Mastocytoma


Article Author:
Aadil Ahmed


Article Editor:
Arif Jan


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
11/13/2019 9:15:49 PM

Introduction

A Mastocytoma is a tumor of mast cells, which are derived from myeloid stem cells and located in connective tissues, predominantly in the skin and mucosal linings. The cytoplasmic granules of mast cells are filled with histamines, peptides and other cytokines which play an active role in immune responses, especially in allergic and anaphylactic reactions.

Clonal proliferation of neoplastic mast cells can lead to localized and systemic manifestations, categorized under the term 'mastocytosis' and classified as a myeloproliferative disorder in the WHO classification of tumors of hematopoietic and lymphoid tissues. Majority of patients with mastocytosis have skin involvement, and while the cutaneous disease is localized to the skin, systemic mastocytosis requires the participation of one or more extracutaneous organ. In adults, the disease tends to be chronic and systemic while the purely cutaneous disease is usually seen in childhood. Cutaneous mastocytosis can range from solitary mastocytoma to diffuse erythrodermic mastocytosis, most commonly presenting as maculopapular lesions known as urticaria pigmentosa (UP)[1]

Etiology

Although etiology of the disease is not completely clear, the microenvironment of the lesional tissue reveals an increased concentration of growth factors and interleukins that induce proliferation of mast cells and melanocytes and inhibit mast cell apoptosis are believed to play a role.  Somatic mutations of the c-kit gene leading to increased activation of mast cell growth factor are also implicated but may not be the initiating factor in the proliferation of abnormal mast cells[2]. The most common c-kit mutation is the D816V in exon 816, found in both adult and childhood cases[3]. Although these mutations are somatic, rare familial cases in autosomal dominant fashion have also been reported[4]

Epidemiology

Cutaneous mastocytosis without systemic involvement tends to affect children with the majority of patients presenting during the first two years of life[5]. Both mastocytoma and UP lesions can also be present at birth. UP constitutes the majority of cases with 70-90%, followed by mastocytomas or nodular proliferations in 10-35% of cutaneous mastocytosis[1]. Diffuse involvement is rare, comprising only 1-3% of cases[1]. Mastocytomas are usually solitary. However, less than four lesions are categorized under mastoctyoma. The disease does not show any predilection for gender or race. Rare cases of adult-onset cutaneous mastocytoma are also reported in the literature[6]

Pathophysiology

While the accumulation of mast cells appear as maculopapular or nodular lesions, physical stimuli like rubbing or pressure on the lesion results in degranulation of mast cells, thus releasing histamine, leukotrienes, and prostaglandins that cause localized and systemic symptoms. 

Histopathology

Histologic examination shows dermal infiltrate of mast cells, primarily in the papillary dermis that can be accompanied by dermal edema and eosinophils. Mast cells tend to aggregate around blood vessels and appear as a spindle to round cells with pale granular cytoplasm and pale nuclei. Nuclear pleomorphism and lobation are also reported in rare case reports[6] However, frank nuclear atypia is not seen and should raise suspicion for malignant transformation. Infrequent mitoses can be observed. Deep dermal and subcutaneous infiltration can be seen in nodular forms. Giemsa or toluidine blue stain highlights metachromatic granules whereas positive immunophenotypic expression of tryptase, C-KIT and aberrant immunophenotypic or flow cytometric positivity for CD25 and less commonly CD2 can confirm the neoplastic nature of mast cells.  

History and Physical

Cutaneous mastocytosis can involve any part of the body, but mostly it is found on the trunk and extremities. Lesions can be single or few, of variable size and appear as yellowish brown pigmented macules, papules or nodules. The lesions are generally non-tender but can be associated with intermittent itching and erythema. Rubbing or stroking the lesion can degranulate the mast cells and cause flushing, itching, and swelling of the skin, known as Darrier's sign which is pathognomic of the disease. The blistering and bullous presentation is common in children less than three years of age and can also be present in diffuse and severe forms of the disease. The difference between mastocytoma and UP is based on the number of lesions present when the number is three or fewer nodules it is a mastocytoma. The diffuse disease presents with thickened, leathery skin without individual lesions.

