The Provider Primer Series: Natural history of SM-AHD, MCL and MCS

Natural history of systemic mastocytosis with associated hematologic disease (SM-AHD):

  • SM-AHD is defined by systemic mastocytosis in the presence of another clonal hematologic disease. SM-AHD is thought to comprise 30-40% of all mastocytosis cases[i].
  • In about 90% of cases, the associated blood disorder is a myeloid neoplasm such as myelodysplastic syndrome, myeloid leukemias, or myeloproliferative diseases such as polycythemia vera or essential thrombocythemia[i] . Janus kinase 2 (JAK2) V617F mutation, which has a known association with myeloproliferative neoplastic conditions such as essential thrombocythemia and polycythemia vera, is sometimes present in SM-AHD patients[vii].
  • In this condition, SM and the other blood disorder are treated as separate entities as if they did not co-occur[i]. The conditions are synchronous and the associated hematologic disease does not occur secondarily to SM or treatment thereof. Prognosis in SM-AHD depends almost exclusively upon the associated hematologic concern. In multiple studies, fatalities are reported as result of associated malignancies[ii].
  • Myeloid neoplasms are the most common AHD, including chronic myelomonocytic leukemia or other leukemias, myelodysplastic syndrome, or myeloproliferative diseases[i].
  • In a 138 patient cohort: about 1/3 demonstrated Hgb <100 g/L and platelets<100×109/L; 51% had elevated white cell count; 31% demonstrated frank eosinophilia <1.5×109/L[vii].
  • SM-AHD patients are at increased risk of leukemic transformation relative to other forms of systemic mastocytosis (excluding mast cell leukemia) with a frequency of 14% in a 138 patient cohort[vii].
  • The SM aspect of SM-AHD is diagnosed and staged according to the SM diagnostic algorithm. It is therefore possible for a patient with SM-AHD to have mast cell leukemia or any other subtype of SM[vii].

Natural history of mast cell leukemia (MCL):

Table 1: Diagnostic criteria for mast cell leukemia[iii] 
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 2: C findings present in acute MCL[iii] 

 

C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

  • Mast cell leukemia is defined by SM where ≥20% nucleated cells in marrow are mast cells. In leukemic variant, >10% of nucleated cells in blood are mast cells; in aleukemic variant, there are <10% mast cells[iii].
  • MCL can occur de novo or from a previous mast cell neoplastic condition such as aggressive systemic mastocytosis or mast cell sarcoma[iii].
  • CKIT D816V mutation is less common in MCL than in other forms of systemic mastocytosis (50-80%). Some patients have mutations elsewhere in the coding regions of CKIT or a non-D816V mutation at CKIT codon 816. An unusual feature of MCL is that when the disease progresses quickly, the patient may lose positivity for the D816V mutation[iv].
  • MCL patients do not typically demonstrate mastocytosis in the skin[iii].
  • In the absence of C findings, some MCL patients have stable disease without markers of progression. This is referred to as chronic MCL[iii] .
  • >90% mature mast cells is a positive prognostic indicator. Presence of mostly immature mast cells is associated with more aggressive disease[iii] .
  • Acute MCL rapidly causes catastrophic organ damage. Median survival in acute cases is six months, though some MCL patients live for years through the use of newer targeted therapies[iv].
  • Hematopoietic stem cell transplant (HSCT) is an experimental option for MCL patients. In one study, overall survival at the three year mark was 17% (2 of 12 patients)[viii].

Natural history of mast cell sarcoma:

  • Mast cell sarcoma is an exceedingly rare tumor with high grade cytology that can present in a variety of tissues[v].
  • Mast cells that comprise the tumor resemble neither morphologically normal mast cells or spindled cells often seen in SM. In mast cell sarcoma, mast cells are often bilobed and multinucleated tumor cells have been reported. Of note, mast cells compromising the sarcoma often express CD30[iv].
  • Mast cell sarcomas often have neither CKIT D816V mutation nor mutations elsewhere in CKIT coding regions[vi].
  • Mast cell sarcomas often induce only local symptoms at the time of diagnosis but systemic involvement rapidly follows. Mast cell sarcoma may progress to mast cell leukemia. Median survival is 12 months[vi].

References:

[i] Gotlib J. (2013). Approach to the diagnosis and management of mastocytosis. The Hematologist, 10(1). Retrieved from: http://www.hematology.org/Thehematologist/Ask/5960.aspx

[ii] Wang SA. (2013). Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): clinical significance and comparison of chromosomal abnormalities in SM and AHNMD components. Am J Hematol, 88(3), 219-224.

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.

[iv] Youk J. (2016). A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data. Blood Res, 51(1), 17-22.

[v] Ryan RJH, et al. (2013). Mast cell sarcoma: a rare and potentially underreecognized diagnostic eneity with specific therapeutic implications. Modern Pathology, 26, 533-543.

[vi] Georgin-Lavialle S, et al. (2013). Mast cell sarcoma: a rare and aggressive entity – report of two cases and review of the literature. JCO, 31(6), e50-e57.

