Mastocytosis constitute a group of very low frequency diseases characterized by pathological accumulation of mast cells in different organs or tissues1. They are considered underdiagnosed diseases with an important impact on patient morbidity12. The recent consensus on diagnostic criteria and the clinical difficulties in suspecting this entity have limited its description and contribute to the current lack of knowledge of this pathology10. This article reports a case series on mastocytosis in adults in Colombia, so far the largest series reported in the region, which mainly showed that there was complete resolution of symptoms in only 25% of patients who received antihistamines or topical corticosteroids, and with little response to the rest of the therapies used. This indicates that it is a difficult pathology to treat.
In this series of patients with mastocytosis, the majority were women and specifically in SM, where 100% corresponded to the female sex. This finding is in accordance with the Vikse series in which 85.7% belonged to this gender and of these, 100% had SM 18. Although there are no data that imply a greater association between mastocytosis in women than in men, a correlation has been reported between elevated estrogen levels and greater severity of the symptoms (especially during pregnancy, representing 30% of severe cases). 19
Skin manifestations were the most common symptomatology in 100% of patients. Despite the heterogeneity that typically characterizes skin lesions in this entity, it was observed that hyperpigmented, monomorphic maculopapular lesions were the most common. This finding is in agreement with that reported in the literature, where Hartmann K, et al, found a higher frequency of presentation of this type of lesions. In this study it was observed that 80% of all patients with mastocytosis presented cutaneous lesions, with urticaria pigmentosa 12 20.
Pruritus was one of the most frequent clinical symptoms in more than 50% of patients, predominantly in patients with CM, a finding that is consistent with Vikse's case series, where it was present in 100% of patients 21. In contrast, gastrointestinal symptoms such as diarrhea were present in only 28% (2/7) of the total series, which corresponded to patients with SM. Bhullar, et al, in their case series of 107 patients, described diarrhea in 68% of patients with SM, but also in 44% of those with CM 22, the latter finding may differ from the result of this series due to the unequal sample sizes of the two studies. Most case series describe that gastrointestinal symptoms are predominant in patients with SM, reaching a prevalence of up to 70% 18. Other systemic symptoms such as headache, insomnia, abdominal pain, were reported in only 14% of this series.
Regarding laboratory variables in this study, serum tryptase levels were found to be elevated (≥ 20 ng/mL) in 67% of patients with SM, with a higher mean tryptase in patients with SM (59.7ng/mL, 95% CI: 14.9–141), compared to patients with CM (6.5 ng/mL, 95% CI: 2.5–15.1). This finding was corroborated by a study in Austria of 59 patients, where 81% of those with SM had levels above 20 ng/mL, compared to 13% of patients with CM 25. In Lange's case series, tryptase levels were found to be elevated in 6 patients out of 10 with CM, a finding different from what was found in this series, in which none of the patients with CM had tryptase levels above 20 ng/mL. Additionally, a relationship between decreasing tryptase levels and improvement of clinical manifestations has been found in the literature26, however in this study, clinical manifestations were not followed up according to tryptase levels. Serum tryptase levels are a useful tool for the follow-up of patients with mastocytosis and have been related to the course of the disease, so it is considered an important prognostic marker for the severity of clinical manifestations 23 24.
It has been observed that eosinophilia, universally considered as equal to or greater than 450 eosinophils/µL27, is an important parameter that can have an important prognostic value8 28. In this case series, 100% of patients with SM presented eosinophilia, contrasting with 25% of all patients with CM. A relevant finding is that patients with SM had a higher mean absolute eosinophil count (2196, 95% CI: 990–4440) than patients with CM (300, 95% CI: 130–720).
Eosinophilia has been most frequently associated with SM in the literature5. In a case series of 123 patients with SM, a prevalence of eosinophilia was observed in 34% of patients, predominantly found in patients with SM associated with myeloproliferative neoplasm28. Other studies have referred to the prognostic value of eosinophilia with respect to the severity of clinical manifestations in SM, and additionally, a correlation has been found between the average number of eosinophils and the average survival, defining that the most favorable average survival is found in patients with SM with mild eosinophilia 8 28.
It is pertinent to highlight that there is an important association between CM and the presence of gain-of-function KIT mutations in approximately 60 to 80% of cases18. In this study, C-KIT mutation positivity was detected in 25% (1/4) of cases with CM.
Regarding the therapeutic approach, symptomatic treatment was given in the majority of patients with CM and SM, without distinguishing between the variants. The mainstay of therapy in all symptomatic patients involves the combination of histamine receptor antagonists HR1 and HR2 2 29. In this study the response to treatment showed complete resolution of symptoms in 25% of all patients managed with antihistamines. This shows a poor response to the current available therapy. Some management guidelines recommend directing therapy depending on the variant of mastocytosis. As an example of the above for urticaria pigmentosa, CM subtype, it is recommended to initiate a dose four times higher than the conventional dose of antihistamines30.
In cases where symptoms persist, the recommendation is the addition of H2 antihistamines and leukotriene antagonists30. Although most patients in this series received second-line medications, symptoms persistence was evident in 100% of patients receiving montelukast. Only ranitidine, a histamine H2-receptor antagonist, achieved complete resolution in 100% of the patients who received it as a second-line drug. This finding is comparable to those found in other case series of similar size, 31 at present there are limitations to symptomatic management. Therapeutic efforts are focused on identifying new potential targets, and on knowing the range of different doses with current treatments12. As an example of this, an in vitro study with terfenadine and loratadine achieved the suppression of spontaneous growth of CM cell lines32; however, these are in vitro findings that have not been demonstrated in vivo.
In this series it was observed that one patient with SM was refractory to first and second line antihistamine management. Therefore, he was treated with a tyrosine kinase inhibitor, such as imatinib, without symptom resolution. It has been demonstrated that the presence of the KIT D816V mutation confers resistance to therapy with imatinib, mastinib and other therapies that have KIT as a therapeutic target7 33. Resistance to treatment with imatinib in patients with SM has been frequently reported in the literature30. However, the existence of other mutations in different genes has also been suggested. Rearrangements in the platelet-derived growth factor (PDGF) gene, has also been associated with resistance to therapy. Other studies mention that the inadequate use of sequencing methods for the D816V KIT mutation can account for a significant number of false negatives34.