Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease.

Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.

Current Challenges in the Diagnosis of Pediatric Cutaneous Mastocytosis.

Pediatric mastocytosis is mostly a cutaneous disease classified as cutaneous mastocytosis (CM), which is characterized by mast cell (MCs) accumulation in the skin and the absence of extracutaneous involvement. Based on the morphology of skin lesions, CM can be divided into three major forms: maculopapular CM (MPCM), diffuse CM (DCM) and mastocytoma of the skin. A positive Darier's sign is pathognomonic for all forms of CM. MPCM is the most common form, presenting with red-brown macules or slightly raised papules. Mastocytoma is characterized by solitary or a maximum of three nodular or plaque lesions. DCM is a rare, severe form which presents as erythroderma, pachydermia and blistering in the infantile period of the disease. CM is associated with MC mediator-related symptoms, most commonly including pruritus, flushing, blistering, diarrhea and cramping. Anaphylactic shock occurs rarely, mainly in patients with extensive skin lesions and a significantly elevated serum tryptase level. Childhood-onset MPCM and mastocytoma are usually benign diseases, associated with a tendency for spontaneous regression, while DCM is associated with severe mediator-related symptoms, an increased risk of anaphylaxis and, in some cases, underlying systemic mastocytosis (SM). In contrast to adults, SM is a rare finding in children, most commonly presenting as indolent SM. However, advanced SM sporadically occurs.

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021.

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.

-2518A/G polymorphism of monocyte chemotactic protein 1 (MCP-1/CCL2) is associated with cutaneous mastocytosis.

INTRODUCTION: Mastocytosis is a rare heterogeneous disease associated with pathological accumulation of mast cells (MCs) in one or more organs. The disease may be limited to the skin (cutaneous mastocytosis - CM), or present an internal organ involvement (systemic mastocytosis - SM). Pathophysiology of the disease is not well established. However altered proliferation, differentiation and chemotaxis of MC may play an essential role in the development of the disease. The monocyte chemotactic protein 1 (MCP-1/CCL2) may be one of the factors responsible for MCs migration to the skin and other organs. AIM: To analyse the frequency of biallelic A/G polymorphisms at position -2518 in the promoter of the MCP-1 gene and compare the serum level of MCP-1 in patients with both forms of mastocytosis and the healthy control group. MATERIAL AND METHODS: Using ARMS-PCR methods we analysed -2518A/G polymorphisms in the promoter region of the MCP-1 gene in 127 mastocytosis patients (95 CM and 32 SM), and 160 healthy controls. Additionally, the MCP-1 serum level was detected with ELISA technique in 70 patients and 40 controls. RESULTS: We have found that CM patients have more frequently the GG genotype of the MCP-1 gene (p = 0.01) in comparison to SM patients and controls. The GG genotype was more frequent in children than in adults (p = 0.02). The MCP-1 serum level was higher in SM patients than in CM patients and controls. CONCLUSIONS: Results of this study indicate that cutaneous mastocytosis could be associated with the -2518 A/G MPC-1 gene polymorphism.

Tachykinin antagonists ameliorate surgically induced impairment of gastrointestinal motility in rats.

The protective effects of tachykinin receptor antagonists: SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor) were tested in rats against a surgically induced postoperative inhibition of gut motility, a common complication of abdominal surgery. The small intestinal transit of Evans blue was measured 24-h post-surgery in untreated rats and animals subjected to skin incision, laparotomy, or laparotomy followed by gut evisceration and manipulation. Surgical procedures were conducted under diethyl ether anesthesia. In comparison to untreated and ether-anesthetized rats, animals undergoing skin incision, laparotomy, or laparotomy with gut evisceration and manipulation showed a significant decrease in the intestinal transit of Evans blue. The pretreatment with NK1 (3-100 µg/kg), NK2 (3-30 µg/kg), and NK3 (10-300 µg/kg) blockers before surgery ameliorated the inhibitory effects of gut manipulation in a dose-dependent manner. Moreover, the submaximal and maximal doses of NK3 antagonists showed a trend toward reversing not only the inhibition caused by gut manipulation but also laparotomy. An additive effect of combining submaximal doses of NK1-3 blockers was observed in animals pretreated with NK1  + NK2 compared to single-agent NK1 and NK2 . Additionally, doublets: NK1  + NK3 or NK2  + NK3 and a triplet: NK1  + NK2  + NK3 proved to be more effective than NK2 antagonist alone. In contrast, NK1-3 blockers have not markedly affected the intestinal propulsion in untreated rats or animals subjected to skin incision or laparotomy. NK1-3 blockers ameliorated the suppressed small-bowel gut motility 24 post-surgery. Combined pretreatment with NK1-3 antagonists provided selective, additive benefits compared to single agents.