[vii] Lim KH, et al. (2009). Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 113(23), 5727-5736.

[viii] Ustun C, et al. (2014). Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol, 32(29), 3264-3274.

Patient questions: Why isn’t tryptase used to track SM progression in patients with SM-AHNMD?

Tryptase can be a useful tool for measuring progression of systemic mastocytosis. However, it is not used in patients with systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD). Patients with SM-AHNMD have systemic mastocytosis and also have another blood disorder that causes excessive proliferation of cells that aren’t mast cells. It is essentially having individual diseases that affect the bone marrow.

The reason tryptase is not tracked in patients with SM-AHNMD is because other proliferative diseases of bone marrow can increase production of mast cells. (Actually, proliferative diseases in most organs can cause increased production of mast cells). This is called mast cell hyperplasia, overproduction of mast cells. It is NOT the same as SM. A patient with no mast cell disease of any kind who has a blood disorder like chronic myelogenous leukemia or essential thrombocythemia could experience an increase in mast cells. It is not uncommon for people with conditions like this to experience allergic symptoms due to mast cell activation.

This can occur for a few reasons. The blood disorder might increase the amount of cells that could become mast cells. The blood disorder could cause increased release and production of molecules that encourage mast cell development. Mast cells are also part of the immune response and heavily involved in tumor biology. Proliferation of another cell type can be interpreted by the body as tumor formation so more mast cells can be made to address the “tumor”, whether or not it actually is a tumor..

A patient with SM-AHNMD may have a baseline tryptase before developing the second blood disorder of 30 ng/mL. (Just making up a number here). After diagnosis with the second blood disorder, a tryptase test could reveal an increase to 35 ng/mL. However, if this were the case, we wouldn’t know if the additional tryptase is coming from mast cells made by SM ramping up or as a side effect of the other blood disorder. Because we can’t tell, it isn’t used as an indicator of increased mast cell production as a direct cause of SM.

For patients with SM-AHNMD, other markers are used to track disease progression of SM. That includes checking for things like inappropriate blood cell counts and organ swelling and dysfunction (B and C findings).

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Literature review (part 2)

There have been several publications on bone involvement in SM. Importantly, not all of these papers define SM the same way. Some define it as ISM, while others define it as ISM, SSM, SM-AHNMD and ASM. (I personally am sloppy about not specifying when I mean ISM versus when I mean any all the systemic proliferative groups. So if it’s not clear, please ask.) Another thing to be aware of is that the terminology for osteosclerosis is not consistent. It is sometimes referred to as osteocondensation (this is primarily a term used by French researchers). I have done some digging recently on this and cannot find any indication that these two terms do not represent the same phenomenon (increased deposition of bone), so if anyone knows of any papers or sources that say they are different, please let me know.

A 2010 paper (Barete 2010) defines SM as ISM, SSM, SM-AHNMD and ASM. They divided the study into two groups: Variant 1 (non-aggressive), ISM and SSM; and Variant 2 (aggressive), SM-AHNMD and ASM.

Overall (ISM, SSM, SM-AHNMD and ASM), 49% of patients had some form of bone involvement. Osteoporosis was most common, occurring in 31% of patients. 17% had a vertebral fracture. 8% had osteosclerosis. 4% had a mixed pattern, so more than one type of bone involvement. 5% had osteopenia with a previous fracture (this could be unrelated to mast cell disease, like an arm broken in a fall). Only one patient had a focal area of osteolysis with spontaneous fracture.

56% of variant 2 (aggressive) group had osteoporosis, compared to 23% of variant 1. However, when they excluded people who were classified as variant 2 based upon bone involvement, the association dropped to 17% variant 2 with osteoporosis and 23% of variant 1. Osteoporosis associated with vertebral fracture affected 48% variant 1 and 8% variant 2. Osteoporosis was also found to be associated with fewer GI symptoms, with 39% variant 1 having GI issues while 65% variant 2 did.

A total of six patients (out of a total group of 75) had osteosclerosis. One ISM, one SSM, three ASM and one SM-AHNMD patient had osteosclerosis. This translates to two in the variant 1 group and four in the variant 2 group, so twice as many in the aggressive group (ASM, SM-AHNMD) as in the non-aggressive group. 66% of patients in variant 2 with osteosclerosis had a blood count abnormality (anemia, thrombocytopenia, eosinophilia) vs 12% in variant 1. 83% of patients in variant 2 with osteosclerosis had received cytoreductive therapy vs 33% in variant 1, and higher tryptase level was associated with osteosclerosis. Overall, this means that osteosclerosis was associated with a more severe disease presentation (a patient with ISM and osteosclerosis may have a blood count abnormality), but this study does not provide any insight as to whether osteosclerosis is a marker associated with progression toward ASM or SM-AHNMD.

