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Year : 2022  |  Volume : 2  |  Issue : 4  |  Page : 221-225

Aggressive Systemic Mastocytosis with a Relatively Non-aggressive Course

1 Department of Pediatrics, Lady Hardinge Medical College, New Delhi, India
2 Department of Dermatology, Lady Hardinge Medical College, New Delhi, India
3 Department of Pathology, Lady Hardinge Medical College, New Delhi, India

Date of Submission04-Jul-2022
Date of Decision14-Sep-2022
Date of Acceptance29-Oct-2022
Date of Web Publication29-Nov-2022

Correspondence Address:
Dr. Sharmila B Mukherjee
Department of Pediatrics, Kalawati Saran Children's Hospital, Bangla Sahib Marg, New Delhi - 110 001
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_164_22

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Background: Mastocytosis is a heterogeneous group of disorders that is characterized by excessive proliferation and pathologic accumulation of mast cells in various body tissues. The mast cells also have abnormal morphology and aberrant expression of surface receptors. Clinical Description: A 4-year-old boy was brought with a history of generalized skin lesions since birth and abdominal distension for 3 years. The diagnosis had not been established to date. General physical examination revealed severe acute malnutrition, pallor, dental staining, facial hypertrichosis, polymorphous skin lesions (cicatricial alopecia, diffuse erythema, multiple plaques of variable diameter, skin-colored nodules, and hypertrophic irregular scars), and positive Darier's sign. He also had hepatosplenomegaly. The differentials considered were congenital erythropoietic porphyria, systemic mastocytosis (SM), multifocal Langerhans cell histiocytosis, and linear immunoglobulin A bullous dermatosis. The presence of mast cells on skin biopsy and elevated serum tryptase levels led us to suspect SM and perform bone marrow studies. The diagnosis of “aggressive” SM was initially made on the application of the diagnostic criteria but revised to “smoldering” SM with the emergence of Vitamin B12 deficiency as the probable cause of pancytopenia. Management: Management was planned by a multidisciplinary team: pediatrician, dermatologist, and hematopathologist. The parents were counseled about the nature, natural history, treatment options, and prognosis of the disorder. The child was provided with nutritional rehabilitation and medication for the cutaneous symptoms (selective histamine H1 receptor inverse agonist, H2-receptor antagonist, and application of topical tacrolimus and calamine lotion). Conclusion: The prognosis varies according to subtype. Careful correlation of clinical and laboratory investigations is required when applying the diagnostic criteria for staging.

Keywords: Darier's sign, KIT mutation, mast cells, serum tryptase, urticaria

How to cite this article:
Madaan A, Yadav V, Kataria S, Mendiratta V, Shukla S, Jyotsna P L, Mukherjee SB. Aggressive Systemic Mastocytosis with a Relatively Non-aggressive Course. Indian Pediatr Case Rep 2022;2:221-5

How to cite this URL:
Madaan A, Yadav V, Kataria S, Mendiratta V, Shukla S, Jyotsna P L, Mukherjee SB. Aggressive Systemic Mastocytosis with a Relatively Non-aggressive Course. Indian Pediatr Case Rep [serial online] 2022 [cited 2023 Jan 30];2:221-5. Available from: http://www.ipcares.org/text.asp?2022/2/4/221/362237

Mastocytosis is a heterogeneous group of disorders that is characterized by excessive proliferation and pathologic accumulation of mast cells in various tissues of the body. The cells may also have abnormal morphology and aberrant expression of surface receptors.[1] The overall prevalence of mastocytosis is 1 in 10,000, out of which two-thirds are diagnosed in children.[1] The age of onset of symptoms is variable; 55% presenting from birth to 2 years, 10% up to 15 years, and 35% in individuals older than 15 years.[2] There is a slight male preponderance, with a sex ratio of 1.4:1.[3] Most cases are sporadic and 4% are familial.[3]

Mastocytosis is classified as cutaneous melanoma (CM) when manifestations are limited to the skin and systemic mastocytosis (SM) when there is additional involvement of other tissues/organs. SM is very rare, accounting for <10% of cases.[4] It is characterized by flushing, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain. These features are due to mast cell mediator release (primarily histamine) and tissue/organ infiltration. The severity and prognosis are variable, depending on the subtype.