Tachykinin Antagonists Reverse Ischemia/Reperfusion Gastrointestinal Motility Impairment in Rats.

BACKGROUND: Supraceliac aortic clamping and unclamping produces ischemia-reperfusion (I/R) injury of the splanchnic organs. The protective effects of tachykinin receptor antagonists, SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor), against I/R-induced inhibition of intestinal motility were tested in rats. MATERIAL AND METHODS: The intestinal transit of Evans blue was measured in untreated rats and animals subjected to skin incision, I/R (1 h superior mesenteric artery occlusion followed by 24 h reperfusion) or sham operation. Surgical procedures were conducted under diethyl ether anesthesia. RESULTS: The gastrointestinal transit has not been markedly affected in rats, which were anesthetized or subjected to skin incision in comparison with untreated animals. In contrast, a sham operation and I/R have significantly reduced the intestinal motility. Pretreatment with NK1-3 blockers (SR140333 [3-30 µg/kg]; SR48968 [3-100 µg/kg]; and SB222200 [10-100 µg/kg]) reversed dose dependently the effects of I/R to the level observed after sham operation only. A combination of NK1+NK2+NK3 inhibitors exerted an additive effect compared with NK1 and NK2 antagonists used as single agents. Similarly, combined NK1+NK2 were more effective than NK2 alone. Sham operation and I/R have shifted the in vitro carbachol concentration-response curves to the right in comparison with untreated animals, a phenomenon partially reversed by NK1-NK3 pretreatment. CONCLUSIONS: Single-agent and combined treatment with NK1-3 antagonists markedly attenuated the gastrointestinal dysmotility evoked by I/R injury. The pretreatment with NK3 blocker proved to be the most active in this experimental setting.

New Approach to Paediatric Mastocytosis: Implications of KIT D816V Mutation Detection in Peripheral Blood.

is missing (Short communication).

The protective effect of endothelin receptor antagonists against surgically induced impairment of gastrointestinal motility in rats.

Endothelin (ET) receptor antagonists: BQ-123 (ETA), BQ-788 (ETB), tezosentan (dual ET receptor antagonist) protect against the development of postoperative ileus (POI) evoked by ischemia-reperfusion (I/R). The current experiments explored whether ET antagonists prevent the occurrence of POI evoked by surgical gut manipulation. Intestinal transit was assessed by measuring the rate of dye migration subsequent to skin incision (SI), laparotomy (L), or laparotomy and surgical gut handling (L+M) in diethyl ether anaesthesized rats (E). Experimental animals were randomly sub-divided into two groups depending on the time of recovery following surgery: viz. either 2 or 24 h (early or late phase POI). E and SI did not affect the gastrointestinal (GI) transit. In contrast, L and L+M significantly reduced GI motility in comparison to untreated group (UN). Tezosentan (10 mg/kg), BQ-123 and BQ-788 (1 mg/kg) protected against development of L+M evoked inhibition of intestinal motility in the course of late phase, but not early phase POI. Furthermore, tezosentan alleviated the decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro induced by L+M. The serum ET(1-21) concentration was not increased in either the early or the late phase POI groups after surgery compared to control animals. This study indicates that delay in the intestinal transit in late phase of surgically induced POI involves an ET-dependent mechanism.

Cutaneous mastocytosis treatment: strategies, limitations and perspectives.