A 2011 paper (Guillaume 2011) assessed bone involvement in a group of CM and SM patients. In this study, SM included ISM, ASM and SM-AHNMD. 45 patients were included.  They found one patient with osteolysis, eight with osteocondensation (a form of osteosclerosis), four with a mixed pattern and three with fractures. They found no association between the presence of radiologic lesions (lesions detected by imaging techniques) and severity (here classified as non-aggressive: ISM and CM, and advanced: ASM and SM-AHNMD).

This study also looked at chemical markers used for bone remodeling. They found that markers associated with both bone resorption and bone formation were higher in mastocytosis patients than in the general population. The higher levels were thought to represent increased number of osteoblasts and osteoclasts due to the increase in mast cells. Osteoprotegerin was also higher in mastocytosis patients. This is a protein released by osteoblasts that regulates the activity of osteoclasts. Levels of C-telopeptide were significantly higher in patients with SM-AHNMD or ASM than in patients with ISM or CM.

A 2011 paper (Rossini 2011) investigated the relationship between tryptase and bone turnover markers (bone specific alkaline phosphatase, C-telopeptide, osteocalcin) in ISM patients. A total of 82 patients were enrolled in the study. 36% had bone involvement. 20% had osteoporosis, with 18.7% found in the spine and 2.5% at the hip. Five patients had a history of bone breaks outside of the spine. 27 patients had vertebral fractures. Two patients had osteosclerotic features and also had particularly high tryptase levels. Another study previously reported that high tryptase can be associated with increased bone density (Kushnir-Sukhov 2006).

This study had a large amount of ISM patients without skin lesions (55%). A very important finding of this particular study was that ISM patients without skin lesions are at the same risk for osteoporosis. As lesions are often one of the more identifiable markers of mastocytosis, the author raises the very valid point that osteoporosis may in some people be the only sign of latent ISM.

This paper reported that “diffuse osteosclerosis associated with SM is not a[n] “osteopetrosis-like osteopathy”, as previously reported, but a skeletal disease characterized by increased bone turnover.” This is important, as they have previously been equated for lack of distinction. The author further notes that the “pathophysiology of SM-related osteosclerosis remains obscure, although it is known that MCs can exert a direct stimulatory effect on osteoblast proliferation, recruitment, and activity.”

This study found that bone mineral density and serum tryptase did not correlate with the serum markers of bone turnover. However, it did find that ISM patients with osteosclerosis had higher tryptase and bone turnover markers (bone specific alkaline phosphatase and C-telopeptides of type I collagen) than ISM patients with other types of bone involvement.

(Literature review continued tomorrow)

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128:344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

One of the more nuanced aspects of mastocytosis is how it affects bone structure. Previously, it was thought that only patients with systemic mastocytosis experienced bone pain, and that bone pain was always a function of increased proliferation in the marrow. This no longer appears to be the case. Some patients with non-proliferative mast cell disease have been found to experience bone pain, likely as a result of mediator activity on the outside of the bone. In particular, histamine can be very irritating to the cells on the outside of the bone.

Generally speaking, bone cells work like this:

Osteoblasts make new bone. Osteoclasts eat away (resorb) at bone so that new bone can be put in that place. When these processes aren’t balanced, you develop bone conditions.

In osteosclerosis, your body is making new bone faster than it can resorbed. In osteoporosis, your body is resorbing bone faster than new bone is made.   In osteolysis, your body is also resorbing bone faster than new bone is made, but to a much larger extent than usually seen in osteoporosis. Both osteoporosis and osteolysis can cause pathologic fractures, meaning that because your bone is weak from osteoporosis or osteolysis, the bone breaks.

Bone involvement in systemic mastocytosis is important because the type of bone involvement present can be used to stage the disease. Specifically, certain types of bone involvement can cause a person with indolent or smouldering systemic mastocytosis to be reclassified as aggressive systemic mastocytosis (ASM). Osteolysis (in which bone is eaten away) is a marker for ASM. If you have ISM or SSM and are found to have a large osteolytic lesion, you now have ASM.

More confusing is the relationship of osteoporosis to ASM. If you have ISM or SSM AND you have osteoporosis AND you have multiple fractures due to the severity of the osteoporosis (known as pathologic fractures), you are classified as having ASM. There is some debate in the community as to whether or not osteoporosis with successive pathologic fractures is a true indication of ASM. However, it is currently included in the diagnostic guidelines, and so if you meet this criteria while also having ISM or SSM, then you are classified as having ASM.

But I want to be very clear about something: the osteoporosis is NOT the factor that classifies someone as having ASM. It is the MULTIPLE FRACTURES as a result of bone disease that classifies someone as having ASM. So if you have SSM and are diagnosed with osteoporosis and have a single vertebral fracture as a result of osteoporosis, you are NOT classified as having ASM. It is easier I think to consider this “bone involvement” criterion of ASM as osteolysis or multiple fractures due to bone deterioration.