The etiology of SM is still unclear. It has frequently been associated with a functional mutation of the somatic proto-oncogene KIT gene (CD117) found on 4q12 and is therefore not hereditary. This locus encodes tyrosine kinase receptors that are expressed on mast cells and hematopoietic stem cells. Most affected adults display mutations of KIT codon D816V in exon 17, in contrast to only 42% of pediatric patients. In children, mutations have also been found in exons 8, 9, 11, and 13.[5] Mutations result in the loss of function of hematopoietic stem cell factor, leading to clonal proliferation and increased longevity of the mast cells.[1]

SM is often mistaken for the more common childhood dermatological disorders associated with pruritis, such as urticaria and eczema secondary to allergens, insect bites, bullous impetigo, rare autoimmune bullous disease, and linear immunoglobulin (Ig) A bullous dermatosis.[6] The purpose of sharing our experiences in managing this case is to increase awareness among clinicians and to highlight the challenges we faced in establishing subtypes.

  Clinical Description Top

A 4-year-old boy presented with generalized skin lesions since birth. Historically, there were two types of lesions. The first was large blisters which ruptured discharging blood and healed with scarring. These had been noted on his back at birth. Since then, they had developed everywhere on his body, except his palms and soles. The parents had noted that fresh lesions appeared after minor trauma or scratching. The second lesions were multiple, itchy, raised, reddish-to-brownish, round-to-oval lesions, of varying size and generalized distribution. These got transiently relieved by medication, the nature of which was unknown. Neither lesion was associated with sneezing, wheezing, or watering, redness of the eyes, or increased exposure to sunlight or ingestion of drugs.

The child also had abdominal distension for 3 years, insidious in onset and gradually increasing. There was no history of abdominal pain, altered bowel habits, vomiting, jaundice, or decreased urine output. There was no significant antenatal, perinatal, or past history. The child was sixth in the birth order, of a nonconsanguineous marriage. Other family members were asymptomatic. He was developmentally normal, completely unimmunized, and belonged to an upper–lower socioeconomic background. He had been treated intermittently, but without symptomatic resolution, or establishment of diagnosis.

The patient was afebrile and hemodynamically stable. His weight was 9.4 kg (−4 z-score), height 77.2 cm (−6 z-score), and mid-upper arm circumference 10.5 cm indicating severe acute malnutrition (SAM). The general physical examination revealed some pallor, dental staining, facial hypertrichosis, significant generalized lymphadenopathy, and multiple polymorphous skin lesions. The abdomen was uniformly distended with visible dilated veins [Figure 1]. The liver was enlarged (8 cm below the costal margin with a span of 14 cm). The surface was smooth and consistently firm, and the margins were sharp. Firm splenomegaly was noted (11 cm below the costal margin). Shifting dullness was absent. The remaining systemic examination was normal. Since the clinical phenotype was a chronic illness with onset since birth, cutaneous manifestations, and hepatosplenomegaly, we consulted colleagues in the dermatology department.
Figure 1: Distended abdomen with dilated veins, mild diffuse thickening of the skin, and postinflammatory hyperpigmentation

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Many different lesions were identified: well-circumscribed (3 cm × 3 cm) plaques with scarring over the occiput suggestive of cicatricial alopecia; faint diffuse erythema on his face, chest, and back; multiple dark-brown macules of variable size (0.5–1 cm in diameter) and diffuse thickening of the skin that resembled melanocytic nevi and mast cell infiltrates; multiple erythematous to skin-colored plaques of variable size (diameter 1–1.5 cm) over his face, neck, back, chest, and extremities [Figure 2]; a positive Darier's sign [Video 1]; multiple skin-colored nodules of variable size (1 cm × 1 cm–3 cm × 3 cm) over his axillae, back, and buttocks [Figure 2]; multiple hypertrophic irregular scars over the upper back suggestive of recurrent blistering [Figure 2], and that made us consider linear IgA bullous dermatosis.
Figure 2: Polymorphic cutaneous lesions on the back showing diffuse, thickness of skin, erythematous to skin-colored plaques and nodules of variable size, scarring, postinflammatory hyperpigmentation, and melanocytic naevi

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[Additional file 1]

The following differential diagnoses were considered: (i) congenital erythropoietic porphyria (CEP) – due to recurrent bullae, dental staining, and organomegaly, although reddish urine and photosensitivity were absent; (ii) SM – typical lesions observed with positive Darier's sign, hepatosplenomegaly, lymphadenopathy, and pallor, but gastrointestinal symptoms were absent; (iii) multifocal Langerhans cell histiocytosis – the presence of pallor, hepatosplenomegaly, generalized lymphadenopathy, and positive Darier's sign, but the absence of characteristic skin lesions, bony tenderness, or pulmonary, endocrinal, and gastrointestinal involvement; (iv) linear IgA bullous dermatosis – points in favor were the blisters, erosions, plaques, erythema, and hepatosplenomegaly (may be associated with lymphoproliferative disorders), whereas points against were the absence of “string of pearls” appearance, presence of nodules, and the fact that remission is seen in most children within 2 years of onset. Two differentials considered in view of generalized lymphadenopathy and hepatosplenomegaly but disregarded due to the polymorphic skin lesions, onset since birth, and indolent course, were acute lymphoblastic leukemia and hemophagocytic lymphohistiocytosis.

