. These patients can have increased numbers of loosely scattered, atypical mast cells in the bone marrow and an increased serum tryptase level but is not considered a World Health Organization subtype of mastocytosis. Also, it is very rare for the FIP1L1-PDGFRA fusion to be found in tandem with the KIT D816V mutation. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Bone densitometry (T score by dual-energy X-ray absorptiometry) to evaluate for bone loss, since mastocytosis is a risk factor for osteoporosis. Individuals with bone pain should have radiographs to evaluate for fracture or a skeletal survey. Although not a standard component of the evaluation, combined positron emission tomography/computed tomography (CT) may help to further assess patients found to have lytic lesions on other imaging studies.

In most cases, some of these studies will have been obtained in order to make the diagnosis of SM. Interpretation of abnormalities in these tests is reviewed separately. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Laboratory studies' and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Bone marrow examination'.)

Advanced testing — Depending on the clinical presentation, the following additional studies may be indicated:

Abdominal imaging, such as ultrasound or CT scan in patients suspected of having systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), aggressive systemic mastocytosis (ASM), or mast cell leukemia (MCL). Abdominal CT is also indicated in patients with abnormal blood counts (suggestive of an AHN), palpable hepatomegaly, splenomegaly, or lymphadenopathy on examination and in those with a moderate or higher mast cell burden (>30 percent, consistent with smoldering systemic mastocytosis [SSM]) or tryptase level that is >100 ng/mL.

Gastrointestinal endoscopy with biopsies in patients with gastrointestinal signs/symptoms.

Next-generation sequencing myeloid mutation panels in patients with suspected ASM, MCL, and SM-AHN to evaluate for additional molecular abnormalities (eg, TET2, SRSF2, ASXL1, RUNX1, CBL) that may impart further prognostic information [5-7]. Such testing could also be considered in SSM. Mutations in SRSF2, ASXL1, RUNX1, and DNMT3A have been shown to have poorer prognostic significance in SM [7].

Biopsy of enlarged lymph nodes is not routine, although it can be helpful in specific situations. As an example, in patients with suspected SM-AHN, lymph node biopsy may confirm and identify the hematologic neoplasm subtype. Similarly, if a patient with SM-AHN has lymphadenopathy causing local signs/symptoms of disease, biopsy would be helpful in determining which process is causing symptoms in that individual.

Liver biopsy should be considered in patients with signs of liver dysfunction, such as elevated transaminases or bilirubin, ascites, or portal hypertension, if there is doubt about whether liver disease is caused by mastocytosis or another entity.

Evaluation for organ enlargement or dysfunction — All patients with SM should be evaluated for B and C findings. B findings refer to significant organ involvement without organ dysfunction. C findings denote organ dysfunction due to excessive mast cell infiltration. C findings are associated with aggressive disease and a poorer prognosis.

B findings — B findings refer to signs of significant organ involvement (manifest as enlargement due to mast cell infiltration) without organ dysfunction and are a marker of increased mast cell burden [8]. B findings are not common in patients with indolent systemic mastocytosis (ISM) but may be found in those with high mast cell burden. The presence of two or more B findings is used to distinguish SSM from ISM. Patients with ASM may have B findings, but unlike SSM or ISM, they will also have at least one marker of organ dysfunction related to the organ with mast cell infiltration (C findings). (See 'C findings' below.)

B findings include the following (table 1) [9]:

Infiltration of bone marrow, such that mast cells comprise >30 percent of cells in bone marrow biopsy sections and/or serum tryptase is >200 ng/mL.

Hypercellular bone marrow with loss of fat cells or discrete signs of myelodysplasia or myeloproliferation (but insufficient to diagnose myelodysplastic syndromes or other myeloproliferative neoplasms), normal blood counts, or a mild cytopenia without progression.

Extramedullary involvement defined as one or more of the following:

Palpable hepatomegaly without ascites or other signs of liver impairment

Palpable lymphadenopathy or visceral node enlargement (>2 cm) found on ultrasound or CT

Palpable splenomegaly without hypersplenism

C findings — C findings denote organ function impairment due to excessive mast cell infiltration and are associated with aggressive disease and a poorer prognosis. They are absent in patients with ISM and SSM. The presence of at least one C finding is required for the diagnosis of ASM. In addition, C findings may be observed in MCL and SM-AHN.