SM is well known as a possible risk factor for osteoporosis. This has been attributed by different groups to either infiltration of bone by mast cells or release of mediators, including histamine, heparin and tryptase. IL-6 levels were also shown to be proportional to disease severity and osteoporosis in mastocytosis patients (Theoharides 2002). Histamine regulates bone resorption by osteoclasts via H1 and H2 receptors (Dobigny 1997). In bone biopsies of osteoporotic patients, the number of osteoclasts is sometimes elevated and sometimes normal.

Up next: literature review of studies on bone involvement in ISM, SSM, SM-AHNMD, and ASM.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Mast cell mutations: SRSF2 in SM-AHNMD

SRSF2 is a splicing protein, which means it is involved in cutting RNA so that a gene makes the correct protein. SRSF2 mutations at position 95 (p95) have been found in 24-37% of SM patients. In nearly all cases, this mutation is found in patients that have SM-AHNMD. SRSF2 mutations at p95 are associated with myelodysplastic syndromes, leukemias and other hematologic diseases, including mastocytosis. After CKIT D816V mutation, it is the most common mutation found in systemic mastocytosis patients.

SRSF2 mutation occurs early in disease. One study indicates that it occurs in the time period between the initial TET2 mutation and the initial CKIT D816V mutation. Like TET2, it may predispose progenitor cells to develop subsequent mutations that cause disease. Patients with SRSF2 mutations are more likely to also have a TET2 mutation, and even more likely to have a mutation affecting another gene with epigenetic activity. SRSF2 alone does not drive neoplastic behavior in mast cells. SRSF2 has been found in patients without the CKIT mutation.

Importantly, SFSR2 is strongly associated with patients who develop SM-AHNMD. One study with a cohort of 72 patients with various forms of mastocytosis, including clonal MCAS (monoclonal mast cell activation syndrome) found that of 17 SM-AHNMD patients, 15 (88%) were positive for SFSR2 mutation. The associated conditions included AML, CMML, MDS, MSD (AREB), MPN, MPN/MDS and Waldenstrom’s macroglobunemia. SRSF2 mutations are not associated with any specific AHNMD and it does not predict survival time. This cohort included three patients who tested positive for the mutation but developed an AHNMD later in the study.

In SM-AHNMD patients, the SRSF2 mutations were found in both mast cells and monocytes in the bone marrow. This indicates that the mutation may cause transformation in both disease portions: SM and the AHNMD.

 

References:

Hanssens K., et al. SRSF2-P95 Hotspot Mutation is Highly Associated with Advanced Forms of Mastocytosis and Mutations in Epigenetic Regulator Genes. Haematologica 2013 [Epub ahead of print.]

Schwaab, J., Schnittger, S., Sotlar, K., Walz, C., Fabarius, A., Pfirrmann, M., et al., 2013.Comprehensive mutational profiling in advanced systemic mastocytosis. Blood122 (October (14)), 2460–2466.

Soucie, E., Brenet, F., Dubreuil, P. Molecular basis of mast cell disease. Molecular Immunology 63 (2015) 55-60.

Mast cell mutations: TET2 and mutation profiles of aggressive subtypes

TET2 (Tet methylcytosine dioxygenase 2) is found to be mutated in 20.8-29% of SM patients. Of note, dozens of mutations have been identified in this gene, including missense, nonsense, frameshift and deletion mutations. These mutations cause formation of a defective and less active TET2 enzyme. TET2 is located at chromosome 4q24 and mutations at this location are associated in both MPN and MDS conditions.

TET2 is involved in DNA methylation and demethylation, although the exact nature of this involvement is not clear. When a methyl group is added to a cytosine at a specific place in front of a gene, the gene is turned off and is not expressed. This is called “methylation.” TET2 adds a hydroxyl group to 5-methylcytosine, but it is not well understood if this turns the gene off. TET2 may also be involved in demethylating DNA, or removing those specific methyl groups. It has been shown to be involved with DNA demethylation during bone development.

One study looked at the mutational profiles of patients with various forms of SM, including ISM, SSM, SM-AHNMD, ASM and MCL, all of whom were positive for CKIT D816V mutation. 15/39 had a TET2 mutation. None of those patients had ISM or SSM. Of those with an aggressive form and a TET2 mutation, 67% had more than one TET2 mutation.

In this study, 24/27 patients with advanced SM (SM-AHNMD, ASM, MCL) had mutations beyond the D816V mutation. 5/5 SM-AHNMD patients and 19/22 ASM or MCL patients had multiple mutations (CKIT and something else.) In contrast, only 3/12 ISM or SSM patients had additional mutations. In advanced SM, 78% had at least 3 mutations, and 41% had at least 5.

These mutational profiles have clear implications clinically. 96% patients with major blood abnormalities (anemia <10 g/dL and/or thrombocytopenia < 100 x 10e9/L in addition to monocytosis > 1 x 10e9/L and/or eosinophilia >10%) had at least one additional molecular mutation regardless of SM subtype.