Management and outcome

The results of the preliminary investigations are given in [Table 1]. Salient findings were macrocytic anemia and bicytopenia, normal liver function test, renal function test, lipid profile, and absence of eosinophilia. There was no evidence of sepsis (C-reactive protein 2.7 mg/dl, blood and urine cultures sterile). The absence of fluorescence on wood lamp examination and normal serum lactate dehydrogenase (253 IU/L) ruled out CEP. The skin biopsy taken from a nodule displayed positive special staining for mast cells indicative of CM. Given the presence of systemic features, we started investigating for SM. The serum tryptase level was increased (>200 μg/L). Fine-needle aspiration cytology of an inguinal lymph node showed polymorphous lymphocytes with numerous mast cells. Bone marrow aspirate showed an increase in mast cells in clusters, as well as scattered spindle forms. A few large atypical mast cells (round-to-oval with granular-to-hypogranular cytoplasm, central round-to-oval-to-spindle-shaped nuclei with coarse chromatin, and irregular nuclear membranes) were present. The erythroid series, myeloid series, and megakaryocytes were normal. Bone marrow biopsy revealed hypercellular marrow spaces (approximately 100%) with infiltration of the paratrabecular and intertrabecular regions by multifocal compact clusters of atypical mast cells [Figure 3]a and [Figure 3]b. There were a few preserved areas of hematopoiesis. CD117 was positive on immunohistochemistry [Figure 3]c.
Table 1: Baseline investigation reports

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Figure 3: (a) Hematoxylin and eosin section of bone marrow aspirate showing increased mast cells in clusters, scattered spindle forms, and atypical and immature mast cells. (b) Special stain for mast cells (toluidine blue) positive. (c) Positive CD117 on immunohistochemistry

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The diagnosis of SM is established by the presence of one major and one minor, or three minor WHO diagnostic criteria. The major criterion is the presence of multifocal, dense infiltrates of mast cells (>15 in aggregates) in bone marrow (BM) or extracutaneous biopsies. The minor criteria include: (i) atypical morphology >25% mast cells on biopsy sections, (ii) KIT point mutation at codon 816 in the BM or another extracutaneous organ, (iii) CD2, and/or CD25 on mast cells, and (iv) serum total tryptase >20 ng/ml. Although mutation analysis or CD testing was not feasible due to financial constraints, one major and one minor criteria were satisfied.

[Table 2] depicts the subtyping of SM based on various parameters: “B findings” or burden of disease, “C findings” or cytoreduction requirement, and mast cell leukemia (MCL). Prima facie, the subtype in this patient appeared to be aggressive SM (ASM) in view of 2 “C” findings, i.e., evidence of BM dysfunction (bicytopenia) and splenomegaly with hypersplenism (two cell lineages involved). However, a major point against it was the fact that survival beyond 2 years was not compatible with the natural history of ASM. The increased mean corpuscular volume and macrocytes prompted us to evaluate Vitamin B12 levels, which were low (109 pg/ml; normal 200–835 pg/ml), whereas folate levels were normal (6.07 nmol/ml). This was a more biologically plausible explanation for the cytopenias, especially since the typical BM findings of B12 deficiency could not be made due to the SM. Thus, on revisiting the criteria [Table 2], the presence of 2 “B” findings (>30% mast cells and hepatosplenomegaly in absence of dysfunction) satisfied “smoldering” SM, which was more in alignment with the clinical phenotype.
Table 2: Parameters required for subtyping of systemic mastocytosis

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Management of SAM and the nutritional deficiencies proceeded as per hospital protocol. The parents were counseled about the nature, natural history, treatment options, and prognosis of SM. The cutaneous manifestations were treated with oral hydroxyzine (selective histamine H1 receptor inverse agonist), levocetirizine (H2-receptor antagonist), and the application of topical tacrolimus and calamine lotion. We could not consider midostaurin, an food and drug administration (FDA)-approved multikinase inhibitor effective in KIT D816V mutation.