Telangiectasia macularis eruptiva perstans is an extremely uncommon variant that may present as red telangiectatic macules and may be found in conjunction with UP. No scarring results from any of the lesions. While there is no systemic involvement in cutaneous mastocytosis, symptoms of wheezing and syncope have been reported. Gastrointestinal symptoms including diarrhea have been reported in about 40% of children. Alternatively, a full-blown acute mast cell activation causing anaphylactic symptoms may also occur.  

Evaluation

While the diagnosis of cutaneous mastocytoma/mastocytosis can be made on the physical appearance of the lesions, especially if Darrier's sign is present, histology and molecular tests are required to differentiate from mast cell hyperplasia or reactive conditions. WHO classification involves the presence of both clinical and histologic findings and exclusion of systemic disease before the diagnosis of cutaneous mastocytosis/mastocytoma is made. A Fine Needle Aspiration Biopsy of the lesion is sufficient to diagnose mast cell proliferation. However, surgical biopsy may be required to fully differentiate as cells can vary from well-differentiated to poorly differentiated. The disease is staged into four stages based on WHO criteria. 

Dermatoscopy findings are non-specific. Baseline serum tryptase level and CBC should be performed before therapy. Elevation of serum tryptase and bone marrow involvement is generally not seen in pediatric cutaneous disease but may be present in adult patients. Pediatric cases with systemic symptoms, abnormal CBC, failure of symptomatic therapy and elevation of tryptase can also be evaluated for bone marrow abnormalities. Abdominal ultrasound can be performed to exclude organomegaly. 

Treatment / Management

Treatment is symptomatic and aimed to reduce triggers (rubbing, change in temperature, dryness, etc) that may cause mast cell release. Oral antihistamines and topical corticosteroids are generally used to alleviate symptoms. Phototherapy has also been used to relieve pruritus. Cytoreductive and surgical therapy is reserved for systemic cases. Epinephrine should be used for any cases showing symptoms of anaphylaxis. 

Differential Diagnosis

  • Congenital or early-onset melanocytic nevus
  • Juvenile xanthogranuloma
  • Tuberous xanthoma

Staging

WHO staging system classifies the disease into four stages based on the number of lesions, the involvement of Lymph nodes and distant metastases

  • Stage I when the disease is restricted to one lesion without any Lymph Node Involvement
  • Stage II when a solitary skin lesion involves the adjacent Lymph Nodes.
  • Stage III when lesions are multiple or a large lesion invades deep into the skin with or without the involvement of Lymph Nodes.
  • Stage IV when mast cell tumor has metastasized. Usually metastasizes to Spleen, Liver or Bone Marrow.

Prognosis

Cutaneous mastocytosis follows a benign course and overall carries a good long term prognosis. Children with the onset of disease before 2 years of age generally end with the complete resolution of the disease by 10 years of age [7]. Unresolved cases and cases that appear after 2 years of age are likely to persist. While adult-onset cases usually manifest with systemic symptoms, persistent cases from childhood can occasionally progress to systemic disease. An increased risk of systemic disease in pediatric cases is seen in those who present with the disease after 2 years of age, the presence of symptoms beyond adolescence or those with abnormal blood counts. Both persistent and adult-onset disease, albeit rare, have a risk of malignant sarcomatous (characterized by atypical mast cells) or leukemic (atypical, immature mast cells in blood) transformation [8][9]

Complications

  • Persistent disease
  • Systemic involvement including anaphylaxis
  • Malignant transformation to mast cell sarcoma or mast cell leukemia (rare)

Deterrence and Patient Education

  • Avoidance of stimuli that trigger symptoms
  • Patients with systemic disease should be made aware of the possibility for anaphylaxis and should carry injectable epinephrine

Pearls and Other Issues

Darrier's sign may be present in only half of the cases. 

