What tests can be done to diagnose Mast Cell Activation Syndrome (MCAS)?

From the Guidelines

To look for Mast Cell Activation Syndrome (MCAS), several tests can help with diagnosis, including serum tryptase levels, 24-hour urine tests for N-methylhistamine, prostaglandin D2, and 11-beta-prostaglandin F2 alpha, and serum histamine levels, as recommended by the most recent guidelines 1. These tests should ideally be performed during or shortly after a flare of symptoms for the most accurate results. Additional testing may include:

• Chromogranin A levels
• Specific IgE testing if allergic triggers are suspected
• Bone marrow biopsy may occasionally be needed to rule out mastocytosis It's essential to work with healthcare providers experienced in mast cell disorders, typically allergists/immunologists, as timing of sample collection is crucial and samples require special handling. Multiple tests over time may be necessary since mast cell mediator levels can fluctuate. Before testing, you should avoid medications that might interfere with results, such as antihistamines, for a period determined by your doctor. These tests help identify abnormal mast cell activation by measuring the chemicals released during mast cell degranulation, which causes the diverse symptoms of MCAS including skin, gastrointestinal, respiratory, and cardiovascular manifestations. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions 1. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS 1. Serum tryptase level may be <20 ng/mL or only transiently elevated, and an increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant 1. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators 1. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders 1. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses 1. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis. Flow cytometry is a complementary tool in the diagnosis or monitoring of mast cell disease. CD117, CD25, and CD2 are standard flow markers; testing for CD30 can also be considered. Optimal techniques for characterization and enumeration of neoplastic mast cells are described in the literature. Chromosome analysis should be obtained in the workup of systemic mastocytosis, especially in cases with a suspected AHN. Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels are not recommended for the detection of KIT D816V; such next-generation sequencing (NGS) assays exhibit low sensitivity of approximately 5%. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. An increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant. Serum tryptase level may be <20 ng/mL or only transiently elevated. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis. Flow cytometry is a complementary tool in the diagnosis or monitoring of mast cell disease. CD117, CD25, and CD2 are standard flow markers; testing for CD30 can also be considered. Optimal techniques for characterization and enumeration of neoplastic mast cells are described in the literature. Chromosome analysis should be obtained in the workup of systemic mastocytosis, especially in cases with a suspected AHN. Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels are not recommended for the detection of KIT D816V; such next-generation sequencing (NGS) assays exhibit low sensitivity of approximately 5%. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. An increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant. Serum tryptase level may be <20 ng/mL or only transiently elevated. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis. Flow cytometry is a complementary tool in the diagnosis or monitoring of mast cell disease. CD117, CD25, and CD2 are standard flow markers; testing for CD30 can also be considered. Optimal techniques for characterization and enumeration of neoplastic mast cells are described in the literature. Chromosome analysis should be obtained in the workup of systemic mastocytosis, especially in cases with a suspected AHN. Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels are not recommended for the detection of KIT D816V; such next-generation sequencing (NGS) assays exhibit low sensitivity of approximately 5%. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. An increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant. Serum tryptase level may be <20 ng/mL or only transiently elevated. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis. Flow cytometry is a complementary tool in the diagnosis or monitoring of mast cell disease. CD117, CD25, and CD2 are standard flow markers; testing for CD30 can also be considered. Optimal techniques for characterization and enumeration of neoplastic mast cells are described in the literature. Chromosome analysis should be obtained in the workup of systemic mastocytosis, especially in cases with a suspected AHN. Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels are not recommended for the detection of KIT D816V; such next-generation sequencing (NGS) assays exhibit low sensitivity of approximately 5%. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. An increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant. Serum tryptase level may be <20 ng/mL or only transiently elevated. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis. Flow cytometry is a complementary tool in the diagnosis or monitoring of mast cell disease. CD117, CD25, and CD2 are standard flow markers; testing for CD30 can also be considered. Optimal techniques for characterization and enumeration of neoplastic mast cells are described in the literature. Chromosome analysis should be obtained in the workup of systemic mastocytosis, especially in cases with a suspected AHN. Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels are not recommended for the detection of KIT D816V; such next-generation sequencing (NGS) assays exhibit low sensitivity of approximately 5%. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. An increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant. Serum tryptase level may be <20 ng/mL or only transiently elevated. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis. Flow cytometry is a complementary tool in the diagnosis or monitoring of mast cell disease. CD117, CD25, and CD2 are standard flow markers; testing for CD30 can also be considered. Optimal techniques for characterization and enumeration of neoplastic mast cells are described in the literature. Chromosome analysis should be obtained in the workup of systemic mastocytosis, especially in cases with a suspected AHN. Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels are not recommended for the detection of KIT D816V; such next-generation sequencing (NGS) assays exhibit low sensitivity of approximately 5%. The main purpose of quantification of serum tryptase at the time of the reaction and at baseline is to confirm mast cell degranulation. It can also help rule out or confirm mast cell disorders and mast cell activation syndromes. Post-mortem sampling of tryptase can be useful when anaphylaxis is suspected as the cause of death. Elevated baseline values can be seen in mast cell disorders and in other situations such as chronic renal failure. An increase in serum tryptase at the time of reaction above 1.2 baseline + 2 mg L-1 is considered clinically relevant. Serum tryptase level may be <20 ng/mL or only transiently elevated. The diagnosis of MCAS is based on a combination of clinical criteria, including recurrent episodes of systemic anaphylaxis with concurrent involvement of at least 2 organ systems, elevation of one or more validated mast cell mediators, and response to targeted therapeutic interventions. A bone marrow biopsy and aspirate are needed to precisely diagnose and stage systemic mastocytosis (SM), which, if present, would increase the possibility of an associated clonal MCAS. Histamine can also be produced by bacteria that colonize mucosal surfaces or contaminate ingested foods, and measurement of urine N-methylhistamine levels has demonstrated little clinical utility for investigating MCAS, but can be supportive if increased levels are found in conjunction with other mediators. Further studies are needed to evaluate how measurement of urine N-methylhistamine levels might be optimally used for the evaluation and management of MCAS. Clinical criteria that lack precision for diagnosing MCAS but nevertheless are in use include fatigue, fibromyalgia-like pain, dermographism, tired appearance, chronically ill appearance, edema, rashes of many sorts, tinnitus, adenopathy, constipation, prostatitis, chronic low back pain, headache, mood disturbances, anxiety, posttraumatic stress disorder, weight change, hypothyroidism, hyperthyroidism, polycythemia, anemia, abnormal electrolytes, an increased or decreased level of at least 1 immunoglobulin isotype, and multiple psychiatric and neurologic disorders. Our recommendation is that patients should undergo an appropriate workup for their symptoms or condition and be treated according to evidence-based medical standards. Even with a precise diagnosis of MCAS based on the clinical and laboratory criteria discussed in this report, other conditions need to be correctly diagnosed and treated independently. The diagnosis of mastocytosis and its subtypes is based on the 2017 WHO Criteria Classification and requires a combination of histopathologic, clinical, laboratory, and cytogenetic/molecular analyses. Patients should be counseled about the signs/symptoms and potential triggers of mast cell activation. Multidisciplinary collaboration with sub-specialists is recommended. Management of cutaneous mastocytosis is not included in these guidelines, and referral to centers with expertise in cutaneous mastocytosis is strongly recommended. Clinical trials are especially encouraged, and all recommendations are category 2A unless otherwise indicated. Participation in clinical trials is especially encouraged. NCCN believes that the best management of any patient with cancer is in a clinical trial. Adapted from: Pardanani A, Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management. The percentage of circulating mast cells should be reported in patients with mast cell leukemia. The aspirate should also be reviewed for features of an associated hematologic neoplasm (AHN). The percentage of abnormal mast cells out of total mast cells should be determined. On the core biopsy, immunohistochemistry with markers for mast cell tryptase, CD117, and CD25 should be performed to optimize quantification of the bone marrow biopsy mast cell burden. Cytoplasmic and/or surface expression of CD30 may be found on mast cells, especially in advanced disease, but is considered an optional immunohistochemical marker. CD34 staining may also be obtained to quantify whether the proportion of myeloblasts are increased, especially in SM-AHN cases. Reticulin and collagen staining should also be undertaken to assess the grade of bone marrow fibrosis.