C findings include [9]:

Cytopenias due to bone marrow infiltration by mast cells, as defined by one or more of the following [10]:

Absolute neutrophil count <1000 cells/microL

Hemoglobin <10 g/dL

Platelets <100,000/microL

In patients with SM-AHN, it may be difficult to determine whether the cytopenias are due to mastocytosis or the associated neoplasm. Comorbid causes should also be ruled out.

Palpable hepatomegaly with ascites, elevated liver function tests (eg, aminotransferases, total/direct bilirubin, and alkaline phosphatase), impaired synthesis of albumin and coagulation factors, and/or portal hypertension. Elevated alkaline phosphatase may be encountered in isolation without other liver function test abnormalities, especially in those with extensive systemic disease, and may be of bone or liver origin [11].

Palpable splenomegaly with hypersplenism (ie, nonimmune hemolytic anemia and other hematologic abnormalities). (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

Malabsorption due to mast cell infiltration of the intestinal tract with hypoalbuminemia and weight loss. (See "Approach to the adult patient with suspected malabsorption".)

Bone lesions with large osteolytic lesions (>2 cm) and/or pathologic fractures. Pathologic fractures caused by osteoporosis are not considered a C finding.

Life-threatening damage in other organ systems that is caused by local mast cell infiltration [12]. Biopsy may be necessary to confirm organ infiltration by mast cells.

REFERRAL — Referral to a specialty center with expertise in mast cell diseases should be considered in patients with uncontrolled symptoms, diagnostic difficulties, or advanced disease. The following websites are helpful in identifying appropriate centers.

European Competence Network on Mastocytosis

The Mastocytosis Society

National Institutes of Health

National Organization for Rare Disorders

DETERMINING THE SUBTYPE — Information gathered from the basic laboratory evaluation, bone marrow findings, and assessment for B and C findings are used to determine the subtype of systemic mastocytosis (SM) (table 1) [1,8].

The following general concepts apply:

Patients who fulfill the clinical criteria for SM and another hematologic disorder according to the World Health Organization's (WHO's) criteria are classified as "systemic mastocytosis with an associated hematologic neoplasm" (SM-AHN). This group can be conceptually subclassified into clinically indolent (ISM-AHN), smoldering (SSM-AHN), aggressive (ASM-AHN), or leukemic (MCL-AHN) variants for management purposes. It can be challenging to distinguish whether signs or symptoms of disease are caused by the SM or AHN component. In this regard, biopsy of the bone marrow or an extracutaneous organ may be helpful in selected cases. (See 'Systemic mastocytosis with an associated hematologic neoplasm' below.)

Patients without an associated hematologic neoplasm for whom mast cells account for at least 20 percent of the total nucleated cells of the bone marrow aspirate smear in an area outside the spicule are classified as mast cell leukemia (MCL). (See 'Mast cell leukemia' below.)

Patients without an associated hematologic neoplasm with fewer than 20 percent mast cells on the bone marrow aspirate are subclassified according to the presence or absence of B and C findings:

Aggressive systemic mastocytosis (ASM) – At least one C finding (see 'Aggressive systemic mastocytosis' below)

Smoldering systemic mastocytosis (SSM) – Two or more B findings and no C findings (see 'Smoldering systemic mastocytosis' below)

Indolent systemic mastocytosis (ISM) – One or fewer B findings and no C findings (see 'Indolent systemic mastocytosis' below)

The treatment, monitoring, and prognosis of the different types of SM are discussed separately. (See "Advanced systemic mastocytosis: Management and prognosis".)

Indolent systemic mastocytosis — The term "indolent systemic mastocytosis" (ISM) is used for patients with SM without an associated hematologic neoplasm and with fewer than 20 percent mast cells in the bone marrow who have one or fewer B findings and no C findings [1]. The clinical course is generally indolent, although severe anaphylaxis was seen more often in patients with ISM compared with those with more aggressive forms of mast cell disease [13]. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

ISM is the most prevalent form of SM in adults [8,14-16]. It is rarely diagnosed in childhood. Most cases of ISM are diagnosed in the fourth to fifth decade of life, although symptoms may have been present for years beforehand [17,18]. In a single institution retrospective analysis, the following clinical features were noted among the 159 patients with indolent subtypes of systemic mastocytosis (ISM or SSM) [17]:

Cutaneous symptoms (75 percent) – Included flushing and pruritus and rarely, urticaria and angioedema. Urticaria pigmentosa/maculopapular cutaneous mastocytosis was present in 63 percent.