Advanced SM patients in this study all had one of the following multiple mutation profiles: 26% KIT-TET2-SRSF2, 18% KIT-SRSF2-RUNX1, 13% KIT-TET2-CBL, 10% KIT-SRSF2-ASXL1 10%, and 10% KIT-TET2-ASXL1. Patients with advanced SM (and therefore multiple mutations) were also found to be significantly older (68 years of age on average) than those with just the CKIT mutation (48 years of age on average.)

Having a TET2 mutation seems to predispose myeloid cells to become neoplastic later in life. It is important to distinguish that the TET2 mutation seems to “allow” this transformation rather than causing it. In mice who don’t have the TET2 gene and thus don’t have the TET2 enzyme, stem and progenitor cells have trouble maintaining balance and spontaneously become neoplastic later in life. In TET2 deficient cells, mast cells with D816V mutation show increase in proliferation and survival as opposed to those without with normal TET2 levels. Presence of TET2 in addition to the presence of CKIT D816V mutation is associated with more aggressive forms of SM (including ASM, MCL and SM-AHNMD.)

 

References:

Damaj, G., Joris, M., Chandersris, O., Hanssens, K., Soucie, E., Canioni, D., et al., 2014.ASXL1 but not TET2 Mutations Adversely Impact Overall Survival of PatientsSuffering Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast-Cell Diseases. PLoS ONE 9 (1), e85362.

Schwaab, J., Schnittger, S., Sotlar, K., Walz, C., Fabarius, A., Pfirrmann, M., et al., 2013.Comprehensive mutational profiling in advanced systemic mastocytosis. Blood122 (October (14)), 2460–2466.

Soucie, E., Hanssens, K., Mercher, T., Georgin-Lavialle, S., Damaj, G., Livideanu, C.,et al., 2012. In aggressive forms of mastocytosis. TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 120 (December (24)), 4846–4849.

Soucie, E., Brenet, F., Dubreuil, P. Molecular basis of mast cell disease. Molecular Immunology 63 (2015) 55-60.

Mast cell mutations: JAK2 and myeloproliferative neoplasms

Janus kinase 2 is also a tyrosine kinase like CKIT, but it is not a receptor on the outside of the cell. JAK2 is a helper protein that helps other molecules to send signals. It also affects the signaling of many clinically important molecules, like interleukin 3, interleukin 5, interleukin 5, interferon gamma, erythropoietin, thrombopoietin, growth hormone and prolactin. These molecules are involved in cell proliferation and the inflammatory response.

JAK2 mutation V617F seems to make hematopoietic cells more responsive to growth factors, causing excessive proliferation. JAK2 V617F is used as a marker for some Philadelphia negaitve myeloproliferative neoplasms (Ph- MPN), which include essential thrombocythemia (ET), an indolent disease in which too many platelets are produced; polycythemia vera (PV), in which too many red cells are produced; and myelofibrosis (MF), in which bone marrow is replaced with connective tissue that cannot make blood cells. JAK2 V617F is present in 40-50% of ET cases, 95% of PV cases, and 60% of MF cases.

In multiple studies, the frequency of JAK2 mutations in SM has ranged from 0-20% depending on the patient group. However, multiple studies have found a frequency of 4.2-5%, which is the generally accepted figure. JAK2 mutation is a strong predictor of myeloproliferative neoplasm but not necessarily of mastocytosis. However, where present in SM patients, it indicates a higher probability of developing another MPN.

In the control group of one study, 10 ISM patients without another myeloprofilerative neoplasm were negative for JAK2 mutation, and 15 MF patients without SM were negative for CKIT mutation. In the patient group, five people had both CKIT+ SM and MF. In four patients, the JAK2 V617F mutation was present. In the four patients with the JAK2 V617F mutation, it was found not only in the myelofibrosis cells (CD15+ myeloid cells), but also in the mast cells. In two of the patients, the CKIT mutation was found in the CD15+ myeloid cells of two patients. The data suggests that the JAK2 mutation may occur before the CKIT mutation in patients who have both SM and an associated hematologic disorder.

One study looked extensively at other mutations present in various types of CKIT+ systemic mastocytosis. The patient group was composed of 39 people, with 10 having ISM, 2 SSM, 5 SM-AHNMD, 15 ASM and 7 MCL. Only 2 patients out of the group were positive for JAK2 mutation. One patient had MCL, the other had SM-AHNMD. Both also had another myeloproliferative neoplasm (in the case of the SM-AHNMD patient, it was MDS.) This study found that presence of at least one other mutation in addition to CKIT D816V was associated with poorer prognosis, although presence of JAK2 V617F was not specifically identified as causing shorter lifespans.

 

References:

Schwaab, Juliana, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122 (14): 2460-2466.

Soucie, Erinn, et al. Molecular basis of mast cell disease. Molecular immunology 2015, 63 (1): 55-60.

J. Molderings. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.

Sotlar, Karl, et al. Systemic mastocytosis associated with chronic idiopathic myelofibrosis. J Mol Diagn Jan 2008; 10(1): 58-66.