Mastocytosis is a rare myeloproliferative disease, characterized by excessive proliferation and accumulation of mast cells in the tissues. In cutaneous mastocytosis (CM), mast cells infiltration is limited to the skin, whereas in systemic mastocytosis (SM) internal organs are involved. The first-line treatment in CM is antimediator therapy (mainly H1 and H2 antihistamines) and short-term topical corticosteroids. Phototherapy is the second-line therapy which may be considered when antihistamines do not produce the expected improvement. New therapeutic options include omalizumab and KIT-targeting agents. Although the disappearance of skin lesions has been reported as a result of cytoreductive therapies in SM, the use of potentially toxic drugs in CM is not recommended. In all adults with mastocytosis and in pediatric patients with severe CM, a persistently elevated serum tryptase level and anaphylaxis in medical history, equipping with epinephrine autoinjector for use in case of anaphylaxis is recommended.

The role of serum tryptase in the diagnosis and monitoring of pediatric mastocytosis: a single-center experience.

INTRODUCTION: In children, cutaneous mastocytosis (CM) is considered to be a benign disease associated with mast cell mediator-related symptoms. However, systemic mastocytosis (SM) and anaphylaxis may also occur. Since the basal serum tryptase (bsT) level reflects mast cell burden, its determination is recommended in the diagnosis and follow-up. AIM: To compare clinical presentation and the course of mastocytosis in children with normal and clearly elevated bsT levels as well as to assess its usefulness in the diagnosis and monitoring of the course of the disease. MATERIAL AND METHODS: A retrospective analysis of 102 medical records of children with mastocytosis diagnosed and followed-up in the Gdansk Mastocytosis Center in 2014 was performed. RESULTS: Maculopapular CM (MPCM) was diagnosed in 91 (89.22%) children, diffuse cutaneous mastocytosis (DCM) in 7 (6.86%) and mastocytoma in 4 (3.92%). The presence of flushing and bullous lesions was more frequent in children with bsT levels > 20 ng/ml in comparison with those who had bsT ≤ 20 ng/ml (p = 0.002 and p = 0.03, respectively). Anaphylaxis occurred in 2 MPCM children with bsT levels in normal ranges. In all of the 3 children with persistently and clearly elevated bsT levels, bone marrow biopsy revealed no mast cells infiltrates corresponding to SM. CONCLUSIONS: Although mastocytosis children with clearly elevated bsT levels frequently develop mediator-related symptoms, the occurrence of anaphylaxis in this age group may be difficult to predict. In pediatric cases with suspected SM, the bsT level is one of the crucial parameters considered before the decision on bone marrow biopsy.

Interleukin-31 Polymorphisms and Serum IL-31 Level in Patients with Mastocytosis: Correlation with Clinical Presen-tation and Pruritus.

Data on interleukin-31 (IL-31) involvement in the patho-genesis of mastocytosis, and its impact on pruritus development in the disease, are limited. The aim of this study was to analyse distinct IL-31 gene polymorphisms in 127 patients (age 0.5-76 years) with mastocytosis and their correlation with clinical presentation, pruritus and serum IL-31 levels. In patients with mastocytosis, the frequency of IL-31 IVS2+12AA genotype and IVS2+12A allele was higher than in control subjects and they were linked to an increased risk of development of mastocytosis. In adult patients, but not in children, -2057AA genotype was also associated with an increased risk of occurrence of mastocytosis. Pruritus affected 83.3% of 78 adult patients with mastocytosis, and a positive correlation between serum IL-31 levels and pruritus was found in these patients. In conclusion, distinct polymorphic variants of the IL-31 gene may be involved in the patho-genesis of mastocytosis, and IL-31 may be involved in the induction of pruritus in patients with mastocytosis.

The role of polymorphism of interleukin-2, -10, -13 and TNF-α genes in cutaneous T-cell lymphoma pathogenesis.