Gastrointestinal symptoms (71 percent) – Included nausea/vomiting, dyspepsia, dysphagia, diarrhea, constipation, abdominal pain/cramping, bloating/flatulence, early satiety, heartburn, gastrointestinal tract bleeding, malabsorption, and steatorrhea.

Other mast cell mediator-related symptoms (69 percent) – Included headache, dizziness/lightheadedness, syncope/presyncope, hypotension, anaphylaxis, palpitations/tachycardia, bronchoconstriction/wheezing, and peptic ulcer disease. Idiopathic and/or recurrent anaphylaxis was present in 33 percent.

Constitutional symptoms (19 percent) – Included weight loss, fever, chills, and night sweats.

Splenomegaly, hepatomegaly, and lymphadenopathy, which were present in 17, 14, and 14 percent, respectively.

Mast cell infiltrates may be detected in various organs (including liver, spleen, and gastrointestinal tract) in ISM, although there is no organ dysfunction. Data are limited regarding the prevalence of mast cell infiltrates in these tissues because they are not routinely biopsied for the purpose of diagnosing mastocytosis. The KIT D816V mutation is detected in bone marrow mast cells and in skin mast cells and less often in peripheral blood cells [19].

Isolated bone marrow mastocytosis — Isolated bone marrow mastocytosis is considered a subvariant of ISM. The prognosis of these patients is generally good, although they can have life-threatening anaphylaxis and/or bone fractures attributable to their disease [20]. These patients do not have skin lesions of mastocytosis and so must be differentiated from ASM and MCL. Unlike the latter two entities, patients with isolated bone marrow mastocytosis have near-normal baseline tryptase levels and no C findings.

Smoldering systemic mastocytosis — In the revised 2016 WHO classification, smoldering systemic mastocytosis (SSM) was classified as a separate form of SM, whereas it had previously been considered a subtype of ISM [1]. SSM is distinguished from ISM by the presence of two or more B findings. Patients with SSM exhibit higher rates of progression to more advanced disease, such as ASM. SSM patients also typically have skin lesions of urticaria pigmentosa/maculopapular cutaneous mastocytosis. The KIT D816V mutation usually involves multiple lineages and is readily detectable in peripheral blood. (See 'B findings' above.)

In the single institution retrospective analysis described above that included 159 patients with indolent subtypes of SM, when compared with the patients with ISM, the 22 patients with SSM were older (median age 64 versus 49 years) and more frequently presented with constitutional symptoms (45 percent versus <20 percent) and elevated mast cell mediator levels [17,18]. (See "Indolent and smoldering systemic mastocytosis: Management and prognosis".)

Systemic mastocytosis with an associated hematologic neoplasm — Patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) fulfill clinical criteria for SM and another hematologic syndrome or neoplasia according to the WHO's criteria [14,21]. The 2016 revisions to the WHO classification uses the shorter term "SM-AHN" interchangeably with or in place of the earlier longer "systemic mastocytosis with an associated hematologic nonmast cell lineage disorder" (SM-AHNMD) [1]. This group can be conceptually subclassified into clinically indolent (ISM-AHN), smoldering (SSM-AHN), aggressive (ASM-AHN), or leukemic (MCL-AHN) variants for management purposes.

Most cases of SM-AHN are diagnosed in the sixth decade of life, usually as part of the evaluation of hematologic abnormalities [17,18]. When compared with the indolent subtypes, SM-AHN are less likely to present with skin findings and symptoms of mediator release and more likely to present with constitutional symptoms, hepatosplenomegaly, and lymphadenopathy. In a single institution retrospective analysis, the following clinical features were noted among the 138 patients with SM-AHN [17]:

Constitutional symptoms (62 percent)

Splenomegaly, hepatomegaly, and lymphadenopathy, which were present in 57, 38, and 29 percent, respectively

Gastrointestinal symptoms (57 percent)