From the Research

Tests for Mast Cell Activation Syndrome (MCAS)

To diagnose MCAS, several tests can be performed, including:

• Laboratory data, such as increased validated urinary or serum markers of MCAS, including:
  • Serum tryptase levels persistently above 15 ng/mL 2, 3
  • 24-h urine histamine metabolites 2, 3
  • PGD2 or its metabolite 2, 3
  • 11-β-prostaglandin F2 alpha 2, 3, 4
• An increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis 5
• Response of MCA symptoms to antimediator therapy 5
• Measurement of 24-hour urine 11β-PGF₂α and serum tryptase levels can help avoid misdiagnosis and overinterpretation of MCAS symptoms in clinical practice 4

Classification of MCAS

Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies 5. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder 5.

Diagnostic Algorithm

A diagnostic algorithm has been proposed, focusing on the practical evaluation and management of patients with suspected MCAS 5. This algorithm includes the assessment of clinical symptoms, laboratory data, and response to therapy.

Laboratory Tests

Laboratory tests, such as serum tryptase and 24-hour urine 11β-PGF₂α, can help identify elevation of mast cell mediators in patients with MCAS 4. These tests can also help monitor the response to therapy and avoid misdiagnosis.

Personalized Medicine

Detailed knowledge about the etiology, underlying pathologies, and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine 6.