Enhancing Healthcare Team Outcomes

While pediatricians may be the first one to encounter the disease, a dermatology consult remains essential. Histologic confirmation is one of the diagnostic criteria and thus a pathologists' interpretation is also needed for the definitive diagnosis. Radiology can be involved in cases with systemic involvement to localize subclinical organomegaly, if present.  It is important to educate the patient on the avoidance of triggers. All patients should be educated on how to use epinephrine and carry the medication with them at all times. A bracelet with an ID and disease identification is highly recommended for patients with a previous anaphylactic reaction. Patients with cutaneous mastocytosis have a good prognosis but those with a malignant cause have a guarded prognosis.[10] (Level V)


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Mastocytoma - Questions

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A 6-year-old girl is brought to the clinic with a single red-brown nodule on her neck that becomes erythematous and itchy every time she feels it. A biopsy is performed that shows dermal proliferation of small round cells with pale cytoplasm that demonstrated CD25 immunopositivity. Which of the following cells is most likely to be seen on biopsy?



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A pathologist receives a skin biopsy from the right cheek of a 3-year-old boy that shows extensive proliferation of bland-looking small round cells with pale cytoplasm and central nuclei, involving the dermis and subcutaneous tissue along with scattered eosinophils. The cells are positive for CDC117, tryptase, and CD25. The pathologist wants to send the specimen for molecular testing to rule out the most common mutation, sometimes found in this disease. Which of the following mutations is the pathologist most likely concerned about?



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A 1-year-old girl is brought to the clinic due to the presence of scattered pigmented papules on her right arm that were noticed a week ago. During the physical examination, the clinician rubbed the lesions, and that made the lesions swell and tender to touch. Which of the following best identifies this sign?



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A 2-month-old boy is brought to the clinic for three tan-yellow, slightly erythematous papules ranging in size from 0.3-0.5 cm that are positive for Darier's sign, and a biopsy confirms the diagnosis. The clinician prescribes antihistamine resulting in the resolution of symptoms. Which of the following best describes the prognosis of this condition?



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A 17-year-old boy had a summer hiking trip with his friends in Northern Connecticut and developed an itchy papular rash over his arms and face the next day. The rash completely resolved in two days. The ovoid to spindle cells that commonly play a key role in developing the rash in this patient are derived from which progenitor cells?



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Mastocytoma - References

References

Castells M,Metcalfe DD,Escribano L, Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. American journal of clinical dermatology. 2011 Aug 1;     [PubMed]
Longley BJ,Tyrrell L,Lu SZ,Ma YS,Langley K,Ding TG,Duffy T,Jacobs P,Tang LH,Modlin I, Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nature genetics. 1996 Mar;     [PubMed]
Ma D,Stence AA,Bossler AB,Hackman JR,Bellizzi AM, Identification of KIT activating mutations in paediatric solitary mastocytoma. Histopathology. 2014 Jan;     [PubMed]
Kettelhut BV,Metcalfe DD, Pediatric mastocytosis. Annals of allergy. 1994 Sep;     [PubMed]
Exposito-Serrano V,Agut-Busquet E,Leal Canosa L,Herrerías Moreno J,Saez A,Luelmo J, Pleomorphic mastocytoma in an adult. Journal of cutaneous pathology. 2018 Feb;     [PubMed]
Azaña JM,Torrelo A,Mediero IG,Zambrano A, Urticaria pigmentosa: a review of 67 pediatric cases. Pediatric dermatology. 1994 Jun;     [PubMed]
Auquit-Auckbur I,Lazar C,Deneuve S,Guillemet C,Cordel N,Blanchard F,Joly P,Courville P, Malignant transformation of mastocytoma developed on skin mastocytosis into cutaneous mast cell sarcoma. The American journal of surgical pathology. 2012 May;     [PubMed]
Chantorn R,Shwayder T, Death from mast cell leukemia: a young patient with longstanding cutaneous mastocytosis evolving into fatal mast cell leukemia. Pediatric dermatology. 2012 Sep-Oct;     [PubMed]
Fett NM,Teng J,Longley BJ, Familial urticaria pigmentosa: report of a family and review of the role of KIT mutations. The American Journal of dermatopathology. 2013 Feb;     [PubMed]
Matito A,Azaña JM,Torrelo A,Alvarez-Twose I, Cutaneous Mastocytosis in Adults and Children: New Classification and Prognostic Factors. Immunology and allergy clinics of North America. 2018 Aug     [PubMed]

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