  Discussion Top

The diagnosis of SM in children is based on the 2016 WHO criteria which are completely investigation based.[7] Further delineation into subtypes based on severity is complex, basically determined by the additional presence of “B findings” indicative of infiltration without dysfunction, “C findings” indicative of infiltration with organ dysfunction, or MCL. There are seven subtypes: CM (no systemic involvement), indolent SM (ISM) (absence of B, C or MCL), smoldering SM (SSM) (≥2 B and no C), ASM (>1 C, no MCL), MCL +, SM associated with hematologic neoplasm (SM-AHN) (additional clonal hematologic nonmast cell lineage disorders), and mast cell sarcoma.[7],[8] The prognosis depends on the subtype. Most studies of median survival of subtypes of SM have been done in adult patients.[9] Outcomes in terms of survival are relatively good in ISM and SSM, although 9.4% of cases of the latter progress to advanced SM.[10] ASM and SM-AHN are associated with poor prognosis, whereas MCL has the worst prognosis. We were unable to find similar studies in children, to help us prognosticate the parents.

Our case displayed some other atypical features. The presence of blisters since birth is exceptionally rare.[11] Bullous formation is due to histamine-induced capillary vasodilation and their presence in the neonatal period indicates a higher probability of having systemic involvement, poor prognosis, and early death.[12] This was not true in this case. At admission, the total leukocyte count was significantly elevated and mainly neutrophilic (in the absence of sepsis). The former can be explained by the release of proinflammatory and chemotactic factors by mast cells that affect leukocyte migration and recruitment, leading to leukocytosis. Our patient also had thrombocytopenia in contrast to the thrombocythemia that has been reported earlier with SM.[13] However, this could be explained by the Vitamin B12 deficiency, rather than BM dysfunction due to a “C” finding [Table 2].

The management of SM is multidisciplinary involving clinicians (the pediatrician and/or dermatologist depending on to whom the child presents) and hematopathologists. As there is currently no available cure, the goals of treatment are to mitigate organ damage, alleviate symptoms, improve the quality of life, and achieve long-term disease control.

Therapeutic options are according to the subtype. In ISM, the goal of treatment is to avoid the induction of mast cell release and control the resultant symptoms. The drugs used for symptomatic relief are H1 or H2-receptor blockers, mast cell membrane stabilizers (sodium tryptophan), leukotriene inhibitors (montelukast), and nonsteroidal anti-inflammatory drugs.[4] ASM should be treated with chemotherapy. Commonly used regimens include interferon-α alone or in combination with prednisone.[14] Tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, midostaurin, hydroxyurea, and metaxalone may be used. Imatinib is suitable in SM due to KIT mutations that are sensitive to the drug, or those without KIT D816V mutations.[14] Midostaurin is the only TKI-approved monotherapy for ASM.[14] There is preliminary evidence that allogeneic hematopoietic stem cell transplantation (HSCT) may improve survival.[14] Since the role is still not definite, HSCT is generally reserved for patients who fail to respond adequately, relapse after initial therapy, or have adverse prognostic features.

It is important that the disease progression be monitored carefully in terms of the clinical and investigation profile. Patients are usually followed up every 1 to 3 months. This depends primarily on the burden of symptoms, overall clinical status, and whether any associated hematologic neoplasm coexists. In conclusion, due to its rarity, this condition may be easily missed unless clinicians keep a high index of suspicion and work in tandem with each other, as well as with hematopathologists.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Lange M, Nedoszytko B, Górska A, et al. Mastocytosis in children and adults: Clinical disease heterogeneity. Arch Med Sci 2012;8:533-41.  Back to cited text no. 4
Bodemer C, Hermine O, Palmérini F, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Invest Dermatol 2010;130:804-15.  Back to cited text no. 5
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Trizuljak J, Sperr WR, Nekvindová L, et al. Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification. Allergy 2020;75:1927-38.  Back to cited text no. 10
Huang A, Fiadorchanka N, Brar K, et al. In utero presentation of aggressive systemic mastocytosis in a neonate. Br J Dermatol 2017;177:1439-41.  Back to cited text no. 11
Murphy M, Walsh D, Drumm B, et al. Bullous mastocytosis: A fatal outcome. Pediatr Dermatol 1999;16:452-5.  Back to cited text no. 12
Cancian M, Cosi E, Pizzi M, et al. Systemic mastocytosis and essential thrombocythemia: Case report and literature overview. Medicina (Kaunas) 2019;55:528.  Back to cited text no. 13
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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