INTRODUCTION: As the pathogenesis of cutaneous T-cell lymphomas (CTCL) is not fully understood, inherited gene polymorphisms are considered to play a role in the development of lymphomas. AIM: To investigate whether certain gene polymorphisms might be involved in the development of CTCL. MATERIAL AND METHODS: In the case-control study we compared the frequency of nine selected single nucleotide polymorphisms (SNP) of seven genes (rs1800587/-889 C/T of interleukin (IL)-1α, rs2069762/-330G/T) and rs2069763/+166G/T of IL-2, rs1800925/-1112 C/T of IL-13, rs1800896/-1082 A/G of IL-10, rs4073/-251 A/T of IL-8, rs5370/K198N, rs180054/-1370T/G of endothelin-1 and rs1800629/-308 G/A of TNF-α) in 43 CTCL and Polish cases using the amplification refractory mutation system polymerase chain reaction method. RESULTS: We have found that two genotypes, -330GG of IL-2 and -1112TT of IL-13 both promoter variants associated with "hypertranscription phenotype", were over-represented in CTCL patients compared to healthy controls, and they increase the risk of malignancy development (OR = 5.82, p = 0.001 for IL-2 -330 GG, and OR = 5.67, p = 0.0024 for IL-13 -1112 TT). On the other hand, high transcription -308A allele of the TNF-α gene and -1082GG of IL-10 genotype is less frequent in lymphoma patients and has protective effects on the development of CTCL (OR = 0.45, p = 0.0466 for -308A of TNF-α, and OR = 0.35, p = 0.0329 for -1082GG of IL-10 genes). CONCLUSIONS: Our results indicate that hypertranscription promoter variants of IL-2 and IL-13 genes could be estimated as the risk factor for development of CTCL, while TNF-α and IL-10 variants have a protective effect.

Diagnosis of Mastocytosis in Children and Adults in Daily Clinical Practice.

Mastocytosis comprises a heterogeneous group of disorders characterized by clonal, neoplastic proliferation of mast cells accumulating in one or multiple organs. In the majority of cases skin involvement is the first clinical manifestation of the disease. Clinical work-up consists of a combination of morphological, immunohistochemical, flow cytometric immunophenotyping and molecular examination. Cutaneous mastocytosis predominates in children, whereas systemic mastocytosis is the most common form of the disease in adults. Therefore, different diagnostic algorithms have to be applied in adult patients and children with suspected mastocytosis. This comprehensive review presents currently defined variants of the disease and recommendations to facilitate diagnostic work-up in children and adults with suspected mastocytosis in daily clinical practice.

Polish Lymphoma Research Group Experience With Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma.

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sézary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

Atopic dermatitis: current treatment guidelines. Statement of the experts of the Dermatological Section, Polish Society of Allergology, and the Allergology Section, Polish Society of Dermatology.

Atopic dermatitis (AD) is a condition frequently encountered in medical practices across the country. More than 60% of children with AD are at risk to develop allergic rhinitis or asthma (the atopic march). Patients with AD have a unique predisposition to colonization or infection by Staphylococcus aureus. Treatments for AD need to rapidly control symptoms of the disease, improve quality of life and prevent exacerbations. Given the chronic and relapsing nature of the disease, therapies need to encourage good compliance and be well tolerated.

Oral retinoids and rexinoids in cutaneous T-cell lymphomas.

Retinoids are biologically active derivatives of vitamin A modulating cell proliferation, differentiation, apoptosis and altering the immune response. They have been used for years in therapy of cutaneous T-cell lymphomas (CTCL) but the exact mechanism of retinoids' action is unclear. It is based on the presence of specific receptors' families, mediating the biological effects of retinoids on the tumor cells: retinoic acid receptor (RAR) and retinoic X receptor (RXR). Orally administrated bexarotene, the first synthetic selective RXR retinoid, was revealed to be active against the cutaneous manifestation of CTCL. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated than classical retinoids, but generally associated with more severe grades of toxicity. Both selective retinoic acid receptor- and retinoic X receptor-mediated retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy and radiotherapy. The authors reviewed the literature on the results of the use of retinoids and rexinoids in patients with mycosis fungoides and Sézary syndrome.

Atopic dermatitis-like pre-Sézary syndrome: role of immunosuppression.

We describe here 4 patients with Sézary syndrome masquerading as adult-onset atopic dermatitis. The patients presented with a clinical picture compatible with wide-spread atopic dermatitis and did not fulfil the criteria for Sézary syndrome (lack of lymphoadenopathy and blood involvement, skin histology without presence of atypical cells). In our patients, overt Sézary syndrome developed after immunosuppressive treatment (including cyclosporine). These cases support the validity of the concept of pre-Sézary syndrome, which is a long-lasting, pre-malignant condition, and which may develop to true malignancy in a state of immunosuppression.