Cutaneous symptoms (30 percent) – Urticaria pigmentosa/maculopapular cutaneous mastocytosis was present in 18 percent

Mediator-related symptoms (28 percent) – Idiopathic and/or recurrent anaphylaxis was present in 1 percent

In approximately 90 percent of cases, the associated hematologic neoplasm is myeloid in origin: usually a myeloproliferative neoplasm (MPN) (eg, chronic myeloid leukemia, primary myelofibrosis, essential thrombocythemia, polycythemia vera, chronic eosinophilic leukemia); myelodysplastic syndrome (MDS); MDS/MPN, unclassifiable (eg, chronic myelomonocytic leukemia) [18]. Rarely, acute myeloid leukemia, a secondary acute leukemia, or a lymphoproliferative disorder (eg, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma) have been reported [22,23].

Most patients present with the activating KIT D816V mutation in the peripheral blood, indicating a multipotential hematopoietic clonal nature of the SM [24,25]. Rare cases of SM associated with MPNs exhibiting both D816V KIT and V617F mutations in Janus kinase 2 have been reported [26].

Aggressive systemic mastocytosis — The term "aggressive systemic mastocytosis" (ASM) is used for patients with SM without an associated hematologic neoplasm and with fewer than 20 percent mast cells in the bone marrow who have one or more C findings (ie, organ function impairment due to excessive mast cell infiltration) (table 1) [1]. (See 'C findings' above.)

ASM is a clinically severe form of SM and occurs in a minority of patients [27]. Most cases are diagnosed in the sixth decade of life [17,18]. In a single institution retrospective analysis, the following clinical features were noted among the 41 patients with ASM [17]:

Gastrointestinal symptoms (63 percent).

Cutaneous symptoms (49 percent) – Urticaria pigmentosa/maculopapular cutaneous mastocytosis was present in 37 percent.

Constitutional symptoms (49 percent).

Splenomegaly, hepatomegaly, and lymphadenopathy, which were present in 44, 39, and 27 percent, respectively.

Mediator-related symptoms (22 percent) – Idiopathic and/or recurrent anaphylaxis was present in 5 percent.

B findings were present in 54 percent. All patients had one or more C findings by definition. The most common were osteolysis/pathologic fractures (44 percent), cytopenias (32 percent), functional liver impairment (27 percent), hypersplenism (22 percent). Malabsorption with weight loss and leukemic transformation were seen in two cases each.

Mast cells in the bone marrow biopsy characteristically occupy >20 percent of the marrow space but are typically less than 20 percent of nucleated cells in the aspirate smear, which distinguishes ASM from MCL. Signs of dysplasia and myeloproliferation can be found but do not fulfill criteria for hematologic malignancy.

Tryptase levels are invariably increased in ASM. KIT mutations are often present, including the most common D816V mutation [28].

Mast cell leukemia — Mast cell leukemia (MCL) is the most rare and most aggressive category of SM. Patients may present with weight loss and fatigue, anemia, or other C findings. Other signs and symptoms may include flushing, hypotension, peptic ulcer disease, diarrhea, and coagulopathy. Urticaria pigmentosa/maculopapular cutaneous mastocytosis lesions are typically absent. In MCL, the bone marrow is infiltrated by large numbers of atypical mast cells. The early stages of MCL usually cannot be distinguished from the other categories of SM.

In MCL, at least 10 percent of peripheral blood white cells or 20 percent of the nucleated cells on bone marrow aspirate (in a nonspicule area) are mast cells [1,2]. In the bone marrow, mast cells can be immature and hypogranulated with blast-like morphology and high nucleus-to-cytoplasm ratios and may contain mitotic figures and multilobed nuclei. For diagnostic purposes, the percentage of mast cells should be determined in a nonspicular part of the bone marrow aspirate smear and not in bone marrow biopsy sections. CD2 staining may be absent, and intracellular tryptase staining may be faint in cases with very immature mast cell morphology.

The number of mast cells circulating in the peripheral blood can vary considerably. Some cases have more than 10 percent circulating mast cells. The term "aleukemic" MCL is used for cases with less than 10 percent mast cells in the peripheral blood. Patients with aleukemic MCL without anemia, thrombocytopenia, or organomegaly appear to have a more chronic form of the disease, with comparably longer survival times [29-31]. However, these patients are uncommon. In a cohort of 28 MCL patients, 26 (93 percent) had one or more signs of organ damage [32]. Even chronic forms of MCL are expected to show progression over time with development of organ damage and compromise of survival. More data are needed to confirm whether the absence of organ damage adequately discriminates prognosis between these two MCL subgroups.