MCAD, MCAS and the hierarchy of mast cell disease classifications

I have seen several posts recently expressing confusion about various mast cell diagnoses so I figured I would put up a post to clear things up.
Mast cell activation disorder (MCAD) is a catch-all term for mast cell disease (MCD.)  MCAD and MCD can be used interchangeably.  So if you have any mast cell disease, you have MCAD.  If you have SM, you have MCAD, because SM is a type of MCAD.  If you have UP, you have MCAD, and so on.  MCAD is an umbrella term.  It is non-specific.  It is similar to being told that you have heart disease when you have mitral valve prolapse.  It is true, but it is not precise enough to give all information needed to treat effectively.
Mast cell activation syndrome (MCAS) is the diagnosis you get if you do not meet the criteria for any of the defined mast cell diseases, but have mast cell mediator related symptoms.  You cannot have MCAS and another mast cell disease because, by its definition, MCAS is ONLY diagnosed if you do NOT meet the criteria for any other mast cell disease.  You cannot have UP and MCAS.  You cannot have SM and MCAS.  I think some people think that MCAS means you have mediator related symptoms.  This is not the case.  You can have mediator related symptoms with pretty much any mast cell disease. 
A paper was published a few years ago by a doctor who considers mast cell activation symptoms to be due exclusively to proliferation (like in SM.)  He wrote a paper that says that MCAS is found in people with SM.  This paper sort of confused the issue for a lot of people.  However, the mast cell community (including researchers and prominent doctors) do not consider this to be the case.  They agree that you cannot have SM and MCAS.
Also confusing is the fact that mast cell activation (MCA) is NOT the same as MCAS.  MCA just means that your mast cells are activated, which occurs in any mast cell disease.  MCA is not a diagnosis, it is a symptom.  So you can have MCA in SM.  But you still can’t have MCAS in SM.
So if you have SM and have lots of mediator related symptoms, you have SM.  If you want to speak broadly, you have SM.
If you test negative for SM and have no CM, but have mast cell symptoms and elevated mast cell markers, you have MCAS. 
If you have UP and then later develop SM, you have SM with skin involvement, or SM with UP. 
If you have UP or TMEP and have lots of mediator related systemic symptoms, you do NOT have UP and MCAS.  You have UP.  UP and TMEP (forms of CM) can cause systemic symptoms.  But you cannot have MCAS because you can only have MCAS if you do not meet the criteria for another mast cell disease.
Let’s review.
If you have UP: you have UP, you have CM, you have MCAD.
If you have TMEP: you have TMEP, you have CM, you have MCAD.
If you have SM: you have SM, you have MCAD.
If you have SM with UP: you have SM with skin involvement, you have UP, you have MCAD.
If you have SM with TMEP: you have SM with skin involvement, you have TMEP, you have MCAD.
If you have SM-AHNMD: you have SM-AHNMD, you have MCAD.
If you have ASM: you have ASM, you have MCAD.
If you have MCL: you have MCL, you have MCAD.

If you have MCAS: you have MCAD.

Reference:
Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.

In which I answer your questions (part 2)

“sm-ahnmd disability”

Systemic mastocytosis with associated hematologic non mast cell lineage disease can be disabling, as can most other types of mast cell disease.  Unfortunately, due to in part to the rarity of mast cell disease, applications for disability are sometimes rejected.  I have not had to apply for long term disability, so unfortunately I am not a great resource for this.  I will reach out to some people and try to do a future post on application for disability.

“mast cell disease and steroid use”
Steroids can be a helpful tool in managing mast cell disease, but they have a laundry list of side effects and long term use can be risky.  The steroids used to treat mast cell disease and anaphylaxis are usually glucocorticocoids.  These medications have a wide range of actions, including suppressing synthesis of some prostaglandins and cytokines, which are associated with inflammation. 
Steroids cause fluid retention and weight gain, including the very typical “moon face” (which I currently have), anxiety and increase in appetite, among other things.  With longer courses, you run the risk of bone loss, joint pain, GI bleeding, and a whole bunch of other stuff.  Steroids are serious medications. 
One of the most serious risks of long term steroid use is suppression of the adrenal gland.  Your body naturally makes steroids, but when you are taking steroids, your body stops making them.  For this reason, steroids often have to be weaned off.  General rules of thumb for when you wean steroids:
-more than 40mg of prednisone (or equivalent of another steroid) daily for at least a week
-steroids have been taken at night daily for at least a week
-steroid treatment has lasted at least two weeks
-several recent courses of steroids.  This is important for people with mast cell disease, because when you have a flare, some people take a Medrol dose pack.  If you do this several times in a short period, you may suppress your adrenal gland.
-steroid treatment within a year of stopping long-term steroid treatment
Steroid withdrawal is real and terrible.  Weaning should be done slowly and cortisol levels should be measured after weaning to ensure that steroid levels return to normal levels.  If you wean too quickly, or your adrenal gland is permanently suppressed, you can develop Addison’s disease or have an Addisonian crisis.  Having had an Addisonian crisis, I assure you it is unpleasant and dangerous.  Our bodies use steroids to do a lot of things and they provide mast cell coverage for us. 
Long term steroid treatment should be avoided if at all possible.  However, this is not always avoidable.