Serum tryptase levels are usually extremely high but vary from patient to patient. In a historical review of 51 cases, the median serum tryptase level was 433 (range 21 to 2357 ng/mL) [29], and in another cohort of 28 cases, the median serum tryptase level was 520 ng/mL [32]. The frequency of the KIT D816V mutation has been reported to be less in MCL compared with other subtypes of SM (eg, in the range of 50 to 70 percent) and may be explained by non-D816V KIT mutations and/or by mutations in other genes that have yet to be identified [29]. In the series of 28 patients with MCL, mutations in KIT were detected in 25 of 28 patients and consisted of D816V (in 19), D816H/Y (in 5), and F522C (in 1) [32]. Prognostically relevant additional mutations in SRSF2, ASXL1, or RUNX1 (S/A/Rpos) were found in 13 of 25 (52 percent) patients, and positivity for one or more of these mutations remained the only independent poor prognostic variable predicting overall survival [32].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mast cell disorders".)

SUMMARY AND RECOMMENDATIONS

The World Health Organization's (WHO) classification system defines five subtypes of systemic mastocytosis (SM) (table 1). Once a patient has been diagnosed with SM, the subtype of disease must be determined, as treatment and prognosis differ for each disorder. (See 'Subtypes of systemic mastocytosis' above.)

Laboratory studies should include a complete blood count with differential, chemistries with liver and renal function, albumin, calcium, and a total serum tryptase level. All patients should have a bone marrow biopsy and aspirate with immunophenotyping and molecular analysis to detect the presence of the D816V mutation in the gene for KIT, the receptor for stem cell factor. In most cases, these studies were already obtained in order to make the diagnosis of SM. We also obtain bone densitometry in all patients. Additional studies, such as ultrasound or computed tomography imaging of the abdomen, are indicated for specific presentations. (See 'Evaluation' above.)

All patients with SM should be evaluated for B and C findings. B findings refer to extensive bone marrow, spleen, or liver involvement without dysfunction. C findings denote organ dysfunction due to excessive mast cell infiltration and are associated with aggressive disease and a poorer prognosis. (See 'Evaluation for organ enlargement or dysfunction' above.)

Information gathered from the basic laboratory evaluation, bone marrow findings, and assessment for B and C findings are used to determine the subtype of SM (table 1):

Indolent systemic mastocytosis (ISM) is the most prevalent form of SM in adults and has the most favorable prognosis. Most patients have skin lesions of urticaria pigmentosa (also known as maculopapular cutaneous mastocytosis). Patients can have one B finding and should have no C findings. (See 'Indolent systemic mastocytosis' above.)

Smoldering systemic mastocytosis (SSM) was classified as a separate form of SM in 2016, whereas it had previously been considered a subtype of ISM. SSM is distinguished from ISM by the presence of two or more B findings. Patients with SSM exhibit higher rates of progression to more advanced forms of disease. (See 'Smoldering systemic mastocytosis' above.)

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is diagnosed when a patient fulfills clinical criteria for SM and another hematologic syndrome or neoplasia according to WHO criteria, most commonly myelodysplastic or myeloproliferative neoplasms or an overlap of the two diseases. (See 'Systemic mastocytosis with an associated hematologic neoplasm' above.)

Aggressive systemic mastocytosis (ASM) is an uncommon but clinically severe form of SM that is characterized by SM without an associated hematologic neoplasm and <20 percent mast cells in the bone marrow. Patients have one or more C findings. (See 'Aggressive systemic mastocytosis' above.)

Mast cell leukemia (MCL) is the most rare and most aggressive category of SM. Urticaria pigmentosa/maculopapular cutaneous mastocytosis lesions are typically absent. In MCL, >20 percent of nucleated cells in the bone marrow or >10 percent in peripheral blood are mast cells. These cells can be immature and hypogranulated with blast-like morphology and high nucleus-to-cytoplasm ratios. (See 'Mast cell leukemia' above.)

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References