“mast hypertension”
Low blood pressure is more common in mast cell patients, but high blood pressure does happen.  This can happen for a few reasons.  One reason is that hyperadrenergic POTS often coincides with mast cell disease, and this can cause high blood pressure.  Another reason is that mast cells release a compound called chymase.  Chymase is tryptase’s less famous relative, and it is involved in the inflammatory response. Chymase converts angiotensin I to angiotensin II.  Once this happens, angiotensin II increases blood pressure through several mechanisms.  I’m realizing that I have never discussed chymase on the blog so I’ll do a post about this in the near future.  But for some people, the release of chymase by mast cells can cause hypertension.

“lymphoid and mast”
I’m guessing this search came after a bone marrow biopsy with a finding of lymphoid cells and mast cells.  Lymphoid aggregates in the bone marrow can be benign.  If they are mostly T cells, they are more likely to be benign.  If they have central cores of B cells in the aggregates, they are more likely to be malignant.  Any lymphoid aggregate should be evaluated for malignant features, but it is completely possible to have benign lymphoid aggregates in the bone marrow.
Occasionally in people with SM, there are both lymphoid aggregates and mast cell aggregates in the bone marrow.  This seems to occur only in the bone marrow and not in other infiltrated organs.  The first mention of this in literature was in the late 80’s. 

“deactivate mast cells”
I’ll let you know when I figure it out.  Ha!  Maintenance medications, low histamine diet and trigger avoidance to the extent it is possible.  Try not to get stressed.  Yes, really.

“can a person die from mast cell disease”
Yes, but it is not common.  Most people who die from mast cell disease have ASM, MCL or SM-AHNMD when the other blood disorder is a more aggressive cancer.  The vast majority of people with mast cell disease have normal life expectancies. 

“histamine and heparin when scratched”
I assume this is a reference to Darier’s sign.  Darier’s sign is when you see a wheal and flare reaction to lightly touching the skin of a person with mast cell disease.  This is due to the release of histamine by mast cells in the skin.  It is usually associated with urticaria pigmentosa or TMEP, but I have heard a few doctors refer to the reaction in people with systemic disease but no skin involvement as “non-lesional Darier’s.”  I had no skin involvement until recently, and every time I saw my mast cell specialist, he would run his thumb down my back and say “positive Darier’s.”  Darier’s sign is considered to be indicative of mast cell disease. 
 
“can i have a baby mastocytosis”
You can do whatever you want with mastocytosis, but some things are inherently risky.  Fortunately, having a baby doesn’t seem to be one of them.  Premeds should be taken at the onset of labor but otherwise many women have found themselves able to have safe pregnancies and deliver healthy babies vaginally or via Caesarian section.  Symptom profiles are super variable during pregnancy when compared to before conception and after delivery.  Some women have complete resolution of their symptoms due to pregnancy.  Some women feel it was the onset of their symptoms.  Like I said, super variable.
 

Diagnosis of mast cell diseases

There seems to be a lot of confusion regarding diagnosis of mast cell diseases, so I figured I’d do a review.

Cutaneous mastocytosis (CM) is diagnosed by skin biopsy.  Urticaria pigmentosa (UP), also called maculopapullar cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM) and telangiectasia macularis eruptive perstans (TMEP) are types of cutaneous mastocytosis.  They each present with a rash and may have accompanying systemic symptoms. 
Mastocytoma of the skin is also diagnosed by skin biopsy.
Systemic mastocytosis (SM) has the following diagnostic criteria:
Major:
1.       Multifocal, dense infiltrates of mast cells (15 or more in an aggregate) detected in sections of bone marrow and/or extracutaneous organ. 
Minor:
1.       In biopsy sections, more than 25% of mast cells in infiltrated area are spindle-shaped or have atypical morphology; or, of all mast cells in bone marrow aspirate smears, more than 25% are immature of atypical. 
2.       Detection of Kit mutation at codon 816 in bone marrow, blood or other extracutaneous organ.
3.       Mast cells in bone marrow, blood or other extracutaneous organ that co-express CD117 with CD2 and/or CD25.
4.       Serum total tryptase persistently >20 ng/mL (if there is not a clonal myeloid disorder.)
SM is diagnosed if a patient has either one major and one minor criteria, or three minor criteria.  So let’s look at how this plays out.
A patient with mast cell symptoms gets a bone marrow biopsy.  It shows more than 25% abnormal mast cells in the section.  They are CKIT negative, have a serum tryptase of 2, and do not express CD2/CD25.  They are diagnosed with SM.
A patient has a biopsy that does not show dense infiltrates.  All their mast cells are shaped normally.  In blood tests, their mast cells are found to express CD2.  They are CKIT+, also from blood.  Their serum tryptase is 28.  They are diagnosed with SM.
A patient has a biopsy that shows dense infiltrates, but they have less than 25% abnormal mast cells and their mast cells do not express CD2/CD25.  They are CKIT- and have a serum tryptase of 18.  They are not diagnosed with SM.
A few things to keep in mind:
Most people with SM are diagnosed by bone marrow biopsy, but a biopsy from any non-skin organ showing mast cell infiltration as described above can be used.  This means if you have a positive lung biopsy, liver biopsy, whatever, you may not necessarily need a bone marrow biopsy. 
It can take up to six bone marrow biopsies to diagnose SM in a patient who has had it the entire time.  This is because there is no way to know where the mast cells will cluster.  A negative bone marrow biopsy does not necessarily mean that you do not have SM.  Hence the minor criteria.
The CKIT test looks for a specific mutation, the D816V mutation.  There are other mutations found in codon 816.  You may have a mutation but test CKIT- because you do not have the D816V mutation.  Also, the blood test for CKIT is not always reliable.  The test way to test this is from a bone marrow sample.  You could test CKIT- in blood and then test CKIT+ in bone marrow.
The serum tryptase criterion refers to persistent baseline level tryptase, not reaction level tryptase. 
So let’s say you have a negative bone marrow biopsy and a blood test that shows you are CKIT+ and have mast cells expressing CD2/CD25.  What do you have?  You have monoclonal mast cell activation syndrome (MMAS.)  MMAS is diagnosed in patients who have one or two of the minor criteria for systemic mastocytosis.
Let’s say you have a negative bone marrow biopsy and blood work that shows normal mast cells and tryptase below 20, but you have systemic symptoms.  What do you have?  You probably have MCAS (mast cell activation syndrome.)  There are some other tests for that.  24 hour urine tests are usually done to measure the levels of histamine metabolites and prostaglandin D2 metabolites.
The following are the diagnostic criteria for MCAS:
1.       Episodic symptoms consistent with mast cell mediator release affecting two or more organ systems: skin (urticarial, angioedema, flushing); GI (nausea, vomiting, diarrhea, cramping); cardiovascular (fainting or near fainting due to low blood pressure, rapid heartbeat); respiratory (wheezing); naso-ocular (itching, nasal stuffiness, red eyes.)
2.       A decrease in frequency or severity; or resolution of symptoms with antihistamines, leukotriene inhibitors or mast cell stabilizers.
3.       Evidence of elevation of urinary or serum marker of mast cell activation: Documentation of elevation of marker during a symptomatic period on at least two occasions, or if baseline tryptase is persistently above 15 ng.  This includes urinary histamine and prostaglandin D2.
4.       Clonal and secondary disorders of mast cell activation ruled out.
MCAS is a diagnosis of exclusion.  It is the diagnosis you receive if you have mast cell symptoms that are ameliorated with mast cell medications if you do not meet the criteria for any other mast cell disease.
Back to SM.  Let’s say you’re positive for SM.  Now what?
They will determine if you have other important markers of disease severity.  These are called B and C findings.  They are as follows:
B findings:
1.       Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/ml).
2.       Hypercellular marrow, signs of overproduction or abnormal development of blood cells, normal or slightly abnormal blood counts that are not abnormal enough to be considered an associated hematologic disorder.
3.       Swelling of the liver that can be felt manually, no free fluid or signs of dysfunction, persistently swollen glands, swelling of the spleen that can be felt manually without signs of dysfunction.
If you have two or more B findings, you have SSM (smoldering systemic mastocytosis.) 
C findings:
1.       Unusual blood counts (low ANC, low Hb, low platelets)
2.       Swelling of the liver that can be felt manually, with impaired liver function, free fluid and/or portal hypertension.
3.       Large osteolytic lesions and/or pathological fractures.
4.       Swelling of the spleen with impaired function.
5.       Malabsorption with weight loss and/or low albumin.
If you have one or more C finding, you have ASM (aggressive systemic mastocytosis.)
How are these B and C findings identified?  Bone marrow biopsy, blood tests and imaging (ultrasounds, MRI, etc.) 
If you have SM and one B finding, or no B findings, you have indolent systemic mastocytosis (ISM.) 
If your bone marrow biopsy shows significant overproduction or abnormal development of a cell type that is not a mast cell, you may be diagnosed with SM-AHNMD (systemic mastocytosis with associated hematologic non-mast cell lineage disease.)  People with this type of SM also have another blood disorder, such as chronic myelogenous leukemia, myelodysplasia, etc.  In these patients, serum tryptase is not reliable to assess mast cell burden.  
Mast cell leukemia (MCL) is extremely rare.  It is diagnosed by >20% mast cells on the bone marrow aspirate smear.   
Mast cell sarcoma is a very aggressive form of sarcoma.  It is diagnosed by biopsy of the tumor.  People with these tumors quickly developed mast cell leukemia.  There have only been three cases reported in literature.  To be clear, this is NOT the same as mastocytoma.  Mastocytomas are benign.
I think I got everything.  Any questions?  Ask